81 results on '"Deborah A. Quinn"'
Search Results
2. CIPHER: a prospective, multicentre study for the identification of biomarker signatures for early detection of pulmonary hypertension
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Martin R. Wilkins, Yiu-Lian Fong, Stephan Rosenkranz, Kelly Chin, Ioana R. Preston, Bradley A. Maron, Dimitri Stamatiadis, David G. Kiely, Cynthia Gargano, Luke Howard, Mark Toshner, and Deborah A. Quinn
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Oncology ,medicine.medical_specialty ,Cipher ,business.industry ,Internal medicine ,medicine ,Biomarker (medicine) ,Early detection ,Identification (biology) ,medicine.disease ,business ,Pulmonary hypertension - Published
- 2020
3. Pulsed inhaled nitric oxide (iNO) improves exercise tolerance and shortness of breath (SOB) in severe COPD subjects with pulmonary hypertension (PH)
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Paul M. Parizel, Francisca Ferreira, Wilfried De Backer, Wim Voss, Annemie Hufkins, Jan De Backer, Peter Fernandes, Bita Hajian, Kathleen Sartoris, Deborah A. Quinn, Cedric Van Holsbeke, Johan Cluckers, and Bharati Shivalkar
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medicine.medical_specialty ,Lung ,business.industry ,medicine.medical_treatment ,Vasodilation ,medicine.disease ,Pulmonary hypertension ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,chemistry ,Oxygen therapy ,Internal medicine ,medicine ,Cardiology ,Breathing ,030212 general & internal medicine ,business ,Blood vessel ,Oxygen saturation (medicine) - Abstract
COPD patients with PH have a high mortality rate. PAH therapies cause global lung vasodilation that can contribute to V/Q mismatch, worsening oxygen saturation. In this study 10 PH-COPD patients on long-term oxygen therapy (LTOT) were administered acute iNO followed by chronic iNO (4 weeks) using the portable INOpulse® delivery system. Using functional respiratory imaging (FRI), all 10 patients had increases in lung blood vessel volumes after acute iNO treatment (+4.2%, p=0.03, Figure 1) with a significant association (p Patients subsequently completing 4 weeks of chronic iNO had reduced pulmonary arterial pressure (PAP)(-19.9%, p=0.02) and 50.4±54.4m increase in 6MWD (p=0.04) from baseline(n=7). 6 of 7 subjects reported improvement in SOB at rest and with exercise. iNO was well tolerated with no safety concerns. FRI analyses showed regional dilatation of lung blood vessels after pulsed acute iNO treatment. Vasodilation in well-ventilated areas is supported by the correlation with lobar ventilation. There were significant reductions in PAP and improvements in 6MWD and SOB with 4 weeks of iNO. Chronic iNO therapy has potential to significantly increase exercise tolerance and SOB in PH-COPD patients.
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- 2018
4. N-Acetylcysteine Inhibits Ventilation-Induced Collagen Accumulation in the Rat Lung
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Bin Ouyang, Deborah A. Quinn, Xiangdong Guan, and Chuanxi Chen
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medicine.medical_specialty ,ARDS ,Time Factors ,Antioxidant ,Pulmonary Fibrosis ,medicine.medical_treatment ,Lung injury ,General Biochemistry, Genetics and Molecular Biology ,Rats, Sprague-Dawley ,Acetylcysteine ,Internal medicine ,Tidal Volume ,medicine ,Animals ,Lung ,Tidal volume ,Mechanical ventilation ,Analysis of Variance ,business.industry ,General Medicine ,medicine.disease ,Respiration, Artificial ,Rats ,Surgery ,Endocrinology ,medicine.anatomical_structure ,Injections, Intravenous ,Breathing ,Collagen ,business ,medicine.drug - Abstract
Mechanical ventilation is the most important life supportive therapy for patients with acute respiratory distress syndrome (ARDS). However, increasing evidence from clinical studies suggests that mechanical ventilation can cause lung fibrosis, which may significantly contribute to morbidity and mortality. Recent studies also found fibroproliferation occurred in early stage of ARDS with poor outcome. We have hypothesized that mechanical ventilation-induced lung injury may be a major contributor to lung fibrosis, and antioxidant could be a potential therapeutic agent for the treatment to mechanic ventilation induced fibroproliferation. We therefore used Sprague-Dawley rats that were ventilated with large tidal volume (20 ml/kg) or low tidal volume (7 ml/kg). We analyzed the time course of collagen level in the lung and the effect of N-acetylcysteine (NAC), a thiol antioxidant, on mechanical ventilation-induced collagen accumulation. In addition, normal human lung fibroblasts (NHLF) were exposed to mechanical stretch, which mimics ventilator-induced lung inflation, to evaluate the collagen secretion in culture medium. We found that ventilation-induced collagen accumulation occurred even after 2-hour ventilation. Pretreatment with NAC (140 mg/kg) inhibited collagen accumulation in lungs of rats ventilated with large tidal volume. Moreover, mechanical stretch caused the accumulation of collagen in the culture medium of NHLF, the magnitude of which was decreased with the pretreatment with NAC (1 mM). These results indicate that mechanical ventilation can induce collagen accumulation within 2 hours. NAC alleviated the collagen accumulation induced by mechanical ventilation with high tidal volume. Therefore, NAC can be considered as a good candidate in preventing ventilation-induced lung fibrosis.
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- 2015
5. Imatinib in Pulmonary Arterial Hypertension: C‐Kit Inhibition
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Deborah A. Quinn, Paul M. Hassoun, Serpil C. Erzurum, Robert P. Frantz, Suzy A.A. Comhair, Raymond L. Benza, Fernando Torres, Raed A. Dweik, Franck Rahaghi, Kewal Asosingh, and Samar Farha
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Pulmonary and Respiratory Medicine ,business.industry ,medicine.drug_class ,Imatinib ,Pharmacology ,medicine.disease ,Pulmonary hypertension ,Tyrosine-kinase inhibitor ,Pathogenesis ,Haematopoiesis ,Right ventricular hypertrophy ,medicine.artery ,Pulmonary artery ,Medicine ,Progenitor cell ,business ,Original Research ,medicine.drug - Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by severe remodeling of the pulmonary artery resulting in increased pulmonary artery pressure and right ventricular hypertrophy and, ultimately, failure. Bone marrow-derived progenitor cells play a critical role in vascular homeostasis and have been shown to be involved in the pathogenesis of PAH. A proliferation of c-Kit(+) hematopoietic progenitors and mast cells has been noted in the remodeled vessels in PAH. Imatinib, a tyrosine kinase inhibitor that targets c-Kit, has been shown to be beneficial for patients with PAH. Here we hypothesize that the clinical benefit of imatinib in PAH could be related to c-Kit inhibition of progenitor cell mobilization and maturation into mast cells. As a corollary to the phase 3 study using imatinib in PAH, blood samples were collected from 12 patients prior to starting study drug (baseline) and while on treatment at weeks 4 and 24. Eight were randomized to imatinib and 4 to placebo. Circulating c-Kit(+) and CD34(+)CD133(+) hematopoietic progenitors as well as biomarkers of mast cell numbers and activation were measured. Circulating CD34(+)CD133(+) and c-Kit(+) progenitor cells as well as c-Kit(+)/CD34(+)CD133(+) decreased with imatinib therapy (all P0.05). In addition, total tryptase, a marker of mast cell load, dropped with imatinib therapy (P = 0.02) and was related to pulmonary vascular resistance (R = 0.7, P = 0.02). The findings support c-Kit inhibition as a potential mechanism of action of imatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy.
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- 2014
6. Pulmonary vascular effects of pulsed inhaled nitric oxide in COPD patients with pulmonary hypertension
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Cedric Van Holsbeke, Wim Vos, Rita Claes, Wilfried De Backer, Bita Hajian, Francisca Ferreira, Jan De Backer, Annemie Hufkens, and Deborah A. Quinn
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Male ,Pulmonary Circulation ,Time Factors ,Computed Tomography Angiography ,Vasodilator Agents ,Vital Capacity ,Vasodilation ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Pulmonary function testing ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Forced Expiratory Volume ,pulmonary hypertension ,Lung ,Oxygen saturation (medicine) ,COPD ,General Medicine ,pulsed inhaled nitric oxide ,Treatment Outcome ,Patient Satisfaction ,Anesthesia ,Cardiology ,Female ,Nasal cannula ,medicine.medical_specialty ,Hypertension, Pulmonary ,Perfusion Imaging ,Pulmonary Artery ,International Journal of Chronic Obstructive Pulmonary Disease ,Nitric Oxide ,03 medical and health sciences ,Internal medicine ,Administration, Inhalation ,medicine ,Humans ,Arterial Pressure ,Antihypertensive Agents ,Aged ,business.industry ,Oxygen Inhalation Therapy ,medicine.disease ,Pulmonary hypertension ,FRI ,Blood pressure ,030228 respiratory system ,Pulmonary blood vessel ,Pulse Therapy, Drug ,Clinical Trial Report ,Human medicine ,business - Abstract
Bita Hajian,1 Jan De Backer,2 Wim Vos,2 Cedric Van Holsbeke,2 Francisca Ferreira,2 Deborah A Quinn,3 Annemie Hufkens,1 Rita Claes,1 Wilfried De Backer1 1Department of Respiratory Medicine, University Hospital Antwerp, Edegem, 2FluidDA nv, Antwerp, Belgium; 3Bellerophon Therapeutics, Warren, NJ, USA Introduction: Severe chronic obstructive pulmonary disease (COPD) is often associated with secondary pulmonary hypertension (PH), which worsens prognosis. PH can be lowered by oxygen, but also by inhaled nitric oxide (NO), which has the potential to improve the health status of these patients. NO is an important mediator in vascular reactions in the pulmonary circulation. Oral compounds can act through NO-mediated pathways, but delivering pulsed inhaled NO (iNO) directly to the airways and pulmonary vasculature could equally benefit patients. Therefore, a proof-of-concept study was performed to quantify pulmonary blood vessel caliber changes after iNO administration using computed tomography (CT)-based functional respiratory imaging (FRI). Methods: Six patients with secondary PH due to COPD received “pulsed” iNO in combination with oxygen for 20minutes via a nasal cannula. Patients underwent a high-resolution CT scan with contrast before and after iNO. Using FRI, changes in volumes of blood vessels and associated lobes were quantified. Oxygen saturation and blood pressure were monitored and patients were asked about their subjective feelings. Results: Pulmonary blood vessel volume increased by 7.06%±5.37% after iNO. A strong correlation (Ω20=0.32, P=0.002) was obtained between ventilation and observed vasodilation, suggesting that using the pulsed system, iNO is directed toward the ventilated zones, which consequently experience more vasodilation. Patients did not develop oxygen desaturation, remained normotensive, and perceived an improvement in their dyspnea sensation. Conclusion: Inhalation of pulsed NO with oxygen causes vasodilation in the pulmonary circulation of COPD patients, mainly in the well-ventilated areas. A high degree of heterogeneity was found in the level of vasodilation. Patients tend to feel better after the treatment. Chronic use trials are warranted. Keywords: pulmonary hypertension, COPD, pulsed inhaled nitric oxide, FRI
- Published
- 2016
7. TLR4 through IFN-β Promotes Low Molecular Mass Hyaluronan-Induced Neutrophil Apoptosis
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Changqing Xu, Yongqing Li, Charles A. Hales, Baoling Liu, Huahao Shen, shaw wei leu, Liyun Shi, Deborah A. Quinn, Hang Zhao, Aviva Shiedlin, Yili Zhao, and Charlie Xiang
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Neutrophils ,medicine.drug_class ,Immunology ,Cell ,Apoptosis ,Inflammation ,Biology ,Monoclonal antibody ,Neutrophil Activation ,Mice ,medicine ,Animals ,Homeostasis ,Immunology and Allergy ,Hyaluronic Acid ,Lung ,Cells, Cultured ,Mice, Knockout ,Interferon-beta ,medicine.disease ,Mice, Inbred C57BL ,Molecular Weight ,Toll-Like Receptor 4 ,medicine.anatomical_structure ,Neutrophil Infiltration ,TLR4 ,Cancer research ,Inflammation Mediators ,medicine.symptom ,Infiltration (medical) - Abstract
Intratracheal administration of low molecular mass (LMM) hyaluronan (200 kDa) results in greater neutrophil infiltration in the lungs of TLR4−/− mice compared with that in wild-type mice. In general, enhanced neutrophil infiltration in tissue is due to cell influx; however, neutrophil apoptosis also plays an important role. We have assessed the effects of TLR4 in the regulation of neutrophil apoptosis in response to administration of LMM hyaluronan. We found that apoptosis of inflammatory neutrophils is impaired in TLR4−/− mice, an effect that depends upon the IFN-β–mediated TRAIL/TRAILR system. IFN-β levels were decreased in LMM hyaluronan-treated TLR4-deficient neutrophils. The treatment of inflammatory neutrophils with IFN-β enhanced the levels of TRAIL and TRAILR 2. LMM hyaluronan-induced inflammatory neutrophil apoptosis was substantially prevented by anti-TRAIL neutralizing mAb. We conclude that decreased IFN-β levels decrease the activity of the TRAIL/TRAILR system in TLR4-deficient neutrophils, leading to impaired apoptosis of neutrophils and resulting in abnormal accumulation of neutrophils in the lungs of LMM hyaluronan-treated mice. Thus, TLR4 plays a novel homeostatic role in noninfectious lung inflammation by accelerating the elimination of inflammatory neutrophils.
