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Background Vaccine efficiency has a significant role in the public perception of vaccination. The current study was designed to evaluate the efficacy of COVID-19 vaccines (AZD-1222, Sputnik-V, Sinopharm, and Covaxin) and the effect of gender on vaccine efficacy. We evaluated the efficacy of these vaccines among 214 health care employees in Iran. Blood samples were taken from all participants on day 0 and 14 days after the second dose. Humoral responses were evaluated by the PT-SARS-CoV-2-Neutralizing-Ab-96. Results The frequency of immunized individuals in the Sputnik V and AZD-1222 groups was 91% and 86%, respectively. This rate was 61% and 67% for Sinopharm and Covaxin vaccines. A comparison of the results obtained from the effectiveness of the vaccines between female and male groups did not demonstrate a significant difference. Conclusion According to the results, Sputnik V and AZD-1222 vaccines were more effective than Sinopharm and Covaxin vaccines. Moreover, the effectiveness of these vaccines is not related to gender.

BACKGROUND: The first case of coronavirus disease 2019 (COVID-19) was reported in December 2019 in Wuhan, China. Healthcare workers (HCWs) are at high risk of acquiring and spreading the COVID-19 infection; using personal protective equipment (PPE) reduces the risk of COVID-19 infection in HCWs. OBJECTIVE: Our study aimed to investigate the seroprevalence of COVID-19 IgG, IgM antibodies among HCWs as well as identifying the factors associated with this seroprevalence. METHODS: This cross-sectional study was performed from July to August 2020 on healthcare workers at two COVID-19 referral hospitals of Birjand University of Medical Sciences. The level of COVID-19 IgG and IgM antibodies in sera was measured by commercial qualitative ELISA kits. RESULTS: In total, 192 individuals participated in the study: physicians (31.25%), nurses (30.2%). 84.2% of participants had contact with confirmed COVID-19 cases and among them 42.9 % of had close contact with COVID-19 patients for more than 3 months, and 31% reported close contact with more than 50 confirmed COVID-19 cases. Mask and gloves were the most frequently used personal protective equipment (PPE) with 92.4% and 77.2% of usage. CONCLUSIONS: The results of the current study showed high level of adherence to the use of PPE among HCWs as well as very low prevalence of seropositivity for of COVID-19 antibodies, hence confirming the effectiveness of PPE in protecting HCWs among COVVID-19 and possibly any other similar infections.

Background Vaccine efficiency has a significant role in the public perception of vaccination. The current study was designed to evaluate the efficacy of COVID-19 vaccines (AZD-1222, Sputnik-V, Sinopharm, and Covaxin) and the effect of age and gender on vaccine efficacy. We evaluated the efficacy of these vaccine between 214 health care employees in Iran. Blood samples were taken from all participants at day 0 and 14 days after the second dose. Humoral responses were evaluated by SARS-CoV 2 Neutralization Ab Detection kit. Results The frequency of immunized individuals in the Sputnik V and AZD-1222 groups was 95% and 93%, respectively. This rate was 73% and 70% for Sinopharm and Covaxin vaccines. Comparison of the results obtained from the effectiveness of the vaccines between female and male groups did not demonstration a significant difference. Moreover, comparison of the results obtained from the effectiveness of vaccines between age groups showed that the rate of immunization in participants

The emerging trend of therapies for chronic inflammatory lung diseases such as COPD has pointed toward the use of monoclonal humanized antibodies referred to as biologics. Several trials have been done to investigate their efficacy, dose-response, and effects and are still ongoing. Biologics such as mepolizumab, reslizumab, benralizumab, and dupilumab has been approved for use as therapies in severe asthma. However, there is no biologic approved or found therapeutically efficacious for the treatment of COPD. Besides, when it comes to the symptoms showing a conjoined effect of asthma and COPD, say, in diseases such as ACOS, there has been a minimal study or trials to cater to the disease. The definition and standard of the disease have been recently classified and agreed upon to diagnose patients. In interstitial lung diseases such as idiopathic pulmonary fibrosis, there are ongoing trials, and we are eagerly waiting to know their outcomes. This chapter summarizes the available biologics and their role in these pulmonary diseases.

We read with interest the article by Taxonera et al outlining a high incidence of diarrhoea in patients with inflammatory bowel disease (IBD) diagnosed with coronavirus disease 19 (COVID‐19).[1] The relationship between these symptoms and faecal calprotectin would be interesting to note. In patients without IBD and COVID‐19, faecal calprotectin was noted to be higher in patients with continuing than resolved diarrhoea, suggesting intestinal inflammation due to COVID‐19.[2]

Despite developments in pulmonary radiotherapy, radiation-induced lung toxicity remains a problem. More sensitive lung imaging able to increase the accuracy of diagnosis and radiotherapy may help reduce this problem. Super-paramagnetic iron oxide nanoparticles are used in imaging, but without further modification can cause unwanted toxicity and inflammation. Complex carbohydrate and polymer-based coatings have been used, but simpler compounds may provide additional benefits. Herein, we designed and generated super-paramagnetic iron oxide nanoparticles coated with the neutral natural dietary amino acid glycine (GSPIONs), to support non-invasive lung imaging and determined particle biodistribution, as well as understanding the impact of the interaction of these nanoparticles with lung immune cells. These GSPIONs were characterized to be crystalline, colloidally stable, with a size of 12 &plusmn, 5 nm and a hydrodynamic diameter of 84.19 &plusmn, 18 nm. Carbon, Hydrogen, Nitrogen (CHN) elemental analysis estimated approximately 20.2 &times, 103 glycine molecules present per nanoparticle. We demonstrated that it is possible to determine the biodistribution of the GSPIONs in the lung using three-dimensional (3D) ultra-short echo time magnetic resonance imaging. The GSPIONs were found to be taken up selectively by alveolar macrophages and neutrophils in the lung. In addition, the GSPIONs did not cause changes to airway resistance or induce inflammatory cytokines. Alveolar macrophages and neutrophils are critical regulators of pulmonary inflammatory diseases, including allergies, infections, asthma and chronic obstructive pulmonary disease (COPD). Therefore, pulmonary Magnetic Resonance (MR) imaging and preferential targeting of these lung resident cells by our nanoparticles offer precise imaging tools, which can be utilized to develop precision targeted radiotherapy as well as diagnostic tools for lung cancer, thereby having the potential to reduce the pulmonary complications of radiation.

