Factors affecting 12-month unplanned readmissions for chronic obstructive pulmonary disease patients: the effect of mental disorders in an Australian cohort.

BACKGROUND: Many individuals with chronic obstructive pulmonary disease (COPD) experience frequent hospitalization and readmissions, which is burdensome on the health system. This study aims to investigate factors associated with unplanned readmissions and mortality following a COPD-related hospitalization over a 12-month period in Australia, focusing on mental disorders and accounting for the acute phase of the COVID-19 pandemic. METHODS: A retrospective cohort study using linked hospitalization and mortality records identified individuals aged ≥40 years who had at least one hospital admission with a principal diagnosis of COPD between 2014 and 2020 in New South Wales, Australia. A semi-competing risk analysis was conducted to examine factors associated with unplanned readmission and mortality. RESULTS: Adults with a mental disorder diagnosis, specifically anxiety, had a higher risk of 12-month unplanned readmission. Individuals with anxiety and dementia also had a higher risk of mortality pre- and post-unplanned readmission. Individuals who were admitted during the acute phase of the COVID-19 pandemic period had lower risk of unplanned readmission, but higher risk of mortality without unplanned readmission. CONCLUSION: Interventions aimed at reducing admissions should consider adults living with mental disorders such as anxiety or dementia to improve healthcare delivery and health outcomes for individuals living with COPD.

Model analysis of multiple breath nitrogen washout data: robustness to variations in breathing pattern.

We recently developed a model-based method for analyzing multiple breath nitrogen washout data that does not require identification of Phase-III. In the present study, we assessed the effect of irregular breathing patterns on the intra-subject variabilities of the model parameters. Nitrogen fraction at the mouth was measured in 18 healthy and 20 asthmatic subjects during triplicate performances of multiple breath nitrogen washout, during controlled (target tidal volume 1 L at 8-12 breaths per minute) and free (unrestricted) breathing. The parameters Scond, Sacin and functional residual capacity (FRC) were obtained by conventional analysis of the slope of Phase-III. Fitting the model to the washout data provided functional residual capacity (FRCM), dead space volume (VD), the coefficient of variation of regional specific ventilation ([Formula: see text]), and the model equivalent of Sacin (Sacin-M). Intra-participant coefficients of variation for the model parameters for both health and asthma were FRCM < 5.2%, VD < 5.4%, [Formula: see text] < 9.0%, and Sacin-M < 45.6% for controlled breathing, and FRCM < 4.6%, VD < 5.3%, [Formula: see text] < 13.2%, and Sacin-M < 103.2% for free breathing. The coefficients of variation limits for conventional parameters were FRC < 6.1%, with Scond < 73.6% and Sacin < 49.2% for controlled breathing and Scond < 35.0% and Sacin < 74.4% for free breathing. The model-fitting approach to multiple breath nitrogen washout analysis