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- 2011
8. High MW hyaluronan inhibits smoke inhalation-induced lung injury and improves survival
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Lunyin Yu, Rejmon Dedaj, Hang Zhao, Hari G. Garg, Deborah A. Quinn, Aviva Shiedlin, Charles A. Hales, Olga Syrkina, Pei-Ming Huang, and Yung‐yang Liu
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Pulmonary and Respiratory Medicine ,Smoke ,Pathology ,medicine.medical_specialty ,Lung ,Smoke Inhalation Injury ,business.industry ,Smoke inhalation ,Inflammation ,respiratory system ,Pharmacology ,Lung injury ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,medicine ,medicine.symptom ,Airway ,business ,Infiltration (medical) - Abstract
Background and objective: High MW hyaluronan (HMW HA) as opposed to low MW hyaluronan (LMW HA) has been shown to have anti-inflammatory and anti-apoptotic effects. We hypothesized that treatment with HMW HA would block smoke inhalation lung injury by inhibiting smoke-induced lung inflammation and airway epithelial cell apoptosis. Methods: Anesthetized, intubated male rats were randomly allocated to either control or smoke inhalation injury groups. Rats were treated with 3-mL subcutaneous normal saline solution (sham) or LMW HA (35 kDa) or HMW HA (1600 kDa) 18 h before exposure to 15 min of cotton smoke (n = 5 each). Rats were also treated post smoke inhalation with 1600 kDa HA by intra-peritoneal injection (3 mL) or intra-tracheal nebulization (200 µL). Lung neutrophil infiltration, airway apoptosis, airway mucous plugging and lung injury were assessed 4 h after smoke inhalation injury. Results: Rats pretreated with 1600 kDa HA had significantly less smoke-induced neutrophil infiltration, lung oedema, airway apoptosis and mucous plugging. Pretreatment with 35 kDa HA, in contrast, increased smoke-induced neutrophil infiltration and lung injury score. Intra-tracheal administration of a single dose 1600 kDa HA, but not intra-peritoneal injection, significantly improved survival post smoke inhalation. Conclusions: High MW hyaluronan (1600 kDa) may prove to be a beneficial therapy for smoke inhalation through inhibition of smoke-induced inflammation, lung oedema, airway epithelial cell apoptosis and airway mucous plugging.
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- 2010
9. Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth
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Stephen Lawler Hasak, Charles A. Hales, Robina Matyal, William S. Hancock, Haven Baker, Cristhiaan D. Ochoa, Deborah A. Quinn, and Aleya Salam
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Pulmonary and Respiratory Medicine ,Patch-Clamp Techniques ,Endothelium ,Cell division ,Clinical Biochemistry ,Cell ,Respiratory Mucosa ,Pulmonary Artery ,Biology ,Muscle, Smooth, Vascular ,von Willebrand Factor ,Thrombospondin 1 ,medicine ,Animals ,Homeostasis ,Molecular Biology ,Cells, Cultured ,Actin ,Cryopreservation ,Thrombospondin ,Cell growth ,Muscle, Smooth ,Articles ,Cell Biology ,Actins ,Cell biology ,Endothelial stem cell ,medicine.anatomical_structure ,Culture Media, Conditioned ,Immunology ,cardiovascular system ,Cattle ,Endothelium, Vascular ,Cell Division - Abstract
Endothelial cells are subjected to mechanical forces in the form of cyclic stretch resulting from blood pulsatility. Pulmonary artery endothelial cells (PAECs) produce factors that stimulate and inhibit pulmonary artery smooth muscle cell (PASMC) growth. We hypothesized that PAECs exposed to cyclic stretch secrete proteins that inhibit PASMC growth. Media from PAECs exposed to cyclic stretch significantly inhibited PASMC growth in a time-dependent manner. Lyophilized material isolated from stretched PAEC-conditioned media significantly inhibited PASMC growth in a dose-dependent manner. This inhibition was reversed by trypsin inactivation, which is consistent with the relevant factor being a protein(s). To identify proteins that inhibited cell growth in conditioned media from stretched PAECs, we used proteomic techniques and found that thrombospondin (TSP)-1, a natural antiangiogenic factor, was up-regulated by stretch. In vitro, exogenous TSP-1 inhibited PASMC growth. TSP-1–blocking antibodies reversed conditioned media–induced inhibition of PASMC growth. Cyclic stretched PAECs secrete protein(s) that inhibit PASMC proliferation. TSP-1 may be, at least in part, responsible for this inhibition. The complete identification and understanding of the secreted proteome of stretched PAECs may lead to new insights into the pathophysiology of pulmonary vascular remodeling.
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- 2008
10. Deficiency of the NHE1 Gene Prevents Hypoxia-induced Pulmonary Hypertension and Vascular Remodeling
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Hari G. Garg, Deborah A. Quinn, Lunyin Yu, and Charles A. Hales
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Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pathology ,Sodium-Hydrogen Exchangers ,Hypertension, Pulmonary ,Critical Care and Intensive Care Medicine ,Mice ,Internal medicine ,medicine.artery ,Ventricular Pressure ,medicine ,Animals ,ROCK1 ,RNA, Messenger ,ROCK2 ,Hypoxia ,Cation Transport Proteins ,Rho-associated protein kinase ,Mice, Knockout ,rho-Associated Kinases ,Sodium-Hydrogen Exchanger 1 ,Hypertrophy, Right Ventricular ,business.industry ,Respiratory disease ,Membrane Proteins ,Hypoxia (medical) ,G. Pulmonary Vascular Disease ,medicine.disease ,Pulmonary hypertension ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Pulmonary artery ,Vascular resistance ,Vascular Resistance ,medicine.symptom ,business - Abstract
Rationale: Our previous studies found that Na+/H+ exchanger (NHE) activity played an essential role in pulmonary artery smooth muscle cell (PASMC) proliferation and in the development of hypoxia-induced pulmonary hypertension and vascular remodeling. Other investigators recently observed increased expression of the NHE isoform 1 (NHE1) gene in rodents with pulmonary hypertension induced by hypoxia. However, a causal role for the NHE1 gene in pulmonary hypertension has not been determined. Objectives: To determine the causal role of the NHE1 gene in pulmonary hypertension and vascular remodeling. Methods: We used NHE1-null mice to define the role of the NHE1 gene in the development of pulmonary hypertension and remodeling induced by hypoxia and to delineate the NHE1 regulatory pathway. Measurements and Main Results: After 2 weeks of exposure to hypoxia, in contrast to wild-type hypoxic littermates, there was no significant increase in right ventricular systolic pressure, in the ratio of right ventricular to left ventricular plus septal weight [RV/(LV + S)], or in medial wall thickness of the pulmonary arterioles in homozygous mice (NHE1−/−). There was a significant decrease in Rho kinase (ROCK1 and ROCK2) expression, accompanied by an increase in p27 expression in NHE1−/− mice. Conclusions: Our study demonstrated that deficiency of the NHE1 gene prevented the development of hypoxia-induced pulmonary hypertension and vascular remodeling in mice and revealed a novel regulatory pathway associated with NHE1 signaling.
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- 2008
11. Oxidant stress mediates inflammation and apoptosis in ventilator-induced lung injury
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Charles A. Hales, Olga Syrkina, Behrouz Jafari, and Deborah A. Quinn
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Pulmonary and Respiratory Medicine ,Isoprostane ,medicine.medical_treatment ,Chemokine CXCL2 ,Apoptosis ,Inflammation ,Lung injury ,Pharmacology ,medicine.disease_cause ,Rats, Sprague-Dawley ,Acetylcysteine ,chemistry.chemical_compound ,medicine ,Animals ,Lung ,Respiratory Distress Syndrome ,Ventilators, Mechanical ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Epithelial Cells ,Free Radical Scavengers ,Pneumonia ,respiratory system ,Glutathione ,Rats ,respiratory tract diseases ,Disease Models, Animal ,Oxidative Stress ,Cytokine ,medicine.anatomical_structure ,chemistry ,Immunology ,medicine.symptom ,business ,Bronchoalveolar Lavage Fluid ,Oxidative stress ,medicine.drug - Abstract
BACKGROUND AND OBJECTIVE: Ventilator-induced lung injury (VILI) leads to airway epithelial cell apoptosis and lung inflammation. High tidal volume ventilation in vivo has been shown to induce MIP-2 production, lung neutrophil sequestration and apoptotic airway cell death. This study aimed to determine the effect of N-acetylcysteine (NAC), a scavenger of oxygen radicals, on lung inflammation and apoptosis in an in vivo model of VILI. METHODS: Sprague-Dawley rats (n = 5 per group) were ventilated at low tidal volume (V(T) 7 mL/kg) or high tidal volume (V(T) 20 mL/kg) with or without administration of 140 mg/kg of intravenous NAC. Animals were ventilated for 30 min, 1 or 2 h, then allowed to recover for 2 h, at which time neutrophil infiltration, MIP-2, TNF-alpha and IL-6 in BAL fluid, as well as the percentage of apoptotic airway epithelial cells, were measured. RESULTS: Ventilation at V(T) 20 mL/kg increased oxidant release, as measured by serum isoprostane, and decreased lung glutathione, the major antioxidant in the lung. NAC treatment during ventilation at V(T) 20 mL/kg prevented the decrease in lung glutathione and significantly lowered serum isoprostane levels, neutrophil infiltration, cytokines in the BAL and apoptosis in the airways as compared with animals ventilated at V(T) 20 mL/kg without NAC (P < 0.05). CONCLUSIONS: These data point to an early role of oxidant-induced inflammation and apoptosis in VILI.
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- 2008
12. Inducible nitric oxide mediates systemic microvascular leak following acid aspiration and mechanical ventilation
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Olga Syrkina, Kun Young Kwon, Kwon Moo Park, Charles A. Hales, Jeong-Wook Seo, Won-Il Choi, Joseph V. Bonventre, Deborah A. Quinn, and Cristhiaan D. Ochoa
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Mechanical ventilation ,Kidney ,Lung ,biology ,medicine.medical_treatment ,General Medicine ,Artificial respiration ,Pathology and Forensic Medicine ,Nitric oxide ,Nitric oxide synthase ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Anesthesia ,medicine ,biology.protein ,Tidal volume ,Evans Blue - Abstract
Background and aims: The systemic effects associated with mechanical ventilation of lungs injured by hydrochloric acid (HCl) aspiration are unexplored. We hypothesize that low dose acid aspiration will predispose the lung and the kidney to damage from large tidal volumes through activation of inducible nitric oxide synthase (iNOS). Materials and methods: Hydrochloric acid (HCl; pH 1.25, 1 mL/kg), or an equal amount of 0.9% sodium chloride (NaCl), were inserted into the trachea of rats immediately prior to mechanical ventilation. Rats were then ventilated with room air at 85 breaths per minute for 2 hours, either with a tidal volume (VT) of 7 mL/kg or 14 mL/kg (VT7, VT14) and zero end expiratory pressure. Kidney microvascular leak, which was assessed by measuring urine protein over 24 hours and by Evans blue dye (EBD) technique, was used as an indicator of systemic microvascular leak. Results: A significant microvascular leak occurred in both lung and kidney exposed to VT14 with HCl compared to those exposed to either VT7 with HCl or the NaCl control group. iNOS activity was significantly increased in the lung and the kidney tissue in VT14 with acid aspiration. The relatively selective iNOS inhibitor, l-N6-(1-iminoethyl)lysine (l-NIL), attenuated the EBD microvascular leak in lung and kidney and the proteinuria in the VT14 with acid aspiration group. Conclusion: iNOS may have mediated the systemic microvascular leak in the present model.