The ovalbumin-induced (OVA) chronic allergic airways murine model is a well-established model for investigating pre-clinical therapies for chronic allergic airways diseases, such as asthma. Here, we examined the effects of several experimental compounds with potential anti-asthmatic effects including resveratrol (RV), relaxin (RLN), l-sulforaphane (LSF), valproic acid (VPA), and trichostatin A (TSA) using both a prevention and reversal model of chronic allergic airways disease. We undertook a novel analytical approach using focal plane array (FPA) and synchrotron Fourier-transform infrared (S-FTIR) microspectroscopic techniques to provide new insights into the mechanisms of action of these experimental compounds. Apart from the typical biological effects, S-FTIR microspectroscopy was able to detect changes in nucleic acids and protein acetylation. Further, we validated the reduction in collagen deposition induced by each experimental compound evaluated. Although this has previously been observed with conventional histological methods, the S-FTIR technique has the advantage of allowing identification of the type of collagen present. More generally, our findings highlight the potential utility of S-FTIR and FPA-FTIR imaging techniques in enabling a better mechanistic understanding of novel asthma therapeutics.

Asthma (chronic allergic airways disease, AAD) is characterized by airway inflammation (AI), airway remodeling (AWR) and airway hyperresponsiveness (AHR). Current treatments for AAD mainly focus on targeting AI and its contribution AHR, with the use of corticosteroids. However, there are no therapies for the direct treatment of AWR, which can contribute to airway obstruction, AHR and corticosteroid resistance independently of AI. The acute heart failure drug, serelaxin (recombinant human gene-2 relaxin, RLX), has potential anti-remodeling and anti-fibrotic effects but only when continuously infused or injected to overcome its short half-life. To alleviate this limitation, we conjugated serelaxin to biodegradable and noninflammatory nanoparticles (NP-RLX) and evaluated their therapeutic potential on measures of AI, AWR and AHR, when intranasally delivered to a preclinical rodent model of chronic AAD and TGF-β1-stimulated collagen gel contraction from asthma patient-derived myofibroblasts. NP-RLX was preferentially taken-up by CD206+-infiltrating and CD68+-tissue resident alveolar macrophages. Furthermore, NP-RLX ameliorated the chronic AAD-induced AI, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), chemokines (CCL2, CCL11) and the pro-fibrotic TGF-β1/IL-1β axis on AWR and resulting AHR, as well as human myofibroblast-induced collagen gel contraction, to a similar extent as unconjugated RLX. Hence, NP-RLX represents a novel strategy for treating the central features of asthma.

Introduction: Novel dilators are required to overcome the reduced efficacy of β2-agonists in inflamed remodelled airways in severe asthma. Relaxin (RLX), a Relaxin Family Peptide Receptor 1 (RXFP1) agonist, reverses established allergen-induced fibrosis and in vivo AHR (Royce, Endocrinology, 2009) and also elicits acute in vitro bronchodilation (Lam, Pharm & Ther, 2018). Aim: To assess if RLX potentiates relaxation to salbutamol (SALB) in inflamed, fibrotic mouse airways or human airways. Methods: Airway responses to SALB +/- RLX (100 nM) were visualised in PCLS from mice (control, 4 day house dust-mite (HDM), 8 weeks dox-induced TGFβ overexpression, n=6-16) or human lungs (unused donors, n=3). Inflammation, fibrosis and RXFP1 expression were assessed. Results: HDM increased BAL neutrophils (x104 cells/ml: control 0.9±0.1; HDM19.0±4.3) and eosinophils (control Conclusion: RLX potentiates relaxation to SALB in mouse airways under inflammatory and fibrotic conditions, and also has efficacy in human airways. RLX may oppose both acute and chronic aspects of airway pathology to improve outcomes in poorly controlled asthma.

BACKGROUND AND PURPOSE: There is growing interest in stem cell‐derived exosomes for their therapeutic and regenerative benefits given their manufacturing and regulatory advantages over cell‐based therapies. As existing fibrosis impedes the viability and efficacy of stem cell/exosome‐based strategies for treating chronic diseases, here we tested the effects of the anti‐fibrotic drug, serelaxin, on the therapeutic efficacy of human amnion epithelial cell (AEC)‐derived exosomes in experimental lung disease. EXPERIMENTAL APPROACH: Female Balb/c mice were subjected to either the 9.5‐week model of ovalbumin and naphthalene (OVA/NA)‐induced chronic allergic airway disease (AAD) or 3‐week model of bleomycin (BLM)‐induced pulmonary fibrosis; then administered increasing concentrations of AEC‐exosomes (5 μg or 25μg), with or without serelaxin (0.5mg/kg/day) for 7‐days. 1x10(6) AECs co‐administered with serelaxin over the corresponding time‐period were included for comparison in both models, as was pirfenidone‐treatment of the BLM model. Control groups received saline/corn oil or saline, respectively. KEY RESULTS: Both experimental models presented with significant tissue inflammation, remodelling, fibrosis and airway/lung dysfunction at the time‐points studied. While AEC‐exosome (5 μg or 25μg)‐administration alone demonstrated some benefits in each model, serelaxin was required for AEC‐exosomes (25μg) to rapidly normalise chronic AAD‐induced airway fibrosis and airway reactivity, and BLM‐induced lung inflammation, epithelial damage and subepithelial/basement membrane fibrosis. Combining serelaxin with AEC‐exosomes (25μg) also demonstrated broader protection compared to co‐administration of serelaxin with 1x10(6) AECs or pirfenidone. CONCLUSIONS AND IMPLICATIONS: Serelaxin enhanced the therapeutic efficacy of AEC‐exosomes in treating basement membrane‐induced fibrosis and related airway dysfunction.

