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Muco-obstructive lung diseases are characterized by airway obstruction and hyperinflation, which can be quantified by imaging. Our aim was to evaluate µCT for longitudinal quantification of muco-obstructive lung disease in β-epithelial Na + channel overexpressing ( Scnn1b -TG) mice and of the effects of neutrophil elastase (NE) knockout on its progression. Lungs from wild-type (WT), NE -/- , Scnn1b -TG, and Scnn1b -TG/NE -/- mice were scanned with 9-µm resolution at 0, 5, 14, and 60 days of age, and airway and parenchymal disease was quantified. Mucus adhesion lesions (MAL) were persistently increased in Scnn1b -TG compared with WT mice from 0 days (20.25 ± 6.50 vs. 9.60 ± 2.07, P < 0.05), and this effect was attenuated in Scnn1b -TG/NE -/- mice (5.33 ± 3.67, P < 0.001). Airway wall area percentage (WA%) was increased in Scnn1b -TG mice compared with WT from 14 days onward (59.2 ± 6.3% vs. 49.8 ± 9.0%, P < 0.001) but was similar in Scnn1b -TG/NE -/- compared with WT at 60 days (46.4 ± 9.2% vs. 45.4 ± 11.5%, P = 0.97). Air proportion (Air%) and mean linear intercept ( L m ) were persistently increased in Scnn1b -TG compared with WT from 5 days on (53.9 ± 4.5% vs. 30.0 ± 5.5% and 78.82 ± 8.44 µm vs. 65.66 ± 4.15 µm, respectively, P < 0.001), whereas in Scnn1b -TG/NE -/- , Air% and L m were similar to WT from birth (27.7 ± 5.5% vs. 27.2 ± 5.9%, P = 0.92 and 61.48 ± 9.20 µm vs. 61.70 ± 6.73 µm, P = 0.93, respectively). Our results suggest that µCT is sensitive to detect the onset and progression of muco-obstructive lung disease and effects of genetic deletion of NE on morphology of airways and lung parenchyma in Scnn1b -TG mice, and that it may serve as a sensitive endpoint for preclinical studies of novel therapeutic interventions for muco-obstructive lung diseases.

Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to persistent inflammation, infection and dysregulated protease activity. Although neutrophilic serine proteases, particularly neutrophil elastase, have been implicated in the propagation of inflammation and local tissue destruction, it is likely that the serine TLPs also contribute to various disease-relevant processes given the roles that a number of these enzymes play in the activation of both the epithelial sodium channel (ENaC) and protease-activated receptor 2 (PAR2). More recently, significant attention has focused on the activation of viruses such as SARS-CoV-2 by host TLPs. The purpose of this review was to highlight key TLPs linked to the activation of ENaC and PAR2 and their association with airway dehydration and inflammatory signalling pathways, respectively. The role of TLPs in viral infectivity will also be discussed in the context of the inhibition of TLP activities and the potential of these proteases as therapeutic targets.

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed., Competing Interests: Declaration of Competing Interest Dr. A Broomfield declares travel assistance from Takeda Pharmaceutical, Sanofi and Biomarin Pharmaceutical and consulting fees from Sanofi, unrelated to this work. Dr. A Ghosh declares travel assistance from Biomarin Pharmaceutical and honoraria from Alexion Pharmaceuticals, unrelated to this work. Dr. KM Stepien has received travel grants from BioMarin, Genzyme, Alexion, Takeda Pharmaceutical and honoraria from Biomarin Pharmaceutical Chiesi, Sanofi, Orchard Therapeutics and Takeda unrelated to this work. K Tylee declares prior travel assistance from Biomarin Pharmaceutical, unrelated to this work. Dr. S Jones declares consultancy for Genzyme, Shire, Alexion Pharmaceuticals, Orchard Therapeutics, Denali Therapeutics, and Ultragenyx Pharmaceutical, unrelated to this work. All other authors declare no conflict of interest., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Environmental pollution has reached a global echo and represents a serious problem for human health. Air pollution encompasses a set of hazardous substances, such as particulate matter and heavy metals (e.g., cadmium, lead, and arsenic), and has a strong impact on the environment by affecting groundwater, soil, and air. An adaptive response to environmental cues is essential for human survival, which is associated with the induction of adaptive phenotypes. The epigenetic mechanisms regulating the expression patterns of several genes are promising candidates to provide mechanistic and prognostic insights into this. Micro-RNAs (miRNAs) fulfil these features given their ability to respond to environmental factors and their critical role in determining phenotypes. These molecules are present in extracellular fluids, and their expression patterns are organ-, tissue-, or cell-specific. Moreover, the experimental settings for their quantitative and qualitative analysis are robust, standardized, and inexpensive. In this review, we provide an update on the role of miRNAs as suitable tools for understanding the mechanisms behind the physiopathological response to toxicants and the prognostic value of their expression pattern associable with specific exposures. We look at the mechanistic evidence associable to the role of miRNAs in the processes leading to environmental-induced pulmonary disease (i.e., chronic obstructive pulmonary disease).

To effectively diagnose, monitor and treat respiratory disease clinicians should be able to accurately assess the spatial distribution of airflow across the fine structure of lung. This capability would enable any decline or improvement in health to be located and measured, allowing improved treatment options to be designed. Current lung function assessment methods have many limitations, including the inability to accurately localise the origin of global changes within the lung. However, X-ray velocimetry (XV) has recently been demonstrated to be a sophisticated and non-invasive lung function measurement tool that is able to display the full dynamics of airflow throughout the lung over the natural breathing cycle. In this study we present two developments in XV analysis. Firstly, we show the ability of laboratory-based XV to detect the patchy nature of cystic fibrosis (CF)-like disease in β-ENaC mice. Secondly, we present a technique for numerical quantification of CF-like disease in mice that can delineate between two major modes of disease symptoms. We propose this analytical model as a simple, easy-to-interpret approach, and one capable of being readily applied to large quantities of data generated in XV imaging. Together these advances show the power of XV for assessing local airflow changes. We propose that XV should be considered as a novel lung function measurement tool for lung therapeutics development in small animal models, for CF and for other muco-obstructive diseases.