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- 2008
13. Inhibition of JNK activation prolongs survival after smoke inhalation from fires
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Deborah A. Quinn, Charles A. Hales, Walter Jung, Bin Ouyang, and Olga Syrkina
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Pulmonary and Respiratory Medicine ,Physiology ,Smoke inhalation ,medicine.medical_treatment ,Respiratory System ,Apoptosis ,Vascular permeability ,Pharmacology ,Lung injury ,Physiology (medical) ,In Situ Nick-End Labeling ,medicine ,Animals ,Dimethyl Sulfoxide ,Respiratory system ,Anthracenes ,Smoke ,Inhalation ,business.industry ,JNK Mitogen-Activated Protein Kinases ,Epithelial Cells ,Cell Biology ,Smoke Inhalation Injury ,respiratory system ,medicine.disease ,Rats ,Enzyme Activation ,Cytokine ,Immunology ,Poly(ADP-ribose) Polymerases ,business - Abstract
Initial injury from smoke inhalation is mainly to the trachea and bronchi and is characterized by mucosal hyperemia and increased microvascular permeability, exfoliation of epithelial lining, mucous secretion, mucous plugging, and an acute inflammatory cell influx. In this study, we explore the role of the c-Jun N-terminal protein kinase (JNK) pathway in smoke inhalation lung injury using a rat model of exposure to smoke from burning cotton. Male Sprague-Dawley rats were exposed to smoke from burning cotton for 15 min, and 1 h after injury a JNK inhibitor (SP-600125) or vehicle was injected. We measured neutrophil influx, cytokine release, percent of apoptotic cells, airway plugging, and survival. Administration of a JNK inhibitor 1 h after smoke inhalation decreased airway apoptosis, mucous plugging, influx of inflammatory cells, and the release of cytokines and significantly prolonged animal survival ( P < 0.05). These in vivo data show that the JNK pathway plays a critical role in smoke-induced lung injury and offer an attractive therapeutic approach for this injury.
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- 2007
14. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension
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Nazzareno Galiè, Hyuk Jae Chang, Hans Klose, Wei Yang, Deborah A. Quinn, Marius M. Hoeper, Andrew J. Peacock, Hiromi Matsubara, Robert P. Frantz, Victor F. Tapson, Yoshihiro Fukumoto, Carmine Dario Vizza, Robyn J. Barst, Michael Pfeifer, James M. Felser, Fernando Torres, Paul M. Hassoun, Adaani E. Frost, Hossein Ardeschir Ghofrani, Gérald Simonneau, Nicholas W. Morrell, David Lawrence, Frost, Adaani E, Barst, Robyn J., Hoeper, Marius M., Chang, Hyuk-Jae, Frantz, Robert P., Fukumoto, Yoshihiro, Galié, Nazzareno, Hassoun, Paul M., Klose, Han, Matsubara, Hiromi, Morrell, Nicholas W., Peacock, Andrew J., Pfeifer, Michael, Simonneau, Gérald, Tapson, Victor F., Torres, Fernando, Dario Vizza, Carmine, Lawrence, David, Yang, Wei, Felser, James M., Quinn, Deborah A., and Ghofrani, Hossein-Ardeschir
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Adult ,Male ,safety ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Time Factors ,Adolescent ,Hypertension, Pulmonary ,efficacy ,Hemodynamics ,Placebo ,law.invention ,Young Adult ,Double-Blind Method ,Randomized controlled trial ,law ,hemic and lymphatic diseases ,pulmonary arterial hypertension ,Internal medicine ,imatinib ,long-term ,adolescent ,adult ,aged ,dose-response relationship, drug ,double-blind method ,exercise tolerance ,female ,follow-up studies ,hemodynamics ,humans ,hypertension, pulmonary ,imatinib mesylate ,male ,middle aged ,protein kinase inhibitors ,retrospective studies ,time factors ,treatment outcome ,young adult ,surgery ,pulmonary and respiratory medicine ,cardiology and cardiovascular medicine ,transplantation ,medicine ,Humans ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Medicine(all) ,Transplantation ,Exercise Tolerance ,Dose-Response Relationship, Drug ,business.industry ,Retrospective cohort study ,Imatinib ,Middle Aged ,medicine.disease ,Pulmonary hypertension ,Discontinuation ,Treatment Outcome ,Anesthesia ,Imatinib Mesylate ,Female ,Surgery ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies ,medicine.drug - Abstract
BACKGROUND: Imatinib is an oral inhibitor of several protein kinases implicated in the pathophysiology of pulmonary hypertension. Treatment with imatinib resulted in improved hemodynamics and exercise capacity in a controlled trial (Imatinib [QTI571] in Pulmonary Arterial Hypertension, a Randomized Efficacy Study [IMPRES]), among pulmonary arterial hypertension (PAH) patients inadequately responsive to 2 to 3 PAH-specific therapies. METHODS: The long-term (up to 204 weeks) safety and efficacy of imatinib in this open-label extension study were reviewed until early study termination on April 16, 2014. Of 202 IMPRES-enrolled patients, 66 imatinib and 78 placebo recipients entered the extension. RESULTS: Overall, 93.8% (135 of 144) of patients discontinued the extension study; administrative issues (i.e., sponsor termination; 32.6%) and adverse events (31.3%) were the primary reasons for discontinuation. Nine patients completed the extension study before it was terminated. Serious and unexpected adverse events were frequent. These included 6 subdural hematomas in the extension study and 17 deaths during or within 30 days of study end. Although the patients who tolerated imatinib and remained in the extension for a longer duration did experience an improvement in functional class and walk distance, most discontinued the drug and the study. CONCLUSIONS: Severe adverse events, significant side effects, and a high discontinuation rate limit the utility of imatinib in the treatment of PAH. These risks outweigh any possible improvements in hemodynamics and walk distance seen in those patients able to remain on drug. The off-label use of this compound in PAH is discouraged.
- Published
- 2015
15. Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension
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Deborah A. Quinn, Charles A. Hales, Lunyin Yu, and Hari G. Garg
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Pyridines ,Cell Cycle Pathway ,Hypertension, Pulmonary ,Biophysics ,Gene Expression ,Cell Cycle Proteins ,Mice, Inbred Strains ,Retinoblastoma-Like Protein p107 ,E2F4 Transcription Factor ,Biology ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Mice ,Cyclin D2 ,Cell quiescence ,Cyclin-dependent kinase ,Cyclins ,medicine ,Animals ,Cyclin-Dependent Kinase Inhibitor p18 ,Hypoxia ,Molecular Biology ,Cells, Cultured ,Cyclin-Dependent Kinase Inhibitor Proteins ,Flavonoids ,Mitogen-Activated Protein Kinase 1 ,Regulation of gene expression ,Mitogen-Activated Protein Kinase 3 ,Heparin ,Cell growth ,Gene Expression Profiling ,Cyclin-Dependent Kinase 2 ,Imidazoles ,Cell Biology ,Hypoxia (medical) ,Cell cycle ,Cell biology ,Cancer research ,biology.protein ,medicine.symptom ,Cyclin-Dependent Kinase Inhibitor p27 - Abstract
The balance between cell proliferation and cell quiescence is regulated delicately by a variety of mediators, in which cyclin-dependent kinases (CDK) and CDK inhibitors (CDKI) play a very important role. Heparin which inhibits pulmonary artery smooth muscle cell (PASMC) proliferation increases the levels of two CDKIs, p21 and p27, although only p27 is important in inhibition of PASMC growth in vitro and in vivo. In the present study we investigated the expression profile of all the cell cycle regulating genes, including all seven CDKIs (p21, p27, p57, p15, p16, p18, and p19), in the lungs of mice with hypoxia-induced pulmonary hypertension. A cell cycle pathway specific gene microarray was used to profile the 96 genes involved in cell cycle regulation. We also observed the effect of heparin on gene expression. We found that (a) hypoxic exposure for two weeks significantly inhibited p27 expression and stimulated p18 activity, showing a 98% decrease in p27 and 81% increase in p18; (b) other CDKIs, p21, p57, p15, p16, and p19 were not affected significantly in response to hypoxia; (c) heparin treatment restored p27 expression, but did not influence p18; (d) ERK1/2 and p38 were mediators in heparin upregulation of p27. This study provides an expression profile of cell cycle regulating genes under hypoxia in mice with hypoxia-induced pulmonary hypertension and strengthens the previous finding that p27 is the only CDKI involved in heparin regulation of PASMC proliferation and hypoxia-induced pulmonary hypertension.
- Published
- 2006
16. Cyclin-Dependent Kinase Inhibitor p27 Kip1 , But Not p21 WAF1/Cip1 , Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice
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Hari G. Garg, Charles A. Hales, Lunyin Yu, and Deborah A. Quinn
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Male ,medicine.medical_specialty ,Physiology ,Hypertension, Pulmonary ,Pulmonary Artery ,Muscle, Smooth, Vascular ,Mice ,In vivo ,Cyclin-dependent kinase ,Internal medicine ,medicine.artery ,medicine ,Animals ,RNA, Messenger ,Hypoxia ,Cells, Cultured ,Cell Proliferation ,Hyperplasia ,biology ,Heparin ,business.industry ,Hypoxia (medical) ,medicine.disease ,Pulmonary hypertension ,Mice, Inbred C57BL ,Ki-67 Antigen ,medicine.anatomical_structure ,Endocrinology ,Ventricle ,Pulmonary artery ,Circulatory system ,biology.protein ,Cattle ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Cyclin-Dependent Kinase Inhibitor p27 ,medicine.drug - Abstract
Heparin has growth inhibitory effects on pulmonary artery smooth muscle cell (PASMC) in vitro and in vivo. However, the mechanism has not been fully defined. In this study, we investigated the role of cyclin-dependent kinase inhibitors, p21 WAF1/cip1 (p21) and p27 Kip1 (p27), in the inhibitory effect of heparin on PASMC proliferation in vitro and on hypoxia-induced pulmonary hypertension in vivo using p21 and p27-null mice. In vitro, loss of the p27 gene negated the inhibitory effect of heparin on PASMC proliferation, but p21 was not critical for this inhibition. In vivo, heparin significantly inhibited the development of hypoxia-induced pulmonary hypertension and remodeling, as evidenced by decreased right ventricular systolic pressure, ratio of right ventricular weight to left ventricle plus septum weight, and percent wall thickness of pulmonary artery, in p21 +/+ , p21 −/− , p27 +/+ , and p27 +/− , but not in p27 −/− mice. We also observed that hypoxia decreased p27 expression significantly in mouse lung, which was restored by heparin. Heparin inhibited Ki67 proliferative index in terminal bronchial vessel walls in p27 +/+ and p27 +/− , but not in p27 −/− mice exposed to hypoxia. Therefore, we conclude that the cyclin-dependent kinase inhibitor p27, but not p21, is required for the inhibition of hypoxic pulmonary vascular remodeling by heparin.
- Published
- 2005
17. Regulation of lung injury and repair by Toll-like receptors and hyaluronan
- Author
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Ruslan Medzhitov, Paul W. Noble, Patty J. Lee, Juan Fan, Richard Bucala, Yi Luo, Hari G. Garg, Dianhua Jiang, Deborah A. Quinn, Suping Chen, Glenn D. Prestwich, Robert J. Homer, Shuang Yu, Jiurong Liang, Daniel R. Goldstein, and Marcella M. Mascarenhas
- Subjects
Chemokine ,Enzyme-Linked Immunosorbent Assay ,Mice, Transgenic ,Inflammation ,Lung injury ,General Biochemistry, Genetics and Molecular Biology ,Mice ,chemistry.chemical_compound ,Hyaluronic acid ,Animals ,Medicine ,Macrophage ,Hyaluronic Acid ,Lung ,Cells, Cultured ,Mice, Knockout ,Wound Healing ,biology ,business.industry ,Epithelial Cells ,Lung Injury ,General Medicine ,Toll-Like Receptor 2 ,Molecular Weight ,Toll-Like Receptor 4 ,TLR2 ,chemistry ,Immunology ,Macrophages, Peritoneal ,Cancer research ,biology.protein ,TLR4 ,Cytokines ,Chemokines ,medicine.symptom ,business ,Wound healing ,Bronchoalveolar Lavage Fluid - Abstract
Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.