The airway remodeling (AWR) associated with chronic allergic airways disease (AAD)/asthma contributes to irreversible airway obstruction. This study compared and combined the antiremodeling and other effects of induced pluripotent stem cell and mesenchymoangioblast-derived mesenchymal stem cells (MCA-MSCs) with the corticosteroid dexamethasone (Dex) in experimental chronic AAD/asthma. Female BALB/c mice subjected to 11 wk of ovalbumin (Ova)-induced chronic AAD were intranasally administered MCA-MSCs (1 × 106 cells/mouse; once weekly on wk 10 and 11), Dex (0.5 mg/ml; once daily for 2 wk), or both combined. MCA-MSC detection and changes in airway inflammation (AI), AWR, and airway hyperresponsiveness (AHR) were measured at the end of wk 11. Mice with chronic AAD had significant AI, goblet cell metaplasia, epithelial damage/thickening, aberrant TGF-β1 levels, subepithelial myofibroblast accumulation, airway/lung fibrosis, and AHR (all P < 0.001 vs. healthy controls). MCA-MSCs were detected in the lungs up to 5-7 d postadministration and demonstrated modest anti-inflammatory but striking antifibrotic effects against Ova-induced AAD, effectively decreasing AHR by 70-75% (all P < 0.05 vs. Ova alone). In comparison, Dex predominantly demonstrated anti-inflammatory effects, decreasing AHR by ∼30%. Combining MCA-MSCs with Dex provided equivalent protection to that offered by either therapy alone. MCA-MSCs reduce chronic AAD-induced AWR and AHR to a greater extent than Dex and may act as a suitable adjunct therapy to corticosteroid treatment of asthma.-Royce, S. G., Mao, W., Lim, R., Kelly, K., Samuel, C. S. iPSC- and mesenchymoangioblast-derived mesenchymal stem cells provide greater protection against experimental chronic allergic airways disease compared with a clinically used corticosteroid.

The peptide hormone relaxin is well-known for its anti-fibrotic actions in several organs, particularly from numerous studies conducted in animals. Acting through its cognate G protein-coupled receptor, relaxin family peptide receptor 1 (RXFP1), serelaxin (recombinant human relaxin) has been shown to consistently inhibit the excessive extracellular matrix production (fibrosis) that results from the aberrant wound-healing response to tissue injury and/or chronic inflammation, and at multiple levels. Furthermore, it can reduce established scarring by promoting the degradation of aberrant extracellular matrix components. Following on from the review that describes the mechanisms and signaling pathways associated with the extracellular matrix remodeling effects of serelaxin (Ng et al., 2019), this review focuses on newly identified tissue targets of serelaxin therapy in fibrosis, and the limitations associated with (se)relaxin research.

Summary Background The use of allergy tests to guide dietary treatment for eosinophilic oesophagitis (EoE) is controversial and data are limited. Aeroallergen sensitisation patterns and food triggers have been defined in Northern Hemisphere cohorts only. Aims To determine if allergy tests that are routinely available can predict food triggers in adult patients with EoE. To define the food triggers and aeroallergen sensitisation patterns in a novel Southern Hemisphere (Australian) cohort of patients. Methods Consecutive patients with EoE who elected to undergo dietary therapy were prospectively assessed, demographic details and atopic characteristics recorded, and allergy tests, comprising skin-prick and skin-patch tests, serum allergen-specific IgE, basophil activation test and serum food-specific IgG, were performed. Patients underwent a six-food elimination diet with a structured algorithm that included endoscopic and histological examination of the oesophagus a minimum of 2 weeks after each challenge. Response was defined as

Background and Purpose We evaluated the extent to which individual versus combination treatments that specifically target airway epithelial damage [trefoil factor-2 (TFF2)], airway fibrosis [serelaxin (RLX)] or airway inflammation [dexamethasone (DEX)] reversed the pathogenesis of chronic allergic airways disease (AAD). Experimental Approach Following induction of ovalbumin (OVA)-induced chronic AAD in 6–8 week female Balb/c mice, animals were i.p. administered naphthalene (NA) on day 64 to induce epithelial damage, then received daily intranasal administration of RLX (0.8 mg·mL−1), TFF2 (0.5 mg·mL−1), DEX (0.5 mg·mL−1), RLX + TFF2 or RLX + TFF2 + DEX from days 67–74. On day 75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. The control group was treated with saline + corn oil (vehicle for NA). Key Results OVA + NA-injured mice demonstrated significantly increased airway inflammation, airway remodelling (AWR) (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix accumulation and fibronectin deposition; total lung collagen concentration), and significantly reduced airway dynamic compliance (cDyn). RLX + TFF2 markedly reversed several measures of OVA + NA-induced AWR and normalized the reduction in cDyn. The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial extracellular matrix accumulation/fibronectin deposition and total lung collagen concentration (by 50–90%) and also normalized the reduction of cDyn. Conclusions and Implications Combining an epithelial repair factor and anti-fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma and may act as an effective adjunct therapy to anti-inflammatory corticosteroids.