The stethoscope is used as first line diagnostic tool in assessment of patients with pulmonary symptoms. However, there is much debate about the diagnostic accuracy of this instrument. This meta-analysis aims to evaluate the diagnostic accuracy of lung auscultation for the most common respiratory pathologies. Studies concerning adult patients with respiratory symptoms are included. Main outcomes are pooled estimates of sensitivity and specificity with 95% confidence intervals, likelihood ratios (LRs), area under the curve (AUC) of lung auscultation for different pulmonary pathologies and breath sounds. A meta-regression analysis is performed to reduce observed heterogeneity. For 34 studies the overall pooled sensitivity for lung auscultation is 37% and specificity 89%. LRs and AUC of auscultation for congestive heart failure, pneumonia and obstructive lung diseases are low, LR- and specificity are acceptable. Abnormal breath sounds are highly specific for (hemato)pneumothorax in patients with trauma. Results are limited by significant heterogeneity. Lung auscultation has a low sensitivity in different clinical settings and patient populations, thereby hampering its clinical utility. When better diagnostic modalities are available, they should replace lung auscultation. Only in resource limited settings, with a high prevalence of disease and in experienced hands, lung auscultation has still a role.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that stimulates glucose-mediated insulin production by pancreatic beta cells. It is also associated with protective effects in multiple tissues. GLP-1 receptor is highly expressed in pulmonary tissue, hinting possible pulmonary delivery of GLP-1 drugs. However, little is known about the role of GLP-1 signaling in the lung, especially in mucus hypersecretory obstructive lung diseases. Here, we showed that treatment with exendin-4, a clinically available GLP-1 receptor agonist, up-regulates mucin expression in normal airway epithelial cells and in the lung of normal mice, indicating mucus stimulatory effect of GLP-1 under physiological condition. Exendin-4 also increased mucin expression in in vitro cellular and in vivo murine models of obstructive lung diseases via the activation of p38 MAP kinase. Notably, mucin induction in vivo exacerbated key pulmonary abnormalities including emphysematous phenotypes, implying that GLP-1 signaling in the lung is detrimental under pulmonary obstructive condition. Another GLP-1 receptor agonist liraglutide had similar induction of mucin. Together, our studies not only demonstrate novel physiological and pathological roles of GLP-1 in the lung but may also caution against the clinical use of inhaled GLP-1 receptor agonists in the patients with obstructive lung diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mucociliary epithelium lining the upper and lower respiratory tract constitutes the first line of defense of the airway and lungs against inhaled pollutants and pathogens. The concerted beating of multiciliated cells drives mucociliary clearance. Abnormalities in both the structure and function of airway cilia have been implicated in obstructive lung diseases. Emerging evidence reveals a close correlation between lung diseases and environmental stimuli such as sulfur dioxide and tobacco particles. However, the underlying mechanism remains to be described. In this review, we emphasize the importance of airway cilia in mucociliary clearance and discuss how environmental pollutants affect the structure and function of airway cilia, thus shedding light on the function of airway cilia in preventing obstructive lung diseases and revealing the negative effects of environmental pollutants on human health., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Airway mucus obstruction is a hallmark of chronic lung diseases such as cystic fibrosis, asthma, and COPD, and the development of more effective mucus-mobilizing therapies remains an important unmet need for patients with these muco-obstructive lung diseases. However, methods for sensitive visualization and quantitative assessment of immediate effects of therapeutic interventions on mucus clearance in vivo are lacking. In this study, we determined whether newly developed high-speed microscopic optical coherence tomography (mOCT) is sensitive to detect and compare in vivo effects of inhaled isotonic saline, hypertonic saline, and bicarbonate on mucus mobilization and clearance in Scnn1b -transgenic mice with muco-obstructive lung disease. In vivo mOCT imaging showed that inhaled isotonic saline-induced rapid mobilization of mucus that was mainly transported as chunks from the lower airways of Scnn1b -transgenic mice. Hypertonic saline mobilized a significantly greater amount of mucus that showed a more uniform distribution compared with isotonic saline. The addition of bicarbonate-to-isotonic saline had no effect on mucus mobilization, but also led to a more uniform mucus layer compared with treatment with isotonic saline alone. mOCT can detect differences in response to mucus-mobilizing interventions in vivo, and may thus support the development of more effective therapies for patients with muco-obstructive lung diseases.

Diagnosing and monitoring pulmonary diseases is highly dependent on imaging, physiological function tests and tissue sampling. Optical coherence tomography (OCT) and confocal laser endomicroscopy (CLE) are novel imaging techniques with near-microscopic resolution that can be easily and safely combined with conventional bronchoscopy. Disease-related pulmonary anatomical compartments can be visualized, real time, using these techniques. In obstructive lung diseases, airway wall layers and related structural remodelling can be identified and quantified. In malignant lung disease, normal and malignant areas of the central airways, lung parenchyma, lymph nodes and pleura can be discriminated. A growing number of interstitial lung diseases (ILDs) have been visualized using OCT or CLE. Several ILD-associated structural changes can be imaged: fibrosis, cellular infiltration, bronchi(ol)ectasis, cysts and microscopic honeycombing. Although not yet implemented in clinical practice, OCT and CLE have the potential to improve detection and monitoring pulmonary diseases and can contribute in unravelling the pathophysiology of disease and mechanism of action of novel treatments. Indeed, assessment of the airway wall layers with OCT might be helpful when evaluating treatments targeting airway remodelling. By visualizing individual malignant cells, CLE has the potential as a real-time lung cancer detection tool. In the future, both techniques could be combined with laser-enhanced fluorescent-labelled tracer detection. This review discusses the value of OCT and CLE in pulmonary medicine by summarizing the current evidence and elaborating on future perspectives., (The Author(s). Published by S. Karger AG, Basel.)

Introduction: DIPNECH is a strictly histological entity according to the WHO 2015 classification and is considered to be at pre-neoplastic risk. It has been proposed that DIPNECH syndrome should be used to describe patients have clinical symptoms, an obstructive ventilatory disorder and compatible radiological abnormalities. The diagnosis is histological and usually based on a surgical lung biopsy., Case Report: We report the case of a 58-year-old woman with a chronic cough for over 20years who had an obstructive airway pattern on spirometry. Diagnoses of asthma and COPD had been discussed. After 7years of follow-up, the DIPNECH hypothesis was evoked on the scanning aspect of mosaic attenuation, expiratory trapping and micronodules, which was subsequently confirmed by surgical pulmonary biopsy., Conclusion: It is necessary to consider the possibility of this rare disease in order to avoid inappropriate treatments and in the hope that future therapeutic advances (somatostatin analogs, mTOR inhibitors) improve patients' experience and the progression of respiratory function., (Copyright © 2019 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), infections and lung cancer. Even though there are various existing anti-inflammatory therapies, which are not enough to control the inflammation caused due to various contributing factors such as anti-inflammatory genes and antioxidant enzymes. This leads to an urgent need of novel drug delivery systems to combat the oxidative stress. This review gives a brief insight into the biological factors involved in causing oxidative stress, one of the emerging hallmark feature in CRDs and particularly, highlighting recent trends in various novel drug delivery carriers including microparticles, microemulsions, microspheres, nanoparticles, liposomes, dendrimers, solid lipid nanocarriers etc which can help in combating the oxidative stress in CRDs and ultimately reducing the disease burden and improving the quality of life with CRDs patients. These carriers improve the pharmacokinetics and bioavailability to the target site. However, there is an urgent need for translational studies to validate the drug delivery carriers for clinical administration in the pulmonary clinic., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We describe herein the management of a 16-year-old girl with cystic echinococcosis of the right ventricle and massive obstruction of the pulmonary vessel system by parasitic metastatic dissemination. After resection of the cardiac cyst, pulmonary thromboendarterectomy was performed to remove parts of the obstructive parasitic material. The treatment reduced the elevated pulmonary arterial pressure, improving the patient's overall condition.