- Published
- 2005
18. Ventilation-induced neutrophil infiltration and apoptosis depend on apoptosis signal-regulated kinase 1 pathway*
- Author
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Deborah A. Quinn, Li-Fu Li, Shuen-Kuei Liao, Chung-Chi Huang, Ying-Huang Tsai, and Cheng-Huei Lee
- Subjects
Male ,Programmed cell death ,medicine.medical_treatment ,Chemokine CXCL2 ,Cell ,Apoptosis ,MAP Kinase Kinase Kinase 5 ,Critical Care and Intensive Care Medicine ,Positive-Pressure Respiration ,Mice ,Thioredoxins ,medicine ,Animals ,ASK1 ,Prospective Studies ,Lung ,Macrophage inflammatory protein ,biology ,Kinase ,business.industry ,JNK Mitogen-Activated Protein Kinases ,Cell biology ,Enzyme Activation ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Cytokine ,Neutrophil Infiltration ,Mitogen-activated protein kinase ,Immunology ,biology.protein ,Chemokines ,business - Abstract
Objective: Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein (MIP)-2, a functional equivalent of human interleukin-8, neutrophil infiltration, and apoptosis. The mechanisms regulating ventilation-induced cytokine production and lung cell death are unclear. Based on our previous in vitro and in vivo models of lung cell stretch, we hypothesized that high tidal volume ventilation-induced MIP-2 production, neutrophil infiltration, and apoptosis are dependent on the activation of apoptosis signal-regulated kinase 1 (ASK1), the upstream activator of c-Jun N-terminal kinase (JNK). Design: Prospective, controlled animal experiment. Setting: University research laboratory. Subjects: Male C57BL/6 mice, weighting 20-25 g. Interventions: C57BL/6 mice were exposed to high tidal volume (30 mL/kg) or low tidal volume (6 mL/kg) mechanical ventilation for 15 mins to 5 hrs. Measurements and Main Results: High tidal volume ventilation induced MIP-2 messenger RNA expression, MIP-2 protein production, neutrophil migration into the lung, airway epithelial cell apoptosis, and activation of ASK1, JNK, and activator protein (AP)-1 DNA binding in a dose-dependent and time-dependent manner. ASK1 inhibition with thioredoxin attenuated high tidal volume ventilation-induced MIP-2 messenger RNA expression, MIP-2 protein production, neutrophil migration into the lung, airway epithelial cell apoptosis, activation of JNK, and AP-1 DNA binding. Conclusions: Our data showed that high tidal volume ventilation-induced MIP-2 production, neutrophil sequestration, and apoptotic cell death were dependent, in part, on activation of the ASK1/JNK/AP-1 pathway.
- Published
- 2005
19. Ventilation-induced Neutrophil Infiltration Depends on c-Jun N-Terminal Kinase
- Author
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Deborah A. Quinn, Li-Fu Li, and Lunyin Yu
- Subjects
Pulmonary and Respiratory Medicine ,Chemokine ,Neutrophils ,medicine.medical_treatment ,Chemokine CXCL2 ,Cell Count ,MAP Kinase Kinase Kinase 3 ,Pharmacology ,Critical Care and Intensive Care Medicine ,p38 Mitogen-Activated Protein Kinases ,Mice ,Intensive care ,medicine ,Animals ,RNA, Messenger ,Lung ,Anthracenes ,Mice, Knockout ,Respiratory Distress Syndrome ,Messenger RNA ,biology ,Kinase ,business.industry ,c-jun ,JNK Mitogen-Activated Protein Kinases ,MAP Kinase Kinase Kinases ,Respiration, Artificial ,Enzyme Activation ,Cytokine ,Mitogen-activated protein kinase ,Immunology ,Knockout mouse ,biology.protein ,Chemokines ,Mitogen-Activated Protein Kinases ,business - Abstract
Positive pressure ventilation with large VTs has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human interleukin-8. The mechanisms regulating ventilation-induced cytokine production are unclear. Based on our previous in vitro model of lung cell stretch, we hypothesized that high VT ventilation-induced MIP-2 production is dependent on the activation of the c-Jun N-terminal kinase (JNK). We exposed C57BL/6 mice to high VT (30 ml/kg) or low VT (6 ml/kg) mechanical ventilation for 5 hours. High VT ventilation-induced neutrophil migration into the lung, MIP-2 protein production, MIP-2 messenger RNA expression, and JNK activation. Large VT ventilation of JNK knockout mice and pharmacologic JNK inhibition with SP600125 attenuated neutrophil sequestration and blocked MIP-2 messenger RNA expression and MIP-2 production. We conclude that lung cell stretch in vivo results in increased lung neutrophil sequestration and increased MIP-2 production, which was, at least in part, dependent upon the JNK pathway.
- Published
- 2004
20. Combined Smoke Inhalation and Scald Burn in the Rat
- Author
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C. A. Hales, O. Syrkina, A. Volokhov, R. Moufarrej, and Deborah A. Quinn
- Subjects
Burn injury ,Time Factors ,Multiple Organ Failure ,Smoke inhalation ,Cardiac Output, Low ,Pulmonary Edema ,Rats, Sprague-Dawley ,Random Allocation ,medicine ,Animals ,General Nursing ,Smoke ,Trauma Severity Indices ,Lung ,Inhalation ,business.industry ,Rehabilitation ,Respiratory disease ,Hemodynamics ,Smoke Inhalation Injury ,medicine.disease ,Pulmonary edema ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Neutrophil Infiltration ,Anesthesia ,General Health Professions ,Emergency Medicine ,Surgery ,Blood Gas Analysis ,Burns ,Multiple organ dysfunction syndrome ,business - Abstract
The combination of burn injury with smoke inhalation from fires significantly increases mortality. The mechanism of increased mortality is poorly understood but has been associated with multiple organ dysfunction syndrome, including cardiac dysfunction. Impaired cardiac function correlates with decreased survival in burn patients. We investigated smoke inhalation from burning cotton combined with a 40% body surface area, third-degree burn during the first 4 hours after injury in rats. In the early phase after injury, burn caused a significant rise in lung neutrophil infiltration but no increase in lung water. Smoke led to a rise in lung water but only a mild increase in neutrophil infiltration. Combined smoke and burn did not increase neutrophil accumulation or lung water above that which occurred with either injury alone. Only in combined smoke and burn was there a drop in cardiac output and stroke volume with pulmonary edema and lung neutrophil influx.
- Published
- 2003
21. Heparin oligosaccharide sequence and size essential for inhibition of pulmonary artery smooth muscle cell proliferation
- Author
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Charuwan Thanawiroon, Robert J. Linhardt, Deborah A. Quinn, Charles A. Hales, Naiyaratana Cindhuchao, Ishan Capila, and Hari G. Garg
- Subjects
Magnetic Resonance Spectroscopy ,Oligosaccharides ,Pulmonary Artery ,Biochemistry ,Muscle, Smooth, Vascular ,Analytical Chemistry ,Glycosaminoglycan ,chemistry.chemical_compound ,Glucosamine ,medicine.artery ,medicine ,Animals ,Tetrasaccharide ,chemistry.chemical_classification ,Muscle Cells ,Heparinase ,Heparin ,Chemistry ,Cell growth ,Organic Chemistry ,General Medicine ,Oligosaccharide ,Molecular Weight ,Carbohydrate Sequence ,Heparin Lyase ,Pulmonary artery ,Cattle ,Cell Division ,medicine.drug - Abstract
Heparin has a wide range of important biological activities including inhibition of pulmonary artery smooth muscle cell proliferation. To determine the minimum size of the heparin glycosaminoglycan chain essential for antiproliferative activity, porcine intestinal mucosal heparin was partially depolymerized with heparinase and fractionated to give oligosaccharides of different sizes. The structure of these oligosaccharides was fully characterized by 1D and 2D 1H NMR spectroscopy. These oligosaccharides were assayed for antiproliferative effects on cultured bovine pulmonary artery smooth muscle cells (PASMCs). The tetrasaccharide (4-mer) exhibited no heparin-like activity. Decasaccharides (10-mers) and dodecasaccharides (12-mers) displayed a reduced level of activity when compared to full-length heparin. Little effect on activity was observed in deca- and dodecasaccharides with one less 2-O-sulfo group. The 14-, 16-, and 18-mers showed comparable growth-inhibition effects on PAMSC as porcine intestinal mucosal heparin. These data suggest that a 14-mer is the minimum size of oligosaccharide that is essential for full heparin-like antiproliferative activity. Since the 14- to 18-mers have no 3-O-sulfo groups in their glucosamine residues, their full activity confirms that these 3-O-sulfonated glucosamine residues, which are required for heparin's anticoagulant activity, are not an essential requirement for antiproliferative activity.
- Published
- 2002
22. Interactions of lung stretch, hyperoxia, and MIP-2 production in ventilator-induced lung injury
- Author
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Ramzi K. Moufarrej, Charles A. Hales, Deborah A. Quinn, and Alexey Volokhov
- Subjects
Pathology ,medicine.medical_specialty ,Neutrophils ,Physiology ,medicine.medical_treatment ,Chemokine CXCL2 ,Positive pressure ,Hyperoxia ,Lung injury ,Antibodies ,Rats, Sprague-Dawley ,Cell Movement ,Physiology (medical) ,Internal medicine ,Edema ,medicine ,Animals ,Mechanical ventilation ,Lung ,business.industry ,Monokines ,Respiratory disease ,respiratory system ,medicine.disease ,Respiration, Artificial ,Rats ,respiratory tract diseases ,Pulmonary Alveoli ,medicine.anatomical_structure ,Extravascular Lung Water ,Cardiology ,medicine.symptom ,Pulmonary alveolus ,business ,Bronchoalveolar Lavage Fluid - Abstract
The use of positive pressure mechanical ventilation can cause ventilator-induced lung injury (VILI). We hypothesized that hyperoxia in combination with large tidal volumes (Vt) would accentuate noncardiogenic edema and neutrophil infiltration in VILI and be dependent on stretch-induced macrophage inflammatory protein-2 (MIP-2) production. In rats ventilated with Vt 20 ml/kg, there was pulmonary edema formation that was significantly increased by hyperoxia. Total lung neutrophil infiltration and MIP-2 in bronchoalveolar lavage (BAL) fluid were significantly elevated, in animals exposed to high Vt both on room air (RA) and with hyperoxia. Hyperoxia markedly augmented the migration of neutrophils into the alveoli. Anti-MIP-2 antibody blocked migration of neutrophils into the alveoli in RA by 51% and with hyperoxia by 65%. We concluded that neutrophil migration into the alveoli was dependent on stretch-induced MIP-2 production. Hyperoxia significantly increased edema formation and neutrophil migration into the alveoli with Vt 20 ml/kg, although BAL MIP-2 levels were nearly identical to Vt 20 ml/kg with RA, suggesting that other mechanisms may be involved in hyperoxia-augmented neutrophil alveolar content in VILI.
- Published
- 2002
23. Case 8-2002
- Author
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Eugene J. Mark and Deborah A. Quinn
- Subjects
medicine.medical_specialty ,Pleural effusion ,business.industry ,Respiratory disease ,General Medicine ,medicine.disease ,Chest pain ,Surgery ,Pleural disease ,Effusion ,medicine ,medicine.symptom ,Complication ,business - Abstract
A 56-year-old woman had pleuritic left-sided chest pain and was admitted to the hospital because of a persistent left-sided pleural effusion.
- Published
- 2002
24. Gene 33/Mig-6, a Transcriptionally Inducible Adapter Protein That Binds GTP-Cdc42 and Activates SAPK/JNK
- Author
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Anthony Makkinje, Carmen L. Cadilla, Thomas Force, Ang Chen, John M. Kyriakis, Joseph V. Bonventre, and Deborah A. Quinn
- Subjects
Kinase ,Cell Biology ,CDC42 ,Transfection ,Biology ,Biochemistry ,Molecular biology ,Muscle hypertrophy ,Cell biology ,Cdc42 GTP-Binding Protein ,Chronic stress ,Molecular Biology ,Gene ,Immediate early gene - Abstract
Chronic stresses, including the mechanical strain caused by hypertension or excess pulmonary ventilation pressure, lead to important clinical consequences, including hypertrophy and acute respiratory distress syndrome. Pathologic hypertrophy contributes to decreased organ function and, ultimately, organ failure; and cardiac and diabetic renal hypertrophy are major causes of morbidity and morality in the developed world. Likewise, acute respiratory distress syndrome is a serious potential side effect of mechanical pulmonary ventilation. Whereas the deleterious effects of chronic stress are well established, the molecular mechanisms by which these stresses affect cell function are still poorly characterized. gene 33 (also called mitogen-inducible gene-6, mig-6) is an immediate early gene that is transcriptionally induced by a divergent array of extracellular stimuli. The physiologic function of Gene 33 is unknown. Here we show that gene 33 mRNA levels increase sharply in response to a set of commonly occurring chronic stress stimuli: mechanical strain, vasoactive peptides, and diabetic nephropathy. Induction ofgene 33 requires the stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinases. This expression pattern suggests that gene 33 is a potential marker for diabetic nephropathy and other pathologic responses to persistent sublethal stress. The structure of Gene 33 indicates an adapter protein capable of binding monomeric GTPases of the Rho subfamily. Consistent with this, Gene 33 interacts in vivo and, in a GTP-dependent manner, in vitro with Cdc42Hs; and transient expression of Gene 33 results in the selective activation of the SAPKs. These results imply a reciprocal, positive feedback relationship between Gene 33 expression and SAPK activation. Expression of Gene 33 at sufficient levels may enable a compensatory reprogramming of cellular function in response to chronic stress, which may have pathophysiological consequences.