Background Ultrathin unsedated transnasal gastroscopy (UTEG) has a number of advantages applicable to eosinophilic esophagitis (EoE) and has not been evaluated for this condition. Aim The aim of the study is to determine the feasibility of UTEG in patients with EoE and the acceptability of histological specimens obtained at biopsy. Method All patients with a diagnosis of EoE presenting to the outpatients department of two hospitals (Box Hill Hospital and The Alfred Hospital, Melbourne Australia) were asked to participate in the study. UTEG was performed on consenting individuals. Feasibility was determined by the success of nasal intubaton, patient perception according to post procedural survey, and adequacy of esophageal biopsies was assessed. Results Ninety-six consecutive patients with EoE were offered UTEG, and 24 agreed to participate in the study. Seventy-four UTEGs were performed over a period of 26 months (September 2012 to December 2014). Nineteen patients had repeat procedures. Successful nasal intubation occurred in 97% (72 of 74 procedures), and 21 of 24 (86%) described high satisfaction with the procedure and minimal discomfort, and would choose UTEG for future procedures. Mean duration was 5 min. Adverse events of epistaxis (three cases) and vomiting of liquid contents during the procedure (two cases) were recorded, cardiorespiratory parameters remaining normal in all patients. All completed procedures produced adequate histological samples. Conclusion In those who decide to undergo UTEG, it is a safe and well-tolerated procedure

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-γ (PPARγ) ligand, is a novel dilator of small airways in mouse precision cut lung slices (PCLS). In this study, relaxation to RGZ and β-adrenoceptor agonists were compared in trachea from naïve mice and guinea pigs and trachea and PCLS from a mouse model of chronic allergic airways disease (AAD). Airways were precontracted with methacholine before addition of PPARγ ligands [RGZ, ciglitazone (CGZ), or 15-deoxy-Δ12,14-prostaglandin J2 (15-deoxy-PGJ2)] or β-adrenoceptor agonists (isoprenaline and salbutamol). The effects of T0070907 and GW9662 (PPARγ antagonists) or epithelial removal on relaxation were assessed. Changes in force of trachea and lumen area in PCLS were measured using preparations from saline-challenged mice and mice sensitized ( days 0 and 14) and challenged with ovalbumin (3 times/wk, 6 wk). RGZ and CGZ elicited complete relaxation with greater efficacy than β-adrenoceptor agonists in mouse airways but not guinea pig trachea, while 15-deoxy-PGJ2 did not mediate bronchodilation. Relaxation to RGZ was not prevented by T0070907 or GW9662 or by epithelial removal. RGZ-induced relaxation was preserved in the trachea and increased in PCLS after ovalbumin-challenge. Although RGZ was less potent than β-adrenoceptor agonists, its effects were additive with salbutamol and isoprenaline and only RGZ maintained potency and full efficacy in maximally contracted airways or after allergen challenge. Acute PPARγ-independent, epithelial-independent airway relaxation to RGZ is resistant to functional antagonism and maintained in both trachea and PCLS from a model of chronic AAD. These novel efficacious actions of RGZ support its therapeutic potential in asthma when responsiveness to β-adrenoceptor agonists is limited.

This study determined if the anti-fibrotic drug, serelaxin (RLN), could augment human bone marrow-derived mesenchymal stem cell (MSC)-mediated reversal of airway remodeling and airway hyperresponsiveness (AHR) associated with chronic allergic airways disease (AAD/asthma). Female Balb/c mice subjected to the 9-week model of ovalbumin (OVA)-induced chronic AAD were either untreated or treated with MSCs alone, RLN alone or both combined from weeks 9–11. Changes in airway inflammation (AI), epithelial thickness, goblet cell metaplasia, transforming growth factor (TGF)-β1 expression, myofibroblast differentiation, subepithelial and total lung collagen deposition, matrix metalloproteinase (MMP) expression, and AHR were then assessed. MSCs alone modestly reversed OVA-induced subepithelial and total collagen deposition, and increased MMP-9 levels above that induced by OVA alone (all p

Introduction: Airway inflammatory disorders are prevalent diseases in need of better management and new therapeutics. Immunotherapies offer a solution to the problem of corticosteroid resistance. Areas covered: The current review focuses on lipopolysaccharide (Gram-negative bacterial endotoxin)-mediated inflammation in the lung and the animal models used to study related diseases. Endotoxin-induced lung pathology is usually initiated by antigen presenting cells (APC). We will discuss different subsets of APC including lung dendritic cells and macrophages, and their role in responding to endotoxin and environmental challenges. Expert commentary: The pharmacotherapeutic considerations to combat airway inflammation should cost-effectively improve quality of life with sustainable and safe strategies. Selectively targeting APCs in the lung offer the potential for a promising new strategy for the better management and treatment of inflammatory lung disease.

Background: Alternative dilator targets need to be identified for severe asthma, as excessive use of β2-adrenoceptor agonists causes desensitization and loss of efficacy. Free fatty acid receptors, FFAR1 and FFAR4, are highly expressed in mouse and human airways but their role in the regulation of contraction is unclear. Aims: To assess FFAR1/FFAR4 agonists as bronchodilators. Methods: Precision cut lung slices (PCLS) containing small airways (100-300 μm diam) were prepared to visualise changes in area in response to the dual FFAR1/FFAR4 agonists TUG891 (FFAR4-biased), GW9508 (FFAR1-biased) or salbutamol. Immunohistochemistry for FFARs was performed in airways from saline- and ovalbumin-challenged mice and from non-asthmatic and asthmatic subjects. Results: TUG891 and GW8508 caused slower relaxation than salbutamol but with greater efficacy in both mouse and human PCLS. β2-mediated relaxation was abolished with increasing pre-contraction with MCh or by overnight incubation with salbutamol. In contrast, responses to TUG891 and GW8508 were maintained in maximally contracted airways or after incubation with the same FFAR agonist or salbutamol. Expression of FFAR1 and FFAR4 was evident in airway epithelium and smooth muscle and unchanged after allergen challenge. Conclusions: FFAR1/FFAR4 agonists elicit airway relaxation under conditions that mimic severe asthma. Their activity profile relative to β2-agonists is favourable, showing resistance to homologous or heterologous desensitization and maintained efficacy in maximally contracted airways. Expression of FFAR1 and FFAR4 in asthmatic airways supports further investigation of these novel dilator targets.