Airway smooth muscle (ASM) is a dynamic and complex tissue involved in regulation of bronchomotor tone, but the molecular events essential for the maintenance of ASM homeostasis are not well understood. Observational and genome-wide association studies in humans have linked airway function to the nutritional status of vitamin A and its bioactive metabolite retinoic acid (RA). Here, we provide evidence that ongoing RA signaling is critical for the regulation of adult ASM phenotype. By using dietary, pharmacologic, and genetic models in mice and humans, we show that (a) RA signaling is active in adult ASM in the normal lung, (b) RA-deficient ASM cells are hypertrophic, hypercontractile, profibrotic, but not hyperproliferative, (c) TGF-β signaling, known to cause ASM hypertrophy and airway fibrosis in human obstructive lung diseases, is hyperactivated in RA-deficient ASM, (d) pharmacologic and genetic inhibition of the TGF-β activity in ASM prevents the development of the aberrant phenotype induced by RA deficiency, and (e) the consequences of transient RA deficiency in ASM are long-lasting. These results indicate that RA signaling actively maintains adult ASM homeostasis, and disruption of RA signaling leads to aberrant ASM phenotypes similar to those seen in human chronic airway diseases such as asthma.

This in vitro study evaluated, for the first time, the safety and the biological activity of a novel urea-crosslinked hyaluronic acid component and sodium ascorbyl phosphate (HA-CL - SAP), singularly and/or in combination, intended for the treatment of inflammatory lung diseases. The aim was to understand if the combination HA-CL - SAP had an enhanced activity with respect to the combination native hyaluronic acid (HA) - SAP and the single SAP, HA and HA-CL components. Sample solutions displayed pH, osmolality and viscosity values suitable for lung delivery and showed to be not toxic on epithelial Calu-3 cells at the concentrations used in this study. The HA-CL - SAP displayed the most significant reduction in interleukin-6 (IL-6) and reactive oxygen species (ROS) levels, due to the combined action of HA-CL and SAP. Moreover, this combination showed improved cellular healing (wound closure) with respect to HA - SAP, SAP and HA, although at a lower rate than HA-CL alone. These preliminary results showed that the combination HA-CL - SAP could be suitable to reduce inflammation and oxidative stress in lung disorders like acute respiratory distress syndrome, asthma, emphysema and chronic obstructive pulmonary disease, where inflammation is prominent., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sound transmission and resulting airway wall vibration in a complex multiscale viscoelastic model of the subglottal bronchial tree was calculated using a modified one-dimensional (1D) branching acoustic waveguide approach. This is an extension of previous work to enable use of complex airway trees that are partially derived from subject-specific medical images, without the need for self-similarity in the geometric structure. The approach was validated numerically for simplified airway geometries, as well as experimentally by comparison to previous studies. A comprehensive conducting airway tree with about 60 000 branches was then modified to create fibrotic, bronchoconstrictive, and pulmonary infiltrate conditions. The fibrotic case-systemic increase in soft tissue stiffness-increased the Helmholtz resonance frequency due to the increased acoustic impedance. Bronchoconstriction, with geometric changes in small conducting airways, decreased acoustic energy transmission to the peripheral airways due in part to the increased impedance mismatch between airway orders. Pulmonary infiltrate significantly altered the local acoustic field in the affected lobe. Calculation of acoustic differences between healthy versus pathologic cases can be used to enhance the understanding of vibro-acoustic changes correlated to pathology, and potentially provide improved tools for the diagnosis of pulmonary diseases that uniquely alter the acoustics of the airways.

Recent advances in mitochondrial biogenesis have provided the emerging recognition that mitochondria do much more than 'simply providing energy for cellular function'. Currently, a constantly improving understanding of the mitochondrial structure and function has been providing valuable insights into the contribution of defects in mitochondrial metabolism to various human diseases, including chronic obstructive pulmonary disease and lung cancer. The growing interest in mitochondria research led to development of new biomedical fields in the two main smoking-related lung diseases. However, there is considerable paucity in our understanding of mechanisms by which mitochondrial dynamics regulate lung diseases. In this review, we will discuss our current knowledge on the role of mitochondrial dysfunction in the pathogenesis of chronic obstructive pulmonary disease and non-small-cell lung cancer.

Background: The usefulness of the controlling nutritional status (CONUT) score for preoperative nutritional assessment has been reported in resected colorectal and esophageal cancer, but not in lung cancer with obstructive lung disease., Patients and Methods: We retrospectively reviewed 109 patients with adenocarcinoma with obstructive pulmonary disease. We set 1 as the cut-off value for the CONUT score and classified patients into high (≥1) and low (0) CONUT groups., Results: Among 109 patients, 35 (32.1%) had low CONUT scores, and 74 (67.8%) had high CONUT scores. The high-CONUT group was significantly associated with a lower body mass index (p=0.025) and wild-type epidermal growth factor receptor mutation status (p=0.011). A multivariate analysis showed that the CONUT score was independently associated with disease-free and overall survival., Conclusion: The results of this study suggest that the CONUT score was an independent prognostic factor for disease-free and overall survival in patients with lung adenocarcinoma with obstructive lung disease., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

NSCLC is a leading cause of morbidity and mortality worldwide. It includes adeno- and squamous cell carcinoma. In the background, COPD and smoking play a vital role in development of NSCLC. Local progression and metastasis of NSCLC has been associated with various mechanisms, but in particular by a process called epithelial mesenchymal transition (EMT), which is implicated in COPD pathogenesis. In this study, we have investigated whether expression of EGFR (activation marker) and S100A4, vimentin and N-cadherin (as EMT) is different both in central and leading edge of NSCLC and to what extent related to EMT activity of both small and large airways, stage and differentiation of NSCLC. We have investigated EMT biomarkers (S100A4, vimentin, and N-cadherin), an epithelial activation marker (EGFR) and a vascularity marker (Type-IV collagen) in surgically resected tissue from patients with NSCLC (adeno- and squamous cell carcinoma), and compared them with expression in the corresponding non-tumorous airways. EGFR, S100A4, vimentin, N-cadherin expression was higher in tumor cells located at the peripheral leading edge of NSCLC when compared with centrally located tumor cells of same subjects (P < 0.01). Type-IV collagen-expressing blood vessels were also more at the leading edge in comparison with central parts of NSCLC. EGFR and S100A4 expression was related to differentiation status (P < 0.05) and TNM stage (P < 0.05) of NSCLC. Moreover, EMT markers in the leading edge were significantly related to airway EMT activity, while peripheral edge vascularity of squamous cell carcinoma only was significantly related to large airway Rbm vascularity (P < 0.05). EGFR- and EMT-related protein expression was markedly high in the peripheral leading edge of NSCLCs and related to tumor characteristics associated with poor prognosis. The relationships between EMT-related tumor biomarker expression and those in the airway epithelium and Rbm provide a background for utility of airway changes in clinical settings.