- Published
- 2000
25. <scp>d</scp>-Dimers in the Diagnosis of Pulmonary Embolism
- Author
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Stephen Johnson, Michael Laposata, Arthur C. Waltman, Cynthia D. Smith, Charles A. Hales, B. Taylor Thompson, Deborah A. Quinn, and Robert B. Fogel
- Subjects
Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Bilirubin ,Enzyme-Linked Immunosorbent Assay ,Critical Care and Intensive Care Medicine ,Malignancy ,Sensitivity and Specificity ,Fibrin Fibrinogen Degradation Products ,chemistry.chemical_compound ,Predictive Value of Tests ,medicine ,Pulmonary angiography ,Humans ,In patient ,Prospective Studies ,Aged ,medicine.diagnostic_test ,business.industry ,Angiography ,Middle Aged ,medicine.disease ,Predictive value ,Latex fixation test ,Pulmonary embolism ,chemistry ,Female ,Radiology ,Pulmonary Embolism ,business ,Latex Fixation Tests - Abstract
The aim of this study was to determine if the absence of circulating D-dimers, as determined by latex agglutination assays, can correctly exclude the presence of pulmonary embolism using pulmonary angiography as the diagnostic endpoint. Blood samples were obtained prospectively at the time of angiography for suspicion of acute pulmonary embolism. Plasma was assayed for D-dimer by five different latex agglutination assays. Angiographic evidence of pulmonary emboli was found in 34% (35/ 103) of patients. The latex agglutination assays had sensitivities of 97 to 100% and specificities of 19 to 29%. The negative predictive value was 94 to 100%. However, a negative D-dimer was rare in patients with recent surgery, malignancy, or total bilirubin34 micromol/L (2 mg/dl). In 31 patients suspected of pulmonary emboli but without these confounding factors, the five D-dimer assays were negative in 46 to 55% of patients with normal pulmonary angiograms. The negative predictive value in these patients was 100% by all five latex agglutination assays tested. The latex agglutination assays for D-dimer, when the pulmonary angiogram is used as the diagnostic endpoint and in the absence of recent surgery, malignancy, or liver disease, appears to be a clinically useful test in the diagnosis of acute pulmonary embolism.
- Published
- 1999
26. Usefulness of Multidetector Spiral Computed Tomography According to Age and Gender for Diagnosis of Acute Pulmonary Embolism
- Author
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Charles A. Hales, John G. Weg, Afzal Beemath, Ronald E. Olson, Alexander Gottschalk, Paul D. Stein, Pamela K. Woodard, Deborah A. Quinn, H. Dirk Sostman, Kenneth V. Leeper, Russell D. Hull, and Lawrence R. Goodman
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Multidetector ct ,Sensitivity and Specificity ,Computed tomographic ,Age and gender ,Sex Factors ,Pulmonary angiography ,medicine ,Humans ,Prospective Studies ,Aged ,Aged, 80 and over ,Ct pulmonary angiography ,business.industry ,Age Factors ,Angiography ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Spiral computed tomography ,Pulmonary embolism ,Acute Disease ,Female ,Radiology ,Pulmonary Embolism ,Cardiology and Cardiovascular Medicine ,business ,Tomography, Spiral Computed ,CT venography - Abstract
Data from the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) were evaluated to test the hypothesis that the performance of multidetector computed tomographic (CT) pulmonary angiography and CT venography is independent of a patient's age and gender. In 773 patients with adequate CT pulmonary angiography and 737 patients with adequate CT pulmonary angiography and CT venography, the sensitivity and specificity for pulmonary embolism for groups of patients aged 18 to 59, 60 to 79, and 80 to 99 years did not differ to a statistically significant extent, nor were there significant differences according to gender. Overall, however, the specificity of CT pulmonary angiography was somewhat greater in women, but in men and women, it wasor =93%. In conclusion, the results indicate that multidetector CT pulmonary angiography and CT pulmonary angiography and CT venography may be used with various diagnostic strategies in adults of all ages and both genders.
- Published
- 2007
27. Amiloride Analogs Inhibit Chronic Hypoxic Pulmonary Hypertension
- Author
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Charles A. Hales, Hong Kai Du, Deborah A. Quinn, and B. Taylor Thompson
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Sodium-Hydrogen Exchangers ,Hypertension, Pulmonary ,Intracellular pH ,Antiporter ,Blood Pressure ,Pulmonary Artery ,Critical Care and Intensive Care Medicine ,Muscle, Smooth, Vascular ,Amiloride ,Rats, Sprague-Dawley ,In vivo ,Internal medicine ,medicine.artery ,medicine ,Animals ,Hypoxia ,Hypertrophy, Right Ventricular ,business.industry ,Respiratory disease ,medicine.disease ,Pulmonary hypertension ,Rats ,Endocrinology ,Hematocrit ,Mechanism of action ,Chronic Disease ,Pulmonary artery ,Vascular Resistance ,medicine.symptom ,business ,Cell Division ,medicine.drug - Abstract
Na+/H+ exchange regulation of intracellular pH may play a permissive role in pulmonary artery smooth muscle cell (PASM) proliferation. Our laboratory has demonstrated that dimethyl amiloride (DMA), an amiloride derivative with enhanced selectivity as an inhibitor of the Na+/H+ antiporter, can inhibit bovine PASM proliferation in vitro. We hypothesized that DMA would inhibit development of hypoxic pulmonary hypertension by interfering with PASM growth in vivo. Sprague-Dawley rats were exposed to 10% O2 for 14 d without (n 9) or with (n = 7) DMA continuous infusion 3 mg/ kg/d. The animals treated with DMA had significant reductions in pulmonary artery pressure and total pulmonary vascular resistance index (TPVRI) when compared with hypoxic control rats (p0.05). Pulmonary vascular remodeling was significantly reduced in animals treated with DMA as measured by percent wall thickness and percentage of thick-walled intra-acinous vessels (p0.05). We used a second Na+/H+ exchange inhibitor, ethylisopropyl amiloride (EIPA, 3 mg/kg/d, n = 9), and found similar reductions in pulmonary artery pressure, TPVRI, and pulmonary vascular remodeling. Polycythemia during hypoxia was unchanged by treatment with DMA or EIPA. In conclusion, despite the hypertensive effects of polycythemia, DMA and EIPA can significantly reduce pulmonary vascular remodeling induced by chronic hypoxia.
- Published
- 1998
28. CHANGE IN LEFT VENTRICULAR FUNCTION MEASURED BY CIRCUMFERENTIAL STRAIN IS A SENSITIVE MARKER OF CHANGES IN PULMONARY HEMODYNAMICS AND RIGHT VENTRICULAR FUNCTION IN PULMONARY ARTERIAL HYPERTENSION
- Author
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Deborah A. Quinn, Patricia Campbell, Scott D. Solomon, Robyn J. Barst, Gabriela Querejeta Roca, and Shah M. Shah
- Subjects
Lv function ,Pressure overload ,medicine.medical_specialty ,Ventricular function ,business.industry ,Internal medicine ,cardiovascular system ,Cardiology ,Medicine ,Circumferential strain ,cardiovascular diseases ,sense organs ,skin and connective tissue diseases ,business ,Pulmonary wedge pressure ,Cardiology and Cardiovascular Medicine ,Pulmonary hemodynamics - Abstract
In pulmonary arterial hypertension (PAH), left ventricular (LV) function can be impaired due to right ventricular (RV) pressure overload and ventricular interdependence. Change in LV function, quantified by circumferential strain (CS), may be a sensitive marker of changes in pulmonary hemodynamics
- Published
- 2013
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29. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study
- Author
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Marius M. Hoeper, Friedrich Grimminger, Andrew J. Peacock, Nazzareno Galiè, Jeremy Feldman, Deborah A. Quinn, Miguel Ángel Gómez-Sánchez, Robert C. Bourge, Hossein Ardeschir Ghofrani, Ekkehard Grünig, Nicholas W. Morrell, David Lawrence, Gérald Simonneau, Fernando Torres, Adaani E. Frost, Victor F. Tapson, Toru Satoh, Paul M. Hassoun, Robyn J. Barst, Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galié N, Gómez-Sánchez MA, Grimminger F, Grünig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, and Ghofrani HA
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Hypertension, Pulmonary ,CARDIAC HAEMODYNAMICS ,Hemodynamics ,Gastroenterology ,Piperazines ,law.invention ,Young Adult ,Double-Blind Method ,Randomized controlled trial ,law ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,DRUGS ,Familial Primary Pulmonary Hypertension ,Protein Kinase Inhibitors ,Aged ,Exercise Tolerance ,business.industry ,Imatinib ,Middle Aged ,medicine.disease ,Brain natriuretic peptide ,Pulmonary hypertension ,Confidence interval ,PULMONARY HYPERTENSION ,Surgery ,Hematoma, Subdural ,Pyrimidines ,Imatinib mesylate ,medicine.anatomical_structure ,Benzamides ,Imatinib Mesylate ,Vascular resistance ,Female ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Background— By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). Methods and Results— Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥800 dyne·s·cm −5 symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12–52; P =0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm −5 (95% confidence interval, −502 to − 255; P Conclusions— Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00902174 (core study); NCT01392495 (extension).
- Published
- 2013
30. Differential effect of three commercial heparins on Na+/H+ exchange and growth of PASMC
- Author
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Joseph V. Bonventre, Charles A. Hales, Deborah A. Quinn, B. T. Thompson, Hari G. Garg, C. G. W. Dahlberg, P. M. Joseph, and C. R. Spence
- Subjects
Pulmonary and Respiratory Medicine ,Sodium-Hydrogen Exchangers ,Physiology ,Sodium ,Antiporter ,Intracellular pH ,chemistry.chemical_element ,Pulmonary Artery ,chemistry.chemical_compound ,Sulfation ,Glucosamine ,Physiology (medical) ,medicine ,Animals ,Cells, Cultured ,Platelet-Derived Growth Factor ,biology ,Heparin ,Muscle, Smooth ,Biological activity ,Cell Biology ,Molecular biology ,Biochemistry ,chemistry ,biology.protein ,Cattle ,Cell Division ,Platelet-derived growth factor receptor ,medicine.drug - Abstract
Heparin preparations vary in chemical content and in antiproliferative activity for pulmonary artery smooth muscle cells (PASMC). Intracellular alkalinization via stimulation of the Na+/H+ antiporter appears to be a permissive event for proliferation of PASMC. We wondered whether the variable effect of heparin preparations on PASMC growth might be due to different degrees of inhibition of the Na+/H+ antiporter and whether variations in chemical formulation might correlate with the inhibition. Fluorescent microscopy of bovine PASMC was done using a dye with which fluorescence varies directly with intracellular pH (pHi). Bovine PASMC were preincubated with three heparin preparations previously shown to vary in antiproliferative activity, at 1.0 microgram/ml for 24 h. Platelet-derived growth factor (PDGF; 60 ng/ml) on PASMC without heparin resulted in a rise in pHi of 0.27 +/- 0.02 pH units. The rise in pH units in heparin-treated PASMC was 0.34 +/- 0.03 with Choay, 0.21 +/- 0.02 with Elkins-Sinn, and 0.07 +/- 0.02 with Upjohn (+/-SE; all P < 0.05; n = 5). Upjohn heparin incubation for as little as 15 min still impeded the rise in pH induced by PDGF. Heparin did not block the Na+/H+ exchanger directly, as it still restored pHi in response to an acid load. Compared with PASMC proliferation induced by 60 ng/ml PDGF, 1 microgram/ml of Choay, Elkins-Sinn, and Upjohn heparin produced -4 +/- 7.4, 1.4 +/- 4.8, and 48 +/- 2.2% inhibition of PDGF control, respectively (P < 0.05 for Upjohn compared with PDGF and Choay). The heparins varied in protein content and amino acid composition. However, amino acid and glucosamine composition, total sulfation, and extent of 3-O-sulfation did not predict their activity. Thus inhibition of PDGF activation of the Na+/H+ antiporter by a given heparin preparation correlated well with its ability to inhibit PASMC proliferation.