The use of nanoparticles for pulmonary delivery poses challenges such as the presence of anatomical barriers and the loss of bioactive components. Excipients are often used to facilitate delivery. Excipients suitable for nanoparticle delivery are still being explored. Herein we introduce for the first time, spray-dried glycine microparticle-based excipients loaded with nanoparticles of the size range known to be taken up by alveolar macrophages. Using a microfluidic jet spray dryer, we produced glycine microparticles-based excipients which are spherical, uniform, cenospheric (hollow at core), and “coral-like” with average diameter of 60 ± 10 μm, 29 ± 0.8% porosity, and showed their effective loading with glycine coated iron oxide superparamagnetic nanoparticles (GSPIONs). Our loading protocol with nanoparticles further increased microsphere porosity and improved aerodynamic performance unlike the dense, solid commercial excipient, Lactohale200™. This demonstrates a feasible approach for delivery of such nanoparticles in the lung.

The most common therapies for asthma and other chronic lung diseases are anti-inflammatory agents and bronchodilators. While these drugs oppose disease symptoms, they do not reverse established structural changes in the airways and their therapeutic efficacy is reduced with increasing disease severity. The peptide hormone, relaxin, is a Relaxin Family Peptide Receptor 1 (RXFP1) receptor agonist with unique combined effects in the lung that differentiates it from these existing therapies. Relaxin has previously been reported to have cardioprotective effects in acute heart failure as well anti-fibrotic actions in several organs. This review focuses on recent experimental evidence of the beneficial effects of chronic relaxin treatment in animal models of airways disease demonstrating inhibition of airway hyperresponsiveness and reversal of established fibrosis, consistent with potential therapeutic benefit. Of particular interest, accumulating evidence demonstrates that relaxin can also acutely oppose contraction by reducing the release of mast cell-derived bronchoconstrictors and by directly eliciting bronchodilation. When used in combination, chronic and acute treatment with relaxin has been shown to enhance responsiveness to both glucocorticoids and β2-adrenoceptor agonists respectively. While the mechanisms underlying these beneficial actions remain to be fully elucidated, translation of these promising combined preclinical findings is critical in the development of relaxin as a novel alternative or adjunct therapeutic opposing multiple aspects of airway pathology in lung diseases.

Background Eosinophilic esophagitis (EoE) is a newly recognised condition that is apparently increasing in prevalence, and the aetiology is poorly understood. The role of aeroallergens in EoE is controversial, given the success of dietary therapy. Massive aeroallergen exposure leading to food bolus obstruction events (FBOE) has been described, and the diagnosis of EoE by esophageal biopsy noted to be more common in the pollen season according to previous case series. Aim To determine if a seasonal variation and a geographical variation occurred in EoE presenting as FBOE in adults, and to track the prevalence of FBOE and EoE over time. Method A retrospective case–control study analysis was performed from January 2002 to January 2012 to identify all FBOE in adults presenting to five tertiary hospitals in Melbourne, Australia. Endoscopy, histopathological reports, case notes and blood tests were examined, and postcodes recorded. Records of pollen counts were obtained. Cases were defined according to esophageal biopsy and grouped based on month of diagnosis. All other causes of FBOE served as controls. Results One thousand, one hundred and thirty-two FBOE were identified. Biopsies were only performed in 278 of these cases, and 85 patients were found to have EoE after biopsy. Patients with EoE were younger (mean age 38 years, range 18–72) compared with those with alternative diagnosis (mean age 64.4 range 22–92), more likely to be male (M : F = 4:1 compared with 1.68:1 ) and had a higher eosinophil count in venous blood. Overall no seasonality was demonstrated in FBOE secondary to any diagnosis, although the six cases of recurrent FBOE secondary to EoE mainly occurred in the grass pollen season in subsequent years. FBOE cases were evenly distributed throughout metropolitan Melbourne irrespective of population density. EoE as a percentage of FBOE increased over time. Conclusion Seasonal aeroallergens may be important for a subgroup of patients with EoE presenting as recurrent FBOE. Esophageal biopsies are performed in a minority of patients, representing a significant departure from ideal management and contributing to recurrent unnecessary FBOE. EoE is an increasingly important cause of FBOE.

BackgroundObesity and atrial fibrillation (AF) are public health issues with significant consequences.ObjectivesThis study sought to delineate the development of global electrophysiological and structural substrate for AF in sustained obesity.MethodsTen sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks; 10 lean sheep with carefully controlled weight served as controls. All sheep underwent electrophysiological and electroanatomic mapping; hemodynamic and imaging assessment (echocardiography and dual-energy x-ray absorptiometry); and histology and molecular evaluation. Evaluation included atrial voltage, conduction velocity (CV), and refractoriness (7 sites, 2 cycle lengths), vulnerability for AF, fatty infiltration, atrial fibrosis, and atrial transforming growth factor (TGF)-β1 expression.ResultsCompared with age-matched controls, chronically obese sheep demonstrated greater total body fat (p 0.8) or ERP heterogeneity (p > 0.3). Obesity was associated with more episodes (p = 0.02), prolongation (p = 0.01), and greater cumulative duration (p = 0.02) of AF. Epicardial fat infiltrated the posterior LA in the obese group (p < 0.001), consistent with reduced endocardial voltage in this region. Atrial fibrosis (p = 0.03) and TGF-β1 protein (p = 0.002) were increased in the obese group.ConclusionsSustained obesity results in global biatrial endocardial remodeling characterized by LA enlargement, conduction abnormalities, fractionated electrograms, increased profibrotic TGF-β1 expression, interstitial atrial fibrosis, and increased propensity for AF. Obesity was associated with reduced posterior LA endocardial voltage and infiltration of contiguous posterior LA muscle by epicardial fat, representing a unique substrate for AF.