Background: Drug-induced sedation endoscopy (DISE) is a diagnostic procedure which allows evaluation of the collapsibility of the upper airway. According to expert opinion, it is possible to imitate nocturnal collapsibility and perform a realistic investigation of the site of obstruction and vibration. This should enable sufficient and precise therapeutic advice to be given solely on the basis of clinical assessment., Objective: The current publication critically evaluates the present state of development of DISE and its potential indications., Materials and Methods: A PubMed literature research was performed using "sleep" and "endoscopy" or "DISE" as keywords. Relevant publications were evaluated., Results: The present publication provides a historical summary of the available publications and relates these to other methods for examining obstructive sleep apnea. The present state of DISE in terms of drugs applied, grading systems, and validity is evaluated. Indications for DISE are described and critically discussed on the basis of literature data., Conclusion: DISE provides deep insights into the genesis of obstructions of the upper airway and snoring. Although its value for diagnosis and treatment of sleep-disordered breathing could not yet be demonstrated for all non-CPAP (continuous positive airway pressure) therapies, DISE could identify predictive parameters some methods. Further potential indications for DISE might be predictive examinations for mandibular advancement devices and respiration-synchronous neurostimulation of the hypoglossal nerve. DISE will thus remain a valuable diagnostic tool for obstructive sleep apnea and rhonchopathy.

Although incidental reactive pulmonary neuroendocrine cell hyperplasia (PNECH) is seen on biopsy specimens in adults with chronic lung disease, disorders characterized by marked PNECH are rare. Primary hyperplasia of neuroendocrine cells in the lung and obstructive lung disease related to remodeling or physiologic constriction of small airways define diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) in the adult and neuroendocrine cell hyperplasia of infancy (NEHI) in children. DIPENCH and NEHI share a similar physiology, typical imaging appearance, and increased neuroendocrine cells on biopsy. However, there are important differences related to the underlying disease mechanisms leading to disparate outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Remodeling of the peripheral airways persists during the asymptomatic phase of heaves. Assessing the histology of large bronchi could facilitate the diagnosis of heaves during remission of the disease., Hypothesis: Airway inflammation and remodeling in endobronchial biopsy (EBB) specimens differentiate horses with heaves from controls, independently of their clinical status (exacerbation or remission)., Animals: Fourteen healthy horses and 24 horses with heaves., Methods: A 14-point scoring system assessing central bronchial wall inflammation and remodeling was developed. The score was validated by 2 pathologists using specimens obtained from 18 horses (6 controls, 6 with heaves exacerbation, and 6 with heaves remission) in which lung function had been assessed with impulse oscillometry. Clinical and research application of the score was evaluated using biopsy specimens obtained from 20 additional horses (8 controls, 6 with heaves exacerbation, and 6 with heaves remission)., Results: The score was repeatable (interclass correlation coefficient = 69%). It differentiated horses with heaves in exacerbation (mean ± SD: 6.2 ± 2.2) from those in remission (4.0 ± 1.0) and controls (3.6 ± 1.7, P < 0.0001). The histological scores of horses with heaves correlated with the ratio of respiratory resistance (R) at 5 and 10 Hz (R 5 : R 10 ratio, r = 0.65, P = 0.03), a parameter assessing airway obstruction., Conclusions and Clinical Significance: The proposed histological scoring system correlates with the degree of airway obstruction measured by impulse oscillometry. However, it does not discriminate horses with heaves in remission from controls. Evaluation of EBB specimens might be considered in future research and clinical studies of respiratory diseases in horses., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

A 45-year-old man who presented with dyspnea and chest tightness was found to have obstructive lung disease and eosinophilia of 10,300 eosinophils/μL. The differential diagnosis encompassed causes of primary eosinophilia and secondary eosinophilia associated with pulmonary disease, including asthma, environmental allergic reaction, eosinophilic granulomatosis with polyangiitis, allergic bronchopulmonary aspergillosis, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, parasitic infections, tuberculosis, fungal infection, sarcoidosis, mastocytosis, drug reaction with eosinophilia and systemic symptoms, lymphoproliferative hypereosinophilic syndrome, and myeloproliferative hypereosinophilic syndrome. Infectious workup, fiberoptic bronchoscopy with biopsy, and tests for myeloproliferative mutations help differentiate among these causes. Identifying the underlying cause of eosinophilia is imperative in guiding treatment.

Background: Heaves is a severe debilitating condition of horses, characterized by lower airway inflammation and permanent structural changes of the bronchial wall. Chronic inflammation promotes the formation of new vessels, a phenomenon known as angiogenesis. Narrow band imaging (NBI) endoscopy is a noninvasive technique that enhances the visualization of submucosal vessels, and commonly is employed for the study of angiogenesis in human patients., Objectives: Using NBI, we aimed to determine whether or not the central airways of horses with heaves undergo angiogenesis., Animals: Horses with heaves during exacerbation of the disease (n = 5) and healthy controls (n = 6)., Methods: A library of NBI images was established from previously recorded videoendoscopies. Images were acquired by an operator blinded to horse ID. Images were obtained from 3 sites: 130 from the trachea (14 ± 9.3 [mean ± SD] images per horse with heaves and 10 ± 5.4 from controls; P = .45), 58 from the carina (5.4 ± 3.2 from horses with heaves and 5.2 ± 2.8 fromn controls; P > .99) and 167 from the intermediate bronchi (17.8 ± 6.7 from horses with heaves and 13 ± 5.6 from controls; P = .17). Using dedicated stereology software (NewCAST, Visiopharm; Denmark), the volume density of superficial and deep vessels was calculated blindly by point counting at each site for all horses., Results: In the trachea, the volume density of superficial vessels was increased in horses with heaves compared to controls (P = .02). No difference was found between groups for the volume density of both superficial and deep vessels at the carina or intermediate bronchi., Conclusion and Clinical Relevance: NBI imaging of the airways was easily performed in standing sedated horses., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Reasons for Performing Study: In clinical practice, veterinarians often depend on owner-reported signs to assess the clinical course of horses with recurrent airway obstruction (RAO)., Objectives: To test whether owner-reported information on frequency of coughing and observation of nasal discharge are associated with clinical, cytological and bronchoprovocation findings in RAO-affected horses in nonstandardised field conditions., Study Design: Cross-sectional study comparing healthy and RAO-affected horses., Methods: Twenty-eight healthy and 34 RAO-affected Swiss Warmblood horses were grouped according to owner-reported 'coughing frequency' and 'nasal discharge'. Differences between these groups were examined using clinical examination, blood gas analyses, endoscopic mucus scores, cytology of tracheobronchial secretion and bronchoalveolar lavage fluid, and airway hyperresponsiveness determined by plethysmography with histamine bronchoprovocation., Results: Frequently coughing horses differed most markedly from healthy control animals. Histamine bronchoprovocation-derived parameters were significantly different between the healthy control group and all RAO groups. Mucus grades and tracheobronchial secretion and bronchoalveolar lavage fluid neutrophil percentages had particularly high variability, with overlap of findings between groups. Owner satisfaction with the clinical status of the horse was high, even in severely affected horses., Conclusions: Owner-reported coughing and nasal discharge are associated with specific clinical and diagnostic findings in RAO-affected horses in field settings. While airway hyperresponsiveness differentiates best between healthy horses and asymptomatic RAO-affected horses, the absence of coughing and nasal discharge does not rule out significant neutrophilic airway inflammation. Owner satisfaction with the clinical status of the horse was uninformative., (© 2014 EVJ Ltd.)