- Published
- 1996
31. The role of Na+/H+ exchange and growth factors in pulmonary artery smooth muscle cell proliferation
- Author
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J. P. Bonventre, C. R. Scheid, Honeyman Tw, B. T. Thompson, Deborah A. Quinn, P. M. Joseph, C. G. W. Dahlberg, and Charles A. Hales
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Sodium-Hydrogen Exchangers ,medicine.medical_treatment ,Intracellular pH ,Clinical Biochemistry ,Alkalies ,Pulmonary Artery ,Biology ,Muscle, Smooth, Vascular ,Muscle hypertrophy ,Amiloride ,Epidermal growth factor ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Platelet-Derived Growth Factor ,Epidermal Growth Factor ,Cell growth ,Growth factor ,Cell Biology ,Hyperplasia ,medicine.disease ,Pulmonary hypertension ,Endocrinology ,biology.protein ,Cattle ,Cell Division ,Platelet-derived growth factor receptor - Abstract
Chronic hypoxia produces pulmonary hypertension, in part because of hypertrophy and hyperplasia of pulmonary artery smooth muscle cells (PA SMC). Platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) have been shown to stimulate SMC proliferation and may be involved in these vascular changes. Both factors cause a rise in intracellular pH (pHi) in systemic vascular SMC through stimulation of the Na+/H+ exchanger, an event that has been thought to be permissive, allowing cell proliferation in response to the growth factor. The present studies examined the possibility that the activation of Na+/H+ exchange is involved in the PA SMC mitogenic response to these growth factors. Na+/H+ exchange activity was assessed by monitoring pHi in cultured cells using the pH-sensitive dye, 2'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). PDGF (60 ng/ml) exposure led to a marked activation of Na+/H+ exchange, evidenced by a rise in pHi (mean +/- SEM) of 0.20 +/- 0.03 pH units (n = 5, P0.05). EGF (60 ng/ml) exposure produced a rise in pHi of 0.27 +/- 0.03 pH units (n = 5, P0.05). Dimethyl amiloride (DMA, 50 microM), a competitive inhibitor of Na+/H+ exchange, blocked the pH response to PDGF and EGF. PA SMC showed a proliferative response when exposed to PDGF and EGF which was attenuated by 50 microM DMA (n = 6). Thus, activation of the Na+/H+ exchanger may be important in pulmonary cell signaling in response to growth factors as it has been found to be in systemic vessels.
- Published
- 1996
32. Low molecular weight hyaluronan, via AP-1 and NF-κB signalling, induces IL-8 in transformed bronchial epithelial cells
- Author
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Christiaan D. Ochoa, Deborah A. Quinn, Charles A. Hales, and Hari G. Garg
- Subjects
Inflammation ,Bronchi ,chemistry.chemical_compound ,Extracellular ,Tidal Volume ,Medicine ,Humans ,Secretion ,Interleukin 8 ,Hyaluronic Acid ,Lung ,business.industry ,Kinase ,Interleukin-8 ,NF-kappa B ,food and beverages ,NF-κB ,Epithelial Cells ,General Medicine ,respiratory system ,Respiration, Artificial ,Cell biology ,Transcription Factor AP-1 ,medicine.anatomical_structure ,chemistry ,Cytoplasm ,Immunology ,medicine.symptom ,business - Abstract
Summary QUESTIONS UNDER STUDY: New evidence demonstrated that high tidal volume mechanical ventilation results in substantial bronchial airway mechanical strain. In addition, high tidal volume mechanical ventilation has been shown to increase IL-8 production in a mechanism mediated, at least in part, by low molecular weight hyaluronan (LWM-HA). In the present study, it was investigated whether LMW-HA synthesised in the lung, in response to cyclic stretch, increased IL-8 production in the bronchial epithelium. METHODS: This question was approached by stimulating a transformed human bronchial epithelial cell line with LMW-HA isolated from stretched human lung fibroblasts and probed for the activation of extracellular signal-regulated kinase pathways. RESULTS: LMW-HA increased IL-8 secretion in transformed bronchial epithelial cells. Additionally, LMW-HA augmented the levels of phospho c-Jun NH2-terminal kinase (JNK) and phospho extracellular signal-regulated kinase 1/2 (ERK1/2), and also mobilised nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) from the cytoplasm to the nucleus. The inhibition of JNK, ERK1/2 and NF-κB blocked IL-8 secretion in response to LMW-HA. CONCLUSION: The data suggest that LMW-HA produced by lung fibroblasts in response to cyclic stretch increases the secretion of IL-8 in transformed bronchial epithelial cells via AP-1 and NF-κB signalling pathways. These findings support the hypothesis that LMW-HA plays an active role in acute lung inflammation triggered by mechanical strain.
- Published
- 2011
33. Signaling Pathway Involved In Heparin Inhibition Of Hypoxia-Induced Pulmonary Artery Smooth Muscle Cell Proliferation
- Author
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Lunyin Yu, Deborah A. Quinn, Charles A. Hales, and Hari G. Garg
- Subjects
Smooth muscle ,Cell growth ,Chemistry ,medicine.artery ,Pulmonary artery ,medicine ,Heparin ,Hypoxia (medical) ,medicine.symptom ,Signal transduction ,medicine.drug ,Cell biology - Published
- 2011
34. High MW hyaluronan inhibits smoke inhalation-induced lung injury and improves survival
- Author
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Pei-ming, Huang, Olga, Syrkina, Lunyin, Yu, Rejmon, Dedaj, Hang, Zhao, Aviva, Shiedlin, Yung-yang, Liu, Hari, Garg, Deborah A, Quinn, and Charles A, Hales
- Subjects
Male ,Rats, Sprague-Dawley ,Mucus ,Neutrophil Infiltration ,Animals ,Apoptosis ,Pulmonary Edema ,Lung Injury ,Pneumonia ,Hyaluronic Acid ,Smoke Inhalation Injury ,Lung ,Rats - Abstract
High MW hyaluronan (HMW HA) as opposed to low MW hyaluronan (LMW HA) has been shown to have anti-inflammatory and anti-apoptotic effects. We hypothesized that treatment with HMW HA would block smoke inhalation lung injury by inhibiting smoke-induced lung inflammation and airway epithelial cell apoptosis.Anesthetized, intubated male rats were randomly allocated to either control or smoke inhalation injury groups. Rats were treated with 3-mL subcutaneous normal saline solution (sham) or LMW HA (35 kDa) or HMW HA (1600 kDa) 18 h before exposure to 15 min of cotton smoke (n = 5 each). Rats were also treated post smoke inhalation with 1600 kDa HA by intra-peritoneal injection (3 mL) or intra-tracheal nebulization (200 µL). Lung neutrophil infiltration, airway apoptosis, airway mucous plugging and lung injury were assessed 4 h after smoke inhalation injury.Rats pretreated with 1600 kDa HA had significantly less smoke-induced neutrophil infiltration, lung oedema, airway apoptosis and mucous plugging. Pretreatment with 35 kDa HA, in contrast, increased smoke-induced neutrophil infiltration and lung injury score. Intra-tracheal administration of a single dose 1600 kDa HA, but not intra-peritoneal injection, significantly improved survival post smoke inhalation.High MW hyaluronan (1600 kDa) may prove to be a beneficial therapy for smoke inhalation through inhibition of smoke-induced inflammation, lung oedema, airway epithelial cell apoptosis and airway mucous plugging.
- Published
- 2010
35. Heparin inhibits pulmonary artery smooth muscle cell proliferation through guanine nucleotide exchange factor-H1/RhoA/Rho kinase/p27
- Author
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Charles A. Hales, Hari G. Garg, Lunyin Yu, and Deborah A. Quinn
- Subjects
Pulmonary and Respiratory Medicine ,RHOA ,Vascular smooth muscle ,Clinical Biochemistry ,Myocytes, Smooth Muscle ,Biology ,Pulmonary Artery ,Models, Biological ,Mice ,medicine ,Animals ,Guanine Nucleotide Exchange Factors ,Humans ,RNA, Small Interfering ,Molecular Biology ,Rho-associated protein kinase ,Cell Proliferation ,rho-Associated Kinases ,Cell growth ,Kinase ,Heparin ,Cell Cycle ,Cell Biology ,Articles ,Molecular biology ,Cell Hypoxia ,Cell biology ,Gene Expression Regulation ,biology.protein ,Cattle ,Guanine nucleotide exchange factor ,Guanosine Triphosphate ,Signal transduction ,rhoA GTP-Binding Protein ,Cyclin-Dependent Kinase Inhibitor p27 ,Rho Guanine Nucleotide Exchange Factors ,medicine.drug - Abstract
Ras homolog gene family member A (RhoA) through Rho kinase kinase (ROCK), one of its downstream effectors, regulates a wide range of cell physiological functions, including vascular smooth muscle cell (SMC) proliferation, by degrading cyclin-dependent kinase inhibitor, p27. Our previous studies found that heparin inhibition of pulmonary artery SMC (PASMC) proliferation and pulmonary hypertension was dependent on p27 up-regulation. To investigate whether ROCK, a regulator of p27, is involved in regulation of heparin inhibition of PASMC proliferation, we analyzed ROCK expression in the lungs from mice and from human PASMCs exposed to hypoxia, and investigated the effect of ROCK expression in vitro by RhoA cDNA transfection. We also investigated the effect of guanine nucleotide exchange factor (GEF)–H1, an upstream regulator of RhoA, on heparin inhibition of PASMC proliferation by GEF-H1 cDNA transfection. We found that: (1) hypoxia increased ROCK expression in mice and PASMCs; (2) overexpression of RhoA diminished the inhibitory effect of heparin on PASMC proliferation and down-regulated p27 expression; and (3) overexpression of GEF-H1 negated heparin inhibition of PASMC proliferation, which was accompanied by increased GTP-RhoA and decreased p27. This study demonstrates that the RhoA/ROCK pathway plays an important role in heparin inhibition on PASMC proliferation, and reveals that heparin inhibits PASMC proliferation through GEF-H1/RhoA/ROCK/p27 signaling pathway, by down-regulating GEF-H1, RhoA, and ROCK, and then up-regulating p27.
- Published
- 2010
36. Long Term Use Of Imatinib In Patients With Severe Pulmonary Arterial Hypertension
- Author
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Andrew J. Peacock, Marius M. Hoeper, Steve Pascoe, Horst Olschewski, Robyn J. Barst, Deborah A. Quinn, Shelley Shapiro, Hossein Ardeschir Ghofrani, and Nicholas W. Morrell
- Subjects
medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Cardiology ,Imatinib ,In patient ,business ,medicine.drug ,Term (time) - Published
- 2010
37. Thrombospondin-1 null mice are resistant to hypoxia-induced pulmonary hypertension
- Author
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Essam Al-Ansari, Lunyin Yu, Charles A. Hales, Deborah A. Quinn, and Cristhiaan D. Ochoa
- Subjects
Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,Pathology ,endocrine system ,Hypertension, Pulmonary ,Cell ,lcsh:Surgery ,030204 cardiovascular system & hematology ,Pulmonary Artery ,Muscle, Smooth, Vascular ,Thrombospondin 1 ,lcsh:RD78.3-87.3 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine.artery ,Internal medicine ,Research article ,medicine ,Animals ,Vasoconstrictor Agents ,Hypoxia ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Hypertrophy, Right Ventricular ,Cell growth ,business.industry ,General Medicine ,lcsh:RD1-811 ,Hypoxia (medical) ,Hyperplasia ,medicine.disease ,Pulmonary hypertension ,3. Good health ,medicine.anatomical_structure ,Vasoconstriction ,lcsh:Anesthesiology ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,Pulmonary artery ,Cardiology ,Ventricular Function, Right ,Surgery ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background and objective Chronic hypoxia induces pulmonary hypertension in mice. Smooth muscle cell hyperplasia and medial thickening characterize the vasculature of these animals. Thrombospondin-1 null (TSP-1-/-) mice spontaneously develop pulmonary smooth muscle cell hyperplasia and medial thickening. In addition, TSP-1 produced by the pulmonary endothelium inhibits pulmonary artery smooth muscle cell growth. Based on these observations we sought to describe the pulmonary vascular changes in TSP-1-/- mice exposed to chronic hypoxia. Methods We exposed TSP-1-/- and wild type (WT) mice to a fraction of inspired oxygen (FiO2) of 0.1 for up to six weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Additionally, right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by right ventricle/left ventricle + septum ratios (RV/LV+S) were measured to evaluate pulmonary hypertensive changes. Finally, acute pulmonary vasoconstriction response in both TSP-1-/- and WT mice was evaluated by acute hypoxia and U-46619 (a prostaglandin F2 analog) response. Results In hypoxia, TSP-1-/- mice had significantly lower RVSP, RV/LV+S ratios and less pulmonary vascular remodeling when compared to WT mice. TSP-1-/- mice also had significantly lower RVSP in response to acute pulmonary vasoconstriction challenges than their WT counterparts. Conclusion TSP-1-/- mice had diminished pulmonary vasoconstriction response and were less responsive to hypoxia-induced pulmonary hypertension than their wild type counterparts. This observation suggests that TSP-1 could play an active role in the pathogenesis of pulmonary hypertension associated with hypoxia.