Significance: Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. Critical Issues: In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFκB. Future Directions: Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anti-cancer compound alone, and in combination with clinically relevant therapeutic and management strategies. Antioxid. Redox Signal. 22, 1382–1424.

Eosinophilic esophagitis (EoE) is considered to be a chronic antigen-driven disease whereby food and/or aeroallergens induce a chronic inflammatory infiltrate in the esophagus, resulting in pathological hyperplasia of the epithelia and muscular layers, and fibrosis of the lamina propria (referred to collectively as remodelling) and the symptoms of dysphagia and food impaction. EoE shares features with other atopic conditions of asthma and atopic dermatitis, such as a TH2 cytokine milieu and a mixed inflammatory infiltrate of eosinophils, mast cells and lymphocytes. Relatively distinct features include the strong male predominance amongst adult patients, and the expression of the eosinophil chemokine eotaxin 3. Current first line treatments such as strict dietary modification and corticosteroids fail many patients. Looking forward, clarification of distinct genotype/phenotype associations, determining the reversibility of remodelling following treatment, and the development of new pharmacotherapies that target fibrotic pathways (as opposed to eosinophilic inflammation per se) or specifically improve barrier integrity appear relevant.

Inert-gas washout measurements using oxygen, in the lungs of small animals, are complicated by the continuous process of oxygen consumption (V̇o2). The multiple-breath nitrogen washout (MBNW) technique uses the alveolar slope to determine measures of ventilation inhomogeneity in the acinar ( Sacin) and conducting ( Scond) airway regions, as well as overall inhomogeneity, as determined by the lung clearance index (LCI). We hypothesized that measured ventilation inhomogeneity in the mouse lung while it is alive is in fact an artifact due to the high V̇o2 in proportion to alveolar gas volume (Va), and not ventilation inhomogeneity per se. In seven male C57BL/6 mice, MBNW was performed alive and postmortem to derive measures with and without the effect of gas exchange, respectively. These results were compared with those obtained from an asymmetric multibranch point mathematical model of the mouse lung. There was no statistical difference in Sacin and LCI between alive and postmortem results ( Sacin alive = 0.311 ± 0.043 ml−1 and Sacin postmortem = 0.338 ± 0.032 ml−1, LCI alive = 7.0 ± 0.1 and LCI postmortem = 7.0 ± 0.1). However, there was a significant decrease in Scond from 0.086 ± 0.005 ml−1 alive to 0.006 ± 0.002 ml−1 postmortem ( P < 0 .01). Model simulations replicated these results. Furthermore, in the model, as V̇o2 increased, so did the alveolar slope. These findings suggests that the MBNW measurement of Scond in the mouse lung is confounded by the effect of gas exchange, a result of the high V̇o2-to-Va ratio in this small animal, and not due to inhomogeneity within the airways.

BACKGROUND: The peptide hormone relaxin plays a key role in the systemic hemodynamic and renovascular adaptive changes that occur during pregnancy, which is linked to its antiremodelling effects. Serelaxin (a recombinant form of human gene-2 relaxin) has been shown to inhibit lung fibrosis in various disease models and reverse airway remodelling and airway hyperresponsiveness (AHR) in allergic airways disease (AAD). OBJECTIVE: Although continuous systemic delivery of exogenous serelaxin alleviates allergic fibrosis and AHR, more direct routes for administration into the lung have not been investigated. Thus, intranasal administration of serelaxin was evaluated for its ability to reverse airway remodelling and AHR associated with AAD. METHODS: Female Balb/c mice were subjected to a 9-week model of chronic AAD. Subgroups of animals (n = 12/group) were then treated intranasally with serelaxin (0.8 mg/mL) or vehicle once daily for 14 days (from weeks 9-11). Saline-sensitized/challenged mice treated with intranasal saline served as additional controls. Differential bronchoalveolar lavage (BAL) cell counts, ovalbumin (OVA)-specific IgE levels, tissue inflammation, parameters of airway remodelling and AHR were then assessed. RESULTS: Chronic AAD was associated with significant increases in differential BAL cell counts, OVA-specific IgE levels, inflammation, epithelial thickening, goblet cell metaplasia, TGF-β1 expression, epithelial Smad2 phosphorylation (pSmad2), subepithelial collagen thickness, total lung collagen concentration and AHR (all P

Asthma is a chronic respiratory disease characterised by airway inflammation, remodeling and hyperresponsiveness. The ability to replicate these asthma traits in the well-established ovalbumin induced chronic model of allergic airways disease is an important tool for asthma research and preclinical drug development. Here, spectra derived from focal plane array and Synchrotron-Fourier transform infrared maps were used to analyse biochemical changes in lung tissue from an ovalbumin-induced murine chronic allergic airways disease model. Analysis of the chemical maps resulted in distinct clusters and significant changes in the lipid and proteins regions of the spectra between the saline control and diseased lung tissue samples. Overall, the utilisation of conventional histological methodologies and Synchrotron infrared microspectroscopy has the ability to expand the characterisation of murine models of asthma.