Laryngeal schwannomas are rare, benign neurogenic tumors. They normally present as a slow-growing, encapsulated, submucosal mass in the supraglottic region. We describe a 20-year-old female presenting with a 2-year history of hoarseness and progressive worsening dyspnea. Fiberoptic laryngoscopy and computed tomography revealed a round, low-density submucosal mass at right false cord and arytenoepiglottic regions with glottic extension. Microlaryngoscopic biopsy and debulking for this solid tumor were performed without tracheostomy. Schwannoma was confirmed by histopathological study. However, rapidly worsening stridor occurred 2 weeks after the surgery. Fiberoptic laryngoscopy showed an exophytic tumor occupying the right hemilarynx with airway compromise. Definite complete excision of the tumor was performed by right vertical hemilaryngectomy. At 5-month follow-up, the laryngeal wound was clear without signs of recurrence. Rapid occurrence of airway obstruction after debulking and biopsy was demonstrated in this case. Vertical hemilaryngectomy was inevitable to cure this potentially life-threatening laryngeal schwannoma in this young female with postoperative serviceable voice.

The aim of the present study was to compare the grade of discharge accumulation in the tracheal lumen, area of tracheal bifurcation, main bronchi and the tracheal septum thickness with the cytology of the tracheal aspirate (TA) and broncho-alveolar lavage fluid (BALF) in horses with recurrent airways obstruction and inflammatory airway disease from those horses. This study was conducted on 96 horses with RAO, 139 horses with IAD and 10 control horses. In all the horses, both clinical and endoscopic examinations were performed. During endoscopy, a score of mucus accumulation was estimated in 3/4 lower of the trachea and in the tracheal bifurcation. In addition, thickening of the tracheal septum was also assessed; tracheal aspirates and broncho-alveolar lavage were performed. An estimate of cell percentage was done in TA and BALF samples. In horses suffering from RAO and IAD, there was a positive correlation between the percentage of neutrophils and the accumulation of discharge, and in the IAD group, there was a negative correlation between the percentage of eosinophils and the accumulation of discharge. There was no correlation between tracheal septum thickening and the percentage of neutrophils and/or eosinophils.

Different noncellular elements, such as round concentric calcified laminated structures, may be found in sputum smears. If these structures appear isolated on the background of the smear, the term usually used to describe them is "calcareous concretions" (CC). On the contrary, when the structures are part of epithelial cell groups or small tissue fragments, the term used to describe them is "Psammoma bodies" (PB). The aim of this work is to establish the relationship between these structures and pulmonary disease, especially lung carcinoma, by searching for the presence of CC and/or PB in sputum smears. Our study has taken as a basis 16.716 sputum smears from 696 patients obtained during a 7-year period (2003-2009). After reviewing them, it was found that from the total, 66 cases (0.39%) contained round calcified structures, 57 of them (0.34%) corresponding to CC, and the remaining 9 ones (0.05%) corresponding to PB. From these 57 CC cases, 56 corresponded to benign entities, and only one was found with lung carcinoma. On the other hand, from the 9 PB cases all of them (100%) were related to lung adenocarcinoma. We conclude that, even having a similar morphological structure, these aforementioned calcified structures we have observed in sputum smears have different and relevant clinical significance., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Despite antiretroviral therapy and trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, Pneumocystis pneumonia remains an important serious opportunistic infection in HIV-infected persons. Pneumocystis (Pc) colonization in HIV-infected individuals and in HIV-uninfected smokers is associated with chronic obstructive pulmonary disease (COPD). We previously developed a nonhuman primate model of HIV infection and Pc colonization and demonstrated that Pc colonization correlated with COPD development. In the present study, we examined kinetics of COPD development in non-human primate and tested the effect of Pc burden reduction on pulmonary function by TMP-SMX treatment., Methods: Cynomolgus macaques (n = 16) were infected with simian/human immunodeficiency virus (SHIV89.6P), and natural Pc colonization was examined by nested polymerase chain reaction of serial bronchoalveolar lavage fluid and anti-Pc serology., Results: Eleven of 16 monkeys became Pc colonized by 16 weeks post simian-human immunodeficiency virus (SHIV) infection. Pc colonization of SHIV-infected monkeys led to progressive declines in pulmonary function as early as 4 weeks after Pc detection. SHIV-infected and Pc-negative monkeys maintained normal lung function. At 25 weeks post-SHIV infection, TMP-SMX treatment was initiated in 7 Pc-positive (Pc+) (TMP: 20 mg/kg and SMX: 100 mg/kg, daily for 48 weeks) and 5 Pc-negative (Pc-) monkeys. Four SHIV+/Pc+ remained untreated for the duration of the experiment. Detection frequency of Pc in serial bronchoalveolar lavage fluid (P < 0.001), as well as plasma Pc antibody titers (P = 0.02) were significantly reduced in TMP-SMX-treated macaques compared with untreated., Conclusions: Reduction of Pc colonization by TMP-SMX treatment did not improve pulmonary function, supporting the concept that Pc colonization results in early, permanent obstructive changes in the lungs of immunosuppressed macaques.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A, which leads to storage of sphingolipids in virtually all human cells and consequently to organ dysfunction. Pulmonary involvement is still debated. But, obstructive lung disease is up to ten times more prevalent in patients with FD compared to general public. Also, an accelerated decline in forced expiratory volume in one second (FEV1) over time was observed in these patients. Lysosomal storage of glycosphingolipids is considered leading to small airway disease via hyperplasia of the bronchiolar smooth muscle cells. Larger airways may become involved with ongoing disease process. There is no evidence for involvement of the lung interstitium in FD. The effect of enzyme replacement therapy on respiratory involvement remains to be determined in large, prospective controlled trials., (Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