- Published
- 2010
38. TLR4 is a negative regulator in noninfectious lung inflammation
- Author
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Katherine A. Fitzgerald, Charles A. Hales, Liyun Shi, Hang Zhao, Gaofeng Zhao, Shaw-Wei Leu, Rejmon Dedaj, Huahao Shen, Hari G. Garg, Aviva Shiedlin, Egil Lien, Lianjun Shen, and Deborah A. Quinn
- Subjects
Chemokine ,Cell Membrane Permeability ,medicine.medical_treatment ,Immunology ,Acute Lung Injury ,Interleukin-1beta ,Down-Regulation ,Inflammation ,Proinflammatory cytokine ,Mice ,In vivo ,medicine ,Immunology and Allergy ,Animals ,Hyaluronic Acid ,Lung ,Cells, Cultured ,Mice, Knockout ,Mice, Inbred C3H ,biology ,food and beverages ,In vitro ,Mice, Inbred C57BL ,Molecular Weight ,Pulmonary Alveoli ,Toll-Like Receptor 4 ,Interleukin 1 Receptor Antagonist Protein ,Cytokine ,medicine.anatomical_structure ,TLR4 ,biology.protein ,Cancer research ,medicine.symptom ,Inflammation Mediators ,Bronchoalveolar Lavage Fluid ,Signal Transduction - Abstract
Low m.w. hyaluronan (LMW HA) has been shown to elicit the expression of proinflammatory cytokines and chemokines in various cells in vitro. However, the effects of this molecule in vivo are unknown. In this study, we report that intratracheal administration of LMW HA (200 kDa) causes inflammation in mouse lung. A lack of TLR4 is associated with even stronger inflammatory response in the lung as shown by increased neutrophil counts and elevated cytokine and chemokine concentrations. We also demonstrate that TLR4 anti-inflammatory signaling is dependent upon a MyD88-independent pathway. TLR4-mediated IL-1R antagonist production plays a negative regulatory role in LMW HA (200 kDa) induced lung inflammation. These data provide a molecular level explanation for the function of TLR4 in LMW HA (200 kDa)-induced lung inflammation, as inhibition of the β form of pro–IL-1 promotes an anti-inflammatory response.
- Published
- 2010
39. Role for nuclear factor-kappaB in augmented lung injury because of interaction between hyperoxia and high stretch ventilation
- Author
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Shuen-Kuei Liao, Deborah A. Quinn, Ying-Huang Tsai, Li-Fu Li, Chung-Chi Huang, and Yung-Yang Liu
- Subjects
Male ,medicine.medical_specialty ,ARDS ,Pathology ,Neutrophils ,medicine.medical_treatment ,Acute Lung Injury ,Lung injury ,Hyperoxia ,Article ,chemistry.chemical_compound ,Mice ,Physiology (medical) ,Internal medicine ,Serpin E2 ,medicine ,Tidal Volume ,Animals ,Lung ,Tidal volume ,Serpins ,Evans Blue ,Mechanical ventilation ,biology ,business.industry ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,NF-kappa B ,General Medicine ,DNA ,respiratory system ,Disseminated Intravascular Coagulation ,medicine.disease ,Respiration, Artificial ,respiratory tract diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,Neutrophil Infiltration ,Myeloperoxidase ,Plasminogen activator inhibitor-1 ,biology.protein ,medicine.symptom ,business ,Peptides ,Protein Binding - Abstract
High-tidal-volume mechanical ventilation and hyperoxia used in patients with acute lung injury (ALI) can induce alveolar coagulopathy and fibrin depositions within the airways. Hyperoxia has been shown to increase ventilator-induced lung injury (VILI), but the mechanisms that regulate interaction between high-tidal-volume mechanical ventilation and hyperoxia are unclear. We hypothesized that mechanical stretch with hyperoxia synergistically augmented neutrophil infiltration and production of plasminogen activator inhibitor-1 (PAI-1) via the nuclear factor-kappaB (NF-kappaB) pathway. C57BL/6 mice (n=5 per group) were exposed to high-tidal-volume (30 mL/kg) or low-tidal-volume (6 mL/kg) mechanical ventilation with room air or hyperoxia for 1 to 5h after 2-microg/g NF-kappaB inhibitor (SN-50) administration. Nonventilated mice with room air or hyperoxia served as control groups. Evans blue dye, myeloperoxidase, electrophoretic mobility shifting of nuclear protein, and inflammatory cytokine were measured. The expression of tumor necrosis factor-alpha (TNF-alpha) and PAI-1 were studied by immunohistochemistry. The addition of hyperoxia to high-tidal-volume ventilation-augmented lung injury, as demonstrated by increased microvascular leak, neutrophil migration into the lung, TNF-alpha and active PAI-1 production, DNA binding activity of NF-kappaB, and NF-kappaB activation. No statistically significant increase of neutrophil infiltration and inflammatory cytokine production was found in the mice ventilated at 6 mL/kg using hyperoxia. Hyperoxia-induced augmentation of VILI was attenuated in mice with pharmacologic inhibition of NF-kappaB activity by SN-50. We conclude that hyperoxia increased high-tidal-volume-induced cytokine production and neutrophil influx through activation of the NF-kappaB pathway.
- Published
- 2009
40. Inhibition of HA synthase 3 mRNA expression, with a phosphodiesterase 3 inhibitor, blocks lung injury in a septic ventilated rat model
- Author
-
Zhao Hang, John Beagle, Deborah A. Quinn, Hari G. Garg, Hicham Mrabat, and Charles A. Hales
- Subjects
Pulmonary and Respiratory Medicine ,Lipopolysaccharides ,Male ,Phosphodiesterase Inhibitors ,medicine.medical_treatment ,Phosphodiesterase 3 ,Acute Lung Injury ,Chemokine CXCL2 ,Anti-Inflammatory Agents ,Down-Regulation ,Pharmacology ,Lung injury ,Phosphodiesterase 3 Inhibitors ,Gene Expression Regulation, Enzymologic ,Sepsis ,Capillary Permeability ,Rats, Sprague-Dawley ,Medicine ,Animals ,RNA, Messenger ,Glucuronosyltransferase ,Hyaluronic Acid ,Lung ,Mechanical ventilation ,biology ,medicine.diagnostic_test ,business.industry ,Hemodynamics ,respiratory system ,medicine.disease ,Respiration, Artificial ,Cyclic Nucleotide Phosphodiesterases, Type 3 ,respiratory tract diseases ,Rats ,Hyaluronan synthase ,Disease Models, Animal ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Neutrophil Infiltration ,Immunology ,biology.protein ,Milrinone ,business ,Bronchoalveolar Lavage Fluid ,Hyaluronan Synthases ,medicine.drug - Abstract
Low-molecular-weight hyaluronan produced by hyaluronan synthase 3 (HAS3) has been shown to play a role in acute lung injury secondary to high-tidal-volume ventilation. Phosphodiesterase 3 inhibitors have been shown to decrease HAS3 expression. We hypothesized that low-molecular-weight hyaluronan (LMW HA) produced by HAS3 mediates LPS-induced lung injury in the mechanically ventilated rat and that milrinone (MIL), by blocking HAS3 mRNA expression, would prevent the injury. Rats were randomized to four groups: controls with mechanical ventilation at 7 cc/kg MV, MV+LPS, MV+MIL, and MV+LPS+MIL. Rats were intubated and ventilated without PEEP for 4 h. Lipopolysaccharide (LPS) (1 mg/kg) was infused into the arterial line 1 h prior to MV. MIL 10 microg/kg/min (or an equivalent volume of saline) was infused through the venous line at the beginning of MV. Bronchoalveolar lavage fluid (BAL) was collected after 4 h of ventilation and lungs were saved for histopathology. LPS significantly increased neutrophil infiltration and protein concentration in the BAL and augmented lung injury score on histology. MIL significantly lowered alveolar protein and neutrophil infiltration as well as lung injury in response to LPS. Furthermore, MIL decreased the mRNA expression for HAS3 and MIP2 in lung tissue and decreased the protein content in BAL. MIL, a commonly used inotropic agent, inhibited LPS-induced lung inflammation and lung injury in mechanically ventilated rats. The anti-inflammatory properties of MIL may be mediated by inhibition of HAS3 and/or MIP2 and could be beneficial in the treatment of sepsis.
- Published
- 2009
41. Toll like Receptor 4, a Negative Regulator in Low Molecular Weight Hyaluronan Induced Acute Lung Injury
- Author
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R Dedaj, A Sheidlin, S Leu, Charles A. Hales, Katherine A. Fitzgerald, L Shi, E Lien, H Zhao, LJ Shen, Gaofeng Zhao, and Deborah A. Quinn
- Subjects
Toll-like receptor ,business.industry ,Immunology ,Medicine ,Lung injury ,business ,Negative regulator - Published
- 2009
42. Effects of Anti-IL-13 (Novartis QAX576) on Inflammatory Responses Following Nasal Allergen Challenge (NAC)
- Author
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Christoph Walker, Andrew J. Tan, John Westwick, Peter J. Barnes, Harsha H. Kariyawasam, David M. Rodman, Trevor T. Hansel, Grant C. Nicholson, Philipp Badorrek, N Syngal, Onn Min Kon, Norbert Krug, Jens M. Hohlfeld, C Boulton, and Deborah A. Quinn
- Subjects
Allergen challenge ,business.industry ,Medicine ,Pharmacology ,business ,Anti il 13 - Published
- 2009
43. High-molecular-weight hyaluronan--a possible new treatment for sepsis-induced lung injury: a preclinical study in mechanically ventilated rats
- Author
-
Yung‐yang Liu, Charles A. Hales, Hicham Mrabat, Rejmon Dedaj, Deborah A. Quinn, Aviva Sheidlin, Hari G. Garg, Hang Zhao, Olga Syrkina, Cheng-Hung Lee, and Pei-Ming Huang
- Subjects
Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Lung injury ,Pharmacology ,Critical Care and Intensive Care Medicine ,Rats sprague dawley ,Proinflammatory cytokine ,Sepsis ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Hyaluronic acid ,medicine ,Animals ,Hyaluronic Acid ,030304 developmental biology ,Mechanical ventilation ,0303 health sciences ,business.industry ,Extramural ,Research ,food and beverages ,Lung Injury ,respiratory system ,medicine.disease ,Respiration, Artificial ,3. Good health ,respiratory tract diseases ,Rats ,Sprague dawley ,chemistry ,030220 oncology & carcinogenesis ,business - Abstract
Introduction Mechanical ventilation with even moderate-sized tidal volumes synergistically increases lung injury in sepsis and has been associated with proinflammatory low-molecular-weight hyaluronan production. High-molecular-weight hyaluronan (HMW HA), in contrast, has been found to be anti-inflammatory. We hypothesized that HMW HA would inhibit lung injury associated with sepsis and mechanical ventilation. Methods Sprague–Dawley rats were randomly divided into four groups: nonventilated control rats; mechanical ventilation plus lipopolysaccharide (LPS) infusion as a model of sepsis; mechanical ventilation plus LPS with HMW HA (1,600 kDa) pretreatment; and mechanical ventilation plus LPS with low-molecular-weight hyaluronan (35 kDa) pretreatment. Rats were mechanically ventilated with low (7 ml/kg) tidal volumes. LPS (1 or 3 mg/kg) or normal saline was infused 1 hour prior to mechanical ventilation. Animals received HMW HA or low-molecular-weight hyaluronan via the intraperitoneal route 18 hours prior to the study or received HMW HA (0.025%, 0.05% or 0.1%) intravenously 1 hour after injection of LPS. After 4 hours of ventilation, animals were sacrificed and the lung neutrophil and monocyte infiltration, the cytokine production, and the lung pathology score were measured. Results LPS induced lung neutrophil infiltration, macrophage inflammatory protein-2 and TNFα mRNA and protein, which were decreased in the presence of both 1,600 kDa and 35 kDa hyaluronan pretreatment. Only 1,600 kDa hyaluronan completely blocked both monocyte and neutrophil infiltration and decreased the lung injury. When infused intravenously 1 hour after LPS, 1,600 kDa hyaluronan inhibited lung neutrophil infiltration, macrophage inflammatory protein-2 mRNA expression and lung injury in a dose-dependent manner. The beneficial effects of hyaluronan were partially dependent on the positive charge of the compound. Conclusions HMW HA may prove to be an effective treatment strategy for sepsis-induced lung injury with mechanical ventilation.