Structural changes known as airway remodeling (AWR) characterize chronic/severe asthma and contribute to lung dysfunction. Thus, we assessed the in vivo efficacy of induced pluripotent stem cell and mesenchymoangioblast-derived mesenchymal stem cells (MCA-MSCs) on AWR in a murine model of chronic allergic airways disease (AAD)/asthma. Female Balb/c mice were subjected to a 9-wk model of ovalbumin (Ova)-induced chronic AAD and treated intravenously or intranasally with MCA-MSCs from weeks 9 to 11. Changes in airway inflammation (AI), AWR, and airway hyperresponsiveness (AHR) were assessed. Ova-injured mice presented with AI, goblet cell metaplasia, epithelial thickening, increased airway TGF-β1 levels, subepithelial myofibroblast and collagen accumulation, total lung collagen concentration, and AHR (all P < 0.001 vs. uninjured control group). Apart from epithelial thickness, all other parameters measured were significantly, although not totally, decreased by intravenous delivery of MCA-MSCs to Ova-injured mice. In comparison, intranasal delivery of MCA-MSCs to Ova-injured mice significantly decreased all parameters measured (all P < 0.05 vs. Ova group) and, most notably, normalized aberrant airway TGF-β1 levels, airway/lung fibrosis, and AHR to values measured in uninjured animals. MCA-MSCs also increased collagen-degrading gelatinase levels. Hence, direct delivery of MCA-MSCs offers great therapeutic benefit for the AWR and AHR associated with chronic AAD.-Royce, S. G., Rele, S., Broughton, B. R. S., Kelly, K., Samuel, C. S. Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease.

Relaxin is a naturally occurring peptide hormone that mediates systemic hemodynamic and renal adaptive changes during pregnancy and abrogates aberrant scar tissue formation (fibrosis) in diverse pathogeneses. However, its efficacy relative to renin–angiotensin system blockade, the most effective antifibrotic strategy currently available, is not known. We compared the individual versus combined antifibrotic effects of serelaxin (a recombinant form of human gene-2 relaxin) and the angiotensin-converting enzyme inhibitor enalapril, in preventative (started before injury) and therapeutic (treatment of established fibrosis) strategies, in a mouse model of isoprenaline-induced cardiac injury (at 17 days). Changes in systolic blood pressure, organ hypertrophy, and tissue remodeling/fibrosis were assessed. Pretreatment with serelaxin (0.5 mg/kg per day via subcutaneous administration) alone reduced cardiac fibrosis to a greater extent than enalapril (200 mg/L via drinking water; equivalent to 48 mg/kg per day) alone ( P P

Caveolin-1 (Cav-1) is the major protein present in invaginations of the plasma membrane of cells known as caveolae. Cav-1 is expressed in numerous resident and inflammatory cells implicated in the pathogenesis of asthma and chronic inflammatory respiratory diseases including chronic obstructive pulmonary disease. A remarkable repertoire of functions has been identified for Cav-1 and these extend to, and have relevance to, asthma and chronic inflammatory respiratory diseases. Important processes influenced by Cav-1 include inflammation, fibrosis, smooth muscle contractility, regulation of apoptosis and cell senescence as well as epithelial barrier function and homeostasis. A better understanding of Cav-1 may be useful in developing new therapies for chronic inflammatory respiratory diseases.

The importance of the role of histone deacetylase enzymes in the pathogenesis of asthma and chronic respiratory diseases is increasingly being recognized. Similarly, the potential clinical utility of histone deacetylase enzymes in the treatment of disease is emerging. In this review, the role of histone deacetylases (HDAC) and their inhibitors in asthma and chronic obstructive pulmonary disease is discussed.HDAC are able to catalyze the hydrolysis of acetyl groups on lysine residues of histones, causing the condensation and coiling of chromosomal DNA around histones, and therefore regulating gene expression. Histone deacetylase inhibitors act specifically or broadly on HDAC and also on nonhistone targets. Some have been used in the oncology therapeutic field for some years, but it is only more recently that they have been suggested in the treatment of asthma and other inflammatory lung diseases.Important developments have been made in the understanding of histone deacetylase expression in normal and diseased airways and pulmonary tissue as well as effects of histone deacetylase inhibitors on structural and inflammatory cells in the lung, including cell proliferation, differentiation and apoptosis and senescence. Many of these discoveries may have implications in addressing airway inflammation, airway remodeling and airway hyperresponsiveness in asthma.

It has been suggested that an inherent airway epithelial repair defect is the root cause of airway remodeling in asthma. However, the relationship between airway epithelial injury and repair, airway remodeling, and airway hyperresponsiveness (AHR) has not been directly examined. We investigated the contribution of epithelial damage and repair to the development of airway remodeling and AHR using a validated naphthalene (NA)-induced murine model of airway injury. In addition, we examined the endogenous versus exogenous role of the epithelial repair peptide trefoil factor 2 (TFF2) in disease pathogenesis. A single dose of NA (200 mg/kg in 10 ml/kg body weight corn oil [CO] vehicle, intraperitoneally) was administered to mice. Control mice were treated with CO (10 ml/kg body weight, intraperitoneally). At 12, 24, 48, and 72 hours after NA or CO injection, AHR and various measures of airway remodeling were examined by invasive plethysmography and morphometric analyses, respectively. TFF2-deficient mice and intranasal treatment were used to examine the role of the epithelial repair peptide. NA treatment induced denudation and apoptosis of airway epithelial cells, goblet cell metaplasia, elevated AHR, and increased levels of endogenous TFF2. Airway epithelial changes peaked at 12 hours after NA treatment, whereas airway remodeling changes were observed from 48 hours. TFF2 was protective against epithelial damage and induced remodeling and was found to mediate organ protection via a platelet-derived growth factor-associated mechanism. Our findings directly demonstrate the contribution of epithelial damage to airway remodeling and AHR and suggest that preventing airway epithelial damage and promoting epithelial repair may have therapeutic implications for asthma treatment.