The aim of the study was to show that changes in thoracoabdominal asynchrony (TAA) between quiet breathing and CO2-induced hyperpnoea can be used to differentiate between horses with healthy airways and those suffering from inflammatory airway disease (IAD) or recurrent airway obstruction (RAO). The level of TAA was displayed by the Pearson's correlation coefficient (PCC) of thoracic and abdominal signals, generated by respiratory ultrasonic plethysmography (RUP) during quiet breathing and hyperpnoea. Changes in TAA were expressed as the quotient of the PCCs (PCCQ) during normal breathing and hyperpnoea. Horses with RAO and IAD showed significant higher median PCCQ than healthy horses. Median PCCQ of horses with RAO and IAD was not significantly different. Horses affected by a pulmonary disorder showed lower TAA compared to the control group. This study suggests that TAA provides a useful parameter to differentiate horses with RAO and IAD from healthy horses., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To use noninvasive respiratory inductance plethysmography (RIP) to investigate differences in breathing patterns between horses with and without recurrent airway obstruction (RAO) during the onset of airway obstruction induced through confinement to stables., Animals: 12 horses with no history or clinical signs of respiratory disease (control horses) and 7 RAO-affected horses., Procedures: The study involved 2 phases. In phase 1, the optimal position of RIP bands for recording pulmonary function was investigated in 12 control horses. In phase 2, 7 RAO-affected and 7 control horses were confined to stables. Respiratory inductance plethysmography bands were applied to horses for 24 h/d to record respiratory rate and total displacement in 4-hour periods for 7 days or until RAO-affected horses developed signs of severe RAO that persisted for 2 consecutive days. Lung function was measured once daily., Results: In phase 1, thoracic and abdominal cavity displacements were best represented by RIP bands positioned at intercostal spaces 6 and 17, respectively. In phase 2, pulmonary function indicated airway obstruction in the RAO-affected group on the final 2 days of stable confinement. Respiratory rate and total degree of respiratory displacement measured by RIP did not differ between the RAO-affected and control groups, but the SDs of these decreased significantly within 8 hours after stable confinement began in RAO-affected horses. Respiratory inductance plethysmography and pulmonary function findings became highly correlated as severity of disease progressed., Conclusions and Clinical Relevance: The decrease in the SDs of RIP measurements indicated a lower degree of variability in breathing patterns of RAO-affected horses. This loss of variability may provide an early indicator of airway inflammation.

Objective: To evaluate the diagnostic value of granulocyte-macrophage colony stimulating factor (GM-CSF) antibody in serum for pulmonary alveolar proteinosis (PAP)., Methods: Twelve PAP patients visiting Peking University People's Hospital or Fujian Provincial Hospital from January 1, 2002 to December 31, 2012, 25 patients with other pulmonary diseases (disease control), and 25 healthy volunteers (healthy control) were recruited in the study. The titer level of GM-CSF antibody in serum was determined with enzyme-linked immunosorbent assay (ELISA), and the clinical characteristics were collected in the PAP patients., Results: The geometric mean titers of GM-CSF antibody in the PAP patients, the disease controls and the healthy controls were 1: 25 349, 1: 311 and 1: 256, respectively. The differences between the disease controls and the healthy controls were of no statistic significance (t = -1.14, P = 0.261) . With 3 times standard error (3s) above the mean value as the higher limit of X value(X = lgT, T standing for the reciprocal of the titer), the upper limit for T was 1698. With the T value ≥ 1698 as the diagnostic threshold for PAP, both the sensitivity and the specificity were 100%. The diagnostic value of GM-CSF antibody was similar to that of surgical lung biopsy and higher than that of transbronchial lung biopsy., Conclusion: The detection of serum GM-CSF is non-invasive, convenient and efficient for the diagnosis of PAP with high sensitivity and specificity.

Background: Reliable enumeration of mast cells and eosinophils in equine bronchoalveolar lavage (BAL) fluid is important because small increases in the percentages of these cells support the clinical diagnosis of inflammatory airway disease (IAD). Increases in BAL neutrophils also occur with IAD but are not specific due to overlap between IAD and recurrent airway obstruction (RAO)., Objectives: The objectives of this study were to evaluate the reliability of a standard 400-cell leukocyte differential count and an alternate method evaluating 5 microscopic fields at 500× magnification in equine BAL fluid cytocentrifuged preparations., Methods: BAL samples from 60 horses with and without pulmonary inflammation were evaluated using 400-cell and 5-field leukocyte differential counting methods. Reliability of enumeration of each leukocyte type was assessed by calculating and comparing intraclass correlation coefficients (ICC). Reliability of mast cell enumeration was further evaluated by comparing ICCs of slides with different cell densities., Results: Reliability was higher for all cell types with the 5-field method; however, overall the difference between methods was not statistically significant. Neutrophil reliability was high (ICC > 0.90) with both methods. Adequate reliability (ICC > 0.85) for mast cells was achieved only with the 5-field method on slides with higher cell density., Conclusion: Enumeration of mast cells is unreliable when the standard 400-cell differential counting method is used, whereas the 5-field method on slides with higher cell density reached acceptable reproducibility. Neutrophil percentages were highly reliable with both methods., (© 2013 American Society for Veterinary Clinical Pathology.)

Background: Improvement in PFT after bronchodilators is characteristic of obstructive airway diseases such as COPD. However, improvement in patients with restrictive pattern is occasionally seen. We aim to determine the clinical significance of a bronchodilator responsive restrictive defect., Methods: Patients with restrictive spirometry and a bronchodilator study were identified at the University of Oklahoma and Oklahoma City VAMC between September 2003 and December 2009. Restriction was defined as a decreased FVC and FEV1, with normal FEV1/FVC. Responsiveness to bronchodilators was defined as an improvement in FEV1 and/or FVC of at least 12% and 200 mL. Patients with lung volume measurements had their clinical and radiographic records reviewed., Results: Twenty-one patients were included in the study. Most were current or ex-smokers, with most being on bronchodilators. The average FVC and FEV1 were 65 ± 11% and 62 ± 10% of the predicted, respectively. Most patients (66%) had a normal TLC, averaging 90 ± 16% of the predicted. RV, RV/TLC, and the TLC-VA values strongly suggested an obstructive defect., Conclusions: Reversible restrictive pattern on spirometry appears to be a variant of obstructive lung disease in which early airway closure results in air trapping and low FVC. In symptomatic patients, a therapeutic trial of bronchodilators may be beneficial.