- Published
- 2008
44. TLR4 enhances resolution of lung inflammation by promoting neutrophil apoptosis
- Author
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Egil Lien, Charles A. Hales, Katherine A. Fitzgerald, Deborah A. Quinn, lian jun shen, Aviva Shiedlin, Hang Zhao, shaw wei leu, Gaofeng Zhao, and Rejmon Dedaj
- Subjects
Lung ,business.industry ,Resolution (electron density) ,Neutrophil apoptosis ,Inflammation ,Biochemistry ,medicine.anatomical_structure ,Genetics ,TLR4 ,Cancer research ,Medicine ,medicine.symptom ,business ,Molecular Biology ,Biotechnology - Published
- 2008
45. Role of sulfidopeptide leukotrienes in synthetic smoke inhalation injury in sheep
- Author
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C. A. Hales, D. Robinson, Deborah A. Quinn, and W. Jung
- Subjects
Leukotrienes ,Pulmonary Circulation ,Physiology ,Smoke Inhalation Injury ,Smoke inhalation ,Pulmonary Edema ,Lung injury ,Physiology (medical) ,medicine ,Animals ,Acrolein ,Pulmonary wedge pressure ,Leukotriene E4 ,Sheep ,Lung ,Inhalation ,Chemistry ,respiratory system ,medicine.disease ,Pulmonary edema ,medicine.anatomical_structure ,Chromones ,Anesthesia ,Vascular resistance ,SRS-A ,Vascular Resistance ,Lymph - Abstract
Acute lung injury with smoke inhalation results in significant morbidity and mortality. Previously we have shown that synthetic smoke composed of carbon and acrolein, a common component of smoke, causes delayed-onset noncardiogenic pulmonary edema. To study the possible role of the vasoactive and edemagenic sulfidopeptide leukotrienes (SPLT) in smoke inhalation injury, we measured pulmonary hemodynamics, lung lymph flow, and SPLT and leukotriene (LT) B4 in lung lymph before and after 10 min of synthetic acrolein smoke exposure. After smoke exposure there was a significant rise in pulmonary vascular resistance caused by a rise in pulmonary arterial pressure, a fall in cardiac output, and no change in pulmonary capillary wedge pressure. This was accompanied by an increase in total systemic vascular resistance (P less than 0.05), lung lymph flow (P less than 0.05), and extravascular lung water-to-lung dry weight ratio (P less than 0.05). Both SPLT and LTB4 clearance rose significantly (P less than 0.05), but there was a 10-fold increase in SPLT over LTB4 clearance. In sheep pretreated with FPL55712, a SPLT antagonist, the early rise in pulmonary vascular resistance was attenuated, and the rise in systemic vascular resistance was blocked. This was associated with an attenuated and delayed fall in cardiac output. FPL55712 had no effect on lung lymph flow or extravascular lung water-to-dry weight ratio. SPLT, and especially LTD4, may have a role in increased pulmonary and systemic vascular resistance after smoke inhalation injury but does not appear to affect vascular permeability.
- Published
- 1990
46. Low-molecular-weight heparin inhibits hypoxic pulmonary hypertension and vascular remodeling in guinea pigs
- Author
-
Lunyin Yu, Hong Kai Du, Hari G. Garg, Charles A. Hales, Essam Al-Ansari, Deborah A. Quinn, and Cristhiaan D. Ochoa
- Subjects
Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,Hypertension, Pulmonary ,Guinea Pigs ,Drug Evaluation, Preclinical ,Hematocrit ,Pulmonary Artery ,Critical Care and Intensive Care Medicine ,Muscle, Smooth, Vascular ,Internal medicine ,medicine.artery ,medicine ,Animals ,Hypoxia ,Analysis of Variance ,Lung ,medicine.diagnostic_test ,Dose-Response Relationship, Drug ,business.industry ,Hemodynamics ,Heparin ,Hypoxia (medical) ,Heparin, Low-Molecular-Weight ,medicine.disease ,Pulmonary hypertension ,Surgery ,medicine.anatomical_structure ,Pulmonary artery ,Circulatory system ,Cardiology ,Cattle ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Enoxaparin sodium ,medicine.drug - Abstract
We have shown previously that antiproliferative unfractionated heparins block hypoxia-induced pulmonary arterial hypertension (PAH) and vascular remodeling, and hypothesized that low-molecular-weight heparins (LMWHs) would too.To determine the potential role and mechanisms of dalteparin and enoxaparin (two LMWHs) in inhibiting hypoxic PAH and vascular remodeling.Male Hartley guinea pigs were exposed for 10 days to normobaric 10% oxygen with dalteparin (5 mg/kg), enoxaparin (5 mg/kg), or with an equivalent volume of normal saline solution. Normoxic control animals (n = 5) received room air for 10 days. Bovine pulmonary artery smooth-muscle cells (PASMCs) were grown in 10% fetal bovine serum without heparin, with dalteparin (1 microg/mL) or with enoxaparin (1 microg/mL).Pulmonary arterial pressure (PAP), cardiac index, right ventricular heart weight divided by left ventricular plus septum weight (RV/LV+S), hematocrit, percentage of wall thickness of intraacinar vessels (%WT-IA), percentage of wall thickness of terminal bronchiole vessels (%WT-TA), and the percentage of thick-walled vessels (%Thick) were determined. In PASMCs, expression of p27 and cell growth were compared because in mice whole heparin depends on p27 for its antiproliferative action.In hypoxic animals, hematocrit, PAP, total pulmonary vascular resistance index, RV/LV+S, %WT-IA, %WT-TA, and %Thick all rose significantly vs normoxic control animals (p0.05); cardiac index was unchanged. Dalteparin but not enoxaparin significantly reduced PAP, total pulmonary vascular resistance index, and RV/LV + S (p0.05 vs hypoxia alone); inhibited PASMC growth; and upregulated p27 expression. Enoxaparin moderately reduced vascular remodeling, which did not translate into less pulmonary hypertension.Not all LMWHs are the same. Dalteparin was more effective than enoxaparin in inhibiting pulmonary hypertension and vascular remodeling in hypoxic guinea pigs.
- Published
- 2007
47. Barotrauma
- Author
-
Charles A. Hales and Deborah A. Quinn
- Subjects
medicine.medical_specialty ,Hematology ,business.industry ,Internal medicine ,medicine ,business ,Intensive care medicine ,Biomedicine - Published
- 2007
48. Involvement of Akt and endothelial nitric oxide synthase in ventilation-induced neutrophil infiltration: a prospective, controlled animal experiment
- Author
-
Cheng-Huei Lee, Li-Fu Li, Shuen-Kuei Liao, Deborah A. Quinn, and Chung-Chi Huang
- Subjects
Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,medicine.medical_treatment ,Lung injury ,Hyperoxia ,Protein Serine-Threonine Kinases ,Critical Care and Intensive Care Medicine ,chemistry.chemical_compound ,Mice ,Random Allocation ,Enos ,Reference Values ,Internal medicine ,medicine ,Animals ,LY294002 ,Prospective Studies ,Protein kinase B ,Lung ,Tidal volume ,Mechanical ventilation ,Mice, Knockout ,biology ,business.industry ,Research ,respiratory system ,biology.organism_classification ,Respiration, Artificial ,respiratory tract diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,Neutrophil Infiltration ,Immunology ,Commentary ,Cytokines ,medicine.symptom ,business - Abstract
Introduction Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human IL-8, and neutrophil infiltration. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between a large tidal volume and hyperoxia are unclear. We hypothesized that large tidal volume ventilation using hyperoxia would increase MIP-2 production and neutrophil infiltration via the serine/threonine kinase/protein kinase B (Akt) pathway and the endothelial nitric oxide synthase (eNOS) pathway. Methods C57BL/6 mice were exposed to large tidal volume (30 ml/kg) mechanical ventilation with room air or hyperoxia for 1–5 hours. Results Large tidal volume ventilation using hyperoxia induced neutrophil migration into the lung, MIP-2 production, and Akt and eNOS activation in a time-dependent manner. Both the large tidal volume ventilation of Akt mutant mice and the pharmacological inhibition of Akt with LY294002 attenuated neutrophil sequestration, MIP-2 protein production, and Akt and eNOS activation. Conclusion We conclude that hyperoxia increased large tidal volume-induced MIP-2 production and neutrophil influx through activation of the Akt and eNOS pathways.
- Published
- 2007
49. Overexpression of RhoA diminishes inhibitory effect of heparin on pulmonary artery smooth muscle cell proliferation
- Author
-
Charles A. Hales, Lunyin Yu, Deborah A. Quinn, and Hari G. Garg
- Subjects
RHOA ,biology ,Chemistry ,Cell growth ,Heparin ,Biochemistry ,Smooth muscle ,medicine.artery ,Pulmonary artery ,Genetics ,medicine ,biology.protein ,Cancer research ,Molecular Biology ,Inhibitory effect ,Biotechnology ,medicine.drug - Published
- 2007
50. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators
- Author
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Deborah A. Quinn, Victor F. Tapson, Russell D. Hull, John D. Buckley, Alexander Gottschalk, Paul D. Stein, Pamela K. Woodard, Thomas A. Sos, Charles A. Hales, Sarah E. Fowler, Thomas W. Wakefield, H. Dirk Sostman, John G. Weg, Kenneth V. Leeper, and Lawrence R. Goodman
- Subjects
Male ,medicine.medical_specialty ,Diagnostic Techniques, Respiratory System ,Risk Assessment ,law.invention ,Computed tomographic ,Decision Support Techniques ,Randomized controlled trial ,law ,Pregnancy ,D-dimer ,Pulmonary angiography ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,In patient ,Practice Patterns, Physicians' ,medicine.diagnostic_test ,Vascular disease ,business.industry ,Decision Trees ,Respiratory disease ,General Medicine ,medicine.disease ,Prognosis ,United States ,Pulmonary embolism ,Angiography ,Acute Disease ,Practice Guidelines as Topic ,Female ,Radiology ,business ,Pulmonary Embolism ,Perfusion ,Lower limbs venous ultrasonography - Abstract
Purpose To formulate comprehensive recommendations for the diagnostic approach to patients with suspected pulmonary embolism, based on randomized trials. Methods Diagnostic management recommendations were formulated based on results of the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) and outcome studies. Results The PIOPED II investigators recommend stratification of all patients with suspected pulmonary embolism according to an objective clinical probability assessment. D-dimer should be measured by the quantitative rapid enzyme-linked immunosorbent assay (ELISA), and the combination of a negative D-dimer with a low or moderate clinical probability can safely exclude pulmonary embolism in many patients. If pulmonary embolism is not excluded, contrast-enhanced computed tomographic pulmonary angiography (CT angiography) in combination with venous phase imaging (CT venography), is recommended by most PIOPED II investigators, although CT angiography plus clinical assessment is an option. In pregnant women, ventilation/perfusion scans are recommended by many as the first imaging test following D-dimer and perhaps venous ultrasound. In patients with discordant findings of clinical assessment and CT angiograms or CT angiogram/CT venogram, further evaluation may be necessary. Conclusion The sequence for diagnostic test in patients with suspected pulmonary embolism depends on the clinical circumstances.
- Published
- 2006
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