Background: The intestinal vitamin D receptor (VDR) remains poorly characterized in patients with inflammatory bowel disease (IBD). Methods: Colonoscopic biopsies and intestinal resection specimens from the terminal ileum, ascending and sigmoid colon, from patients with and without IBD, were analyzed for VDR mRNA quantification by polymerase chain reaction, and protein localization and semi-quantification by immunohistochemistry. The relationship between VDR and intestinal inflammation, serum 25(OH)D and oral vitamin D intake was elicited. Results: A total of 725 biopsies from 20 patients with Crohn’s disease (CD), 15 with ulcerative colitis (UC) and 14 non-IBD controls who underwent colonoscopy were studied. VDR gene expression and protein staining intensity was similar across all three groups, and across the intestinal segments. Sigmoid colon VDR mRNA expression inversely correlated with faecal calprotectin ( r = −0.64, p = 0.026) and histological score ( r = −0.67, p = 0.006) in UC, and histological score ( r = −0.58, p = 0.019) in patients with CD. VDR staining intensity was higher in quiescent than diseased segments. No relationship with serum 25(OH)D or oral vitamin D intake was noted. Immunohistochemical staining of 28 intestinal resection specimens from 15 patients (5 each with CD, UC and non-IBD controls) showed diffuse VDR staining in the mucosa, submucosa and circular muscle. Conclusions: VDR transcript expression and protein staining intensity are inversely related to inflammation in IBD, but unrelated to serum 25(OH)D, and similar to non-IBD controls. Strategies to upregulate intestinal VDR, potentially translating to modulation of disease activity, require investigation.

Background and Purpose The conversion of plasminogen into plasmin by interstitial urokinase plasminogen activator (uPA) is potentially important in asthma pathophysiology. In this study, the effect of uPA-mediated plasminogen activation on airway smooth muscle (ASM) cell proliferation was investigated. Experimental Approach Human ASM cells were incubated with plasminogen (0.5–50 μg·mL−1) or plasmin (0.5–50 mU·mL−1) in the presence of pharmacological inhibitors, including UK122, an inhibitor of uPA. Proliferation was assessed by increases in cell number or MTT reduction after 48 h incubation with plasmin(ogen), and by earlier increases in [3H]-thymidine incorporation and cyclin D1 expression. Key Results Plasminogen (5 μg·mL−1)-stimulated increases in cell proliferation were attenuated by UK122 (10 μM) or by transfection with uPA gene-specific siRNA. Exogenous plasmin (5 mU·mL−1) also stimulated increases in cell proliferation. Inhibition of plasmin-stimulated ERK1/2 or PI3K/Akt signalling attenuated plasmin-stimulated increases in ASM proliferation. Furthermore, pharmacological inhibition of cell signalling mediated by the EGF receptor, a receptor trans-activated by plasmin, also reduced plasmin(ogen)-stimulated cell proliferation. Knock down of annexin A2, which has dual roles in both plasminogen activation and plasmin-signal transduction, also attenuated ASM cell proliferation following incubation with either plasminogen or plasmin. Conclusions and Implications Plasminogen stimulates ASM cell proliferation in a manner mediated by uPA and involving multiple signalling pathways downstream of plasmin. Targeting mediators of plasminogen-evoked ASM responses, such as uPA or annexin A2, may be useful in the treatment of asthma.

Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown.To examine the effect of progressive weight gain on the substrate for AF.Thirty sheep were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor.Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P.001), increase in conduction heterogeneity index (P.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels.Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF.

The extent to which individual vs combination treatments that specifically targeted epithelial damage (trefoil factor-2, TFF2), fibrosis (serelaxin, RLX) or inflammation (AI; dexamethasone, DEX) reversed the pathogenesis of chronic allergic airways disease (AAD) was assessed. Following induction of a 9-week ovalbumin (OVA)-induced model of chronic AAD in 6-8week old female Balb/c mice, animals were i.p-administered with naphthalene (NA); then received daily i.n-administration of saline (vehicle); RLX (0.8mg/ml); TFF2 (0.5mg/ml); DEX (0.5mg/ml); RLX+TFF2; or RLX+TFF2+DEX from d67-74. On d75, lung function was assessed by plethysmography, beforelung tissue was taken for analysis. A control group treated with saline+corn oil (Saline/CO; vehicle for NA) was included. A significant increase in AI, epithelial damage/thickness; myofibroblast differentiation; subepithelial/total collagen and fibronectin deposition; and a significant reduction in airway dynamic compliance (cDyn) was observed in OVA+NA injured mice (all p

Bronchopulmonary dysplasia (BPD) is a chronic disease of extreme prematurity that has serious long-term consequences including increased asthma risk. We earlier identified IL-1 receptor antagonist (IL-1Ra) as a potent inhibitor of murine BPD induced by combining perinatal inflammation (intraperitoneal LPS to pregnant dams) and exposure of pups to hyperoxia (fraction of inspired oxygen = 0.65). In this study, we determined whether airway remodeling and hyperresponsiveness similar to asthma are evident in this model, and whether IL-1Ra is protective. During 28-day exposure to air or hyperoxia, pups received vehicle or 10 mg/kg IL-1Ra by daily subcutaneous injection. Lungs were then prepared for histology and morphometry of alveoli and airways, or for real-time PCR, or inflated with agarose to prepare precision-cut lung slices to visualize ex vivo intrapulmonary airway contraction and relaxation by phase-contrast microscopy. In pups reared under normoxic conditions, IL-1Ra treatment did not affect alveolar or airway structure or airway responses. Pups reared in hyperoxia developed a severe BPD-like lung disease, with fewer, larger alveoli, increased subepithelial collagen, and increased expression of α-smooth muscle actin and cyclin D1. After hyperoxia, methacholine elicited contraction with similar potency but with an increased maximum reduction in lumen area (air, 44%; hyperoxia, 89%), whereas dilator responses to salbutamol were maintained. IL-1Ra treatment prevented hyperoxia-induced alveolar disruption and airway fibrosis but, surprisingly, not the increase in methacholine-induced airway contraction. The current study is the first to demonstrate ex vivo airway hyperreactivity caused by systemic maternal inflammation and postnatal hyperoxia, and it reveals further preclinical mechanistic insights into IL-1Ra as a treatment targeting key pathophysiological features of BPD.