Background: Lidocaine decreases neutrophilic inflammation in models of acute lung injury and decreases inflammation in asthmatic patients. Neutrophilic bronchiolitis develops in recurrent airway obstruction (RAO), but it remains unknown if lidocaine infusion decreases neutrophil migration into the airways., Hypothesis: Lidocaine decreases neutrophilic inflammation as measured in BALF in RAO-affected horses., Animals: Six RAO-susceptible horses in remission., Methods: In a randomized cross-over design, horses received lactated Ringer's solution (LRS) IV or lidocaine hydrochloride IV with a minimum of 4 weeks at pasture between treatments. Treatments were delivered as continuous infusions beginning 4 hours before and for 68 hours during exposure to hay and straw challenge. Clinical score (CS, grade 0-8), maximal change in pleural pressure (∆Ppl(max) ), and bronchoalveolar lavage fluid (BALF) cytology were measured at baseline and the end of challenge (day 4). Plasma lidocaine concentrations were monitored daily., Results: At baseline, there were no significant differences in variables between treatments. Plasma lidocaine concentration was consistently > 1100 ng/mL. After challenge, CS increased significantly [baseline: 2/8 (2-3), [median (interquartile range)]; day 4: 4/8 (4-5) P = .0006] as did ∆Ppl(max) [baseline: 3.6 (2.63-4.95) cmH(2) 0; day 4: 9.62 (6.5-16) P = .0036], but there was no difference between treatments. Percentage of neutrophils was not different between treatments, but lidocaine infusion significantly increased BALF total cells [baseline: LRS 2.18 ± 0.82 × 10(5) cells/mL (mean ± SD), lidocaine 1.6 ± 0.3 × 10(5) , day 4: LRS 2.0 ± 0.88 × 10(5) , lidocaine 4.4 ± 2 × 10(5) (P = .0045)]., Conclusions and Clinical Importance: Lidocaine does not decrease neutrophilic inflammation in RAO., (Copyright © 2012 by the American College of Veterinary Internal Medicine.)

Background: β-Lactam resistance genotype trends in clinical isolates of Haemophilus influenzae and their correlation with the clinical background were analyzed., Methods: Five hundred and ten respiratory isolates of H. influenzae collected during the period 2002-2009 were classified by PCR into gBLNAS (genotype for β-lactamase-negative ampicillin-susceptible), gBLNAR (genotype for β-lactamase-negative ampicillin-resistant) and 3 other genotypes. The associations with host clinical data and antimicrobial susceptibility were analyzed in all 144 isolates between 2008 and 2009., Results: The 8-year trend analysis detected an increase in gBLNAR with a decrease in gBLNAS. The probability of being a causative pathogen did not differ between genotypes. Host clinical characteristics such as age and gender did not differ with gBLNAR or gBLNAS, but the underlying respiratory diseases did differ. gBLNAR was found at the highest rate in 83% of isolates from patients with nontuberculous mycobacteriosis. In contrast, gBLNAR accounted for as little as 33% of isolates from chronic obstructive pulmonary disease., Conclusions: There were no differences in the pathogenicity of gBLNAR and gBLNAS. The underlying respiratory diseases may be related to the resistance genotype., (Copyright © 2012 S. Karger AG, Basel.)

Airway smooth muscle has classically been of interest for its contractile response linked to bronchoconstriction. However, terminally differentiated smooth muscle cells are phenotypically plastic and have multifunctional capacity for proliferation, cellular hypertrophy, migration, and the synthesis of extracellular matrix and inflammatory mediators. These latter properties of airway smooth muscle are important in airway remodeling which is a structural alteration that compounds the impact of contractile responses on limiting airway conductance. In this overview, we describe the important signaling components and the functional evidence supporting a view of smooth muscle cells at the core of fibroproliferative remodeling of hollow organs. Signal transduction components and events are summarized that control the basic cellular processes of proliferation, cell survival, apoptosis, and cellular migration. We delineate known intracellular control mechanisms and suggest future areas of interest to pursue to more fully understand factors that regulate normal myocyte function and airway remodeling in obstructive lung diseases., (© 2012 American Physiological Society)

Purpose: To develop and test a method to noninvasively assess the functional lung microstructure., Materials and Methods: The Multiple exchange time Xenon polarization Transfer Contrast technique (MXTC) encodes xenon gas-exchange contrast at multiple delay times permitting two lung-function parameters to be derived: (i) MXTC-F, the long exchange-time depolarization value, which is proportional to the tissue to alveolar-volume ratio and (ii) MXTC-S, the square root of the xenon exchange-time constant, which characterizes thickness and composition of alveolar septa. Three healthy volunteers, one asthmatic, and two chronic obstructive pulmonary disease (COPD) (GOLD stage I and II) subjects were imaged with MXTC MRI. In a subset of subjects, hyperpolarized xenon-129 ADC MRI and CT imaging were also performed., Results: The MXTC-S parameter was found to be elevated in subjects with lung disease (P-value = 0.018). In the MXTC-F parameter map it was feasible to identify regional loss of functional tissue in a COPD patient. MXTC-F maps showed excellent regional correlation with CT and ADC (P ≥ 0.90) in one COPD subject., Conclusion: The functional tissue-density parameter MXTC-F showed regional agreement with other imaging techniques. The newly developed parameter MXTC-S, which characterizes the functional thickness of alveolar septa, has potential as a novel biomarker for regional parenchymal inflammation or thickening., (Copyright © 2011 Wiley-Liss, Inc.)

During an 18 day test, we measured the cytokine mRNA expression (Interleukin-1beta [IL-1beta], Interleukin-8 [IL-8], Interferon-gamma [IFN-gamma], Tumor Necrosis Factor-alpha [TNF-alpha]) of cells from bronchoalveolar lavage fluid [BALF] in five horses previously diagnosed with RAO, before and during challenge exposure, and after the desensitization phase which involved dexamethasone treatment and environmental modification. Simultaneously, the same cytokine mRNA expression of cells from BALF in four asymptomatic RAO-affected horses maintained outdoors was analyzed. An evident respiratory distress was observed in the challenge group within 3 days, with a significant overexpression of IL-8 and TNF-alpha mRNA on the ninth day. The pharmacological and environmental desensitization provided a down regulation of all the cytokines. No statistical modification characterized the cytokine kinetics of the asymptomatic horses maintained outdoors. A comparison for each time point of the cytokines between the exposed and unexposed horses showed no significant differences. The study suggested that a standardized exposure protocol and sampling time in experimental studies of RAO is mandatory for a correct comparison of the results obtained by different Authors. However, the absence of significant changes between the exposed and unexposed horses could depend on the lack of the sample uniformity since the evolution of the disease represents a continuum from a healthy to a pathological condition.

Human metapneumovirus (HMPV) is a paramyxovirus causing acute respiratory tract infections in humans. The effects of a monoclonal antibody (MAb 338, MedImmune, Inc.) directed against the HMPV fusion protein were assessed in vivo. Different groups of BALB/c mice received an intraperitoneal injection of 25 or 50mg/kg of MAb 338 either 24h before or 48h after viral infection. Lung samples were collected on days 5 and 42 after infection for determination of viral titers and histopathological changes. Pulmonary functions were also evaluated by plethysmography. On day 5 post-infection, lung viral titers were significantly decreased in mice treated with 25 or 50mg/kg before or after viral infection compared to HMPV-infected control mice. Similarly, HMPV copy numbers on day 42 were decreased for all prophylactic and therapeutic interventions. Histopathological changes were also less severe in all treated groups of mice on days 5 and 42 post-infection, correlating with decreased airways obstruction. Finally, on day 42, all treated groups had a significant decrease in airways hyperresponsiveness following treatment with MAb 338. Both prophylactic and, to a lesser extent, therapeutic administration of MAb 338 improved acute and late consequences of HMPV infection in a relevant mouse model., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A chronic respiratory load was produced in Wistar rats by tracheal binding to produce a twofold increase of pleural pressure oscillation amplitude during respiration. Eight weeks after the surgery, a higher proportion of type-I muscle fibers (MFI) in the costal diaphragm along with a greater MFI cross-section area and a higher succinate dehydrogenase activity in MFII in the crural diaphragm were observed. During recording the mechanical activity of ring preparations of diaphragm arteries under isometric conditions, an increase in endothelium-dependent relaxation was found, whereas endothelium-independent relaxation and arterial reactivity to noradrenaline did not change. Tracheal binding did not produce any changes of MF in the gastrocnemius muscle, but endothelium-dependent relaxation of gastrocnemius feed arteries was reduced. We conclude that chronic respiratory load affects the endothelial function in diaphragm arteries in a manner favorable for blood flow control in the diaphragm. Functional alterations in gastrocnemius arteries may be associated with the reduced locomotor activity of operated rats.

Objective: We prospectively examined the relationship between lung function and risk of type-2 diabetes and fatal and nonfatal coronary heart disease (CHD) events and investigated the hypothesis that inflammation may underlie these associations., Research Design and Methods: A prospective study of 4,434 men aged 40-59 years with no history of cardiovascular disease (CHD or stroke) or diabetes drawn from general practices in 24 British towns and followed up for 20 years., Results: There were 680 major CHD events (276 fatal, 404 nonfatal) and 256 incident type 2 diabetes during the 20 years follow-up. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) but not FEV(1)-to-FVC ratio were significantly and inversely associated with incident type 2 diabetes and fatal CHD events (not nonfatal events) after adjustment for age, potential confounders, and metabolic risk factors. The adjusted relative risk (RR) for type 2 diabetes (Quartile 1 vs. Quartile 4) were 1.59 (1.07-2.56) and 1.74 (1.16-2.61) for FVC and FEV(1), respectively (P = 0.03 and P = 0.04 for trend). The corresponding RR for fatal CHD were 1.48 (1.00-2.21) and 1.81 (1.19-2.76) (P = 0.002 and P = 0.0003 for trend). Lung function was significantly and inversely associated with C-reactive protein and interleukin-6; the inverse associations with type 2 diabetes for FVC and FEV(1) were attenuated after further adjustment for these factors (P = 0.14 and P = 0.11 for trend) but remained significant for fatal CHD (P = 0.03 and P = 0.01, respectively)., Conclusions: Restrictive rather than obstructive impairment of lung function is associated with incident type 2 diabetes (and fatal CHD) with both associations partially explained by traditional and metabolic risk factors and inflammation.

Cigarette smoking has been causally linked several diseases, primarily lung cancer and chronic obstructive lung disease (COPD). The diagnosis of COPD currently involves an assessment of smoking and/or occupational exposures, a history of cough, sputum and dyspnea and spirometric measures of airflow obstruction and since spirometric measures take long follow up times to detect significant changes, surrogate measures of outcome capable of predicting long-term health changes have been sought for. These include biomarkers of oxidative stress, inflammation and tissue damage in sputum, bronchoalveolar lavage, exhaled breath and serum. Published biomarker studies have not always accurately compared patients with COPD with age-matched cigarette smokers and non-smoking normal subjects without significant airflow limitation, also comparable for other exposures. Consequently, the interpretation of biomarker association studies is somewhat difficult. The purpose of this narrative review is to summarize publications reporting cellular, soluble or volatile marker of obstructive lung disease in populations of healthy non-smokers and healthy smokers, in order to determine whether the biomarkers examined could be specifically associated with exposure to tobacco smoke rather than with inflammation and airway hyper-reactivity. As induced sputum has been the most widely used investigative tool, this review has been aimed at assessing induced sputum biomarkers, referring to lung biopsy, bronchoalveolar lavage and exhaled breath markers as supporting evidence for biomarkers associations identified with induced sputum studies.

Chronic lung diseases such as asthma, chronic obstructive pulmonary disease and interstitial lung disease are characterized by inflammation and tissue remodeling processes that compromise pulmonary function. Adenosine is produced in the inflamed and damaged lung where it plays numerous roles in the regulation of inflammation and tissue remodeling. Extracellular adenosine serves as an autocrine and paracrine signaling molecule by engaging cell surface adenosine receptors. Preclinical and cellular studies suggest that adenosine plays an anti-inflammatory role in processes associated with acute lung disease, where activation of the A(2A)R and A(2B)R has promising implications for the treatment of these disorders. In contrast, there is growing evidence that adenosine signaling through the A(1)R, A(2B)R and A(3)R may serve pro-inflammatory and tissue remodeling functions in chronic lung diseases. This review discusses the current progress of research efforts and clinical trials aimed at understanding the complexities of these signaling pathway as they pertain to the development of treatment strategies for chronic lung diseases.

Recurrent airway obstruction (RAO) and insect bite hypersensitivity (IBH) are allergic conditions that are commonly encountered in the horse. Whilst complete allergen avoidance is an effective management strategy for both diseases, this may not be achievable in all cases and treatment options are therefore required. The inflammatory response is the main therapeutic target for glucocorticoids given to horses with RAO and severe cases of IBH, whilst the bronchodilators used in RAO primarily target airway smooth muscle. Such drugs are effective in most but not all individuals and there may be unwanted adverse effects. This article will review how knowledge of drug action and the pathogenesis of RAO and IBH can be utilised to identify potential targets for novel therapeutic agents that, in the longer term, may be safer and/or more effective in managing the allergic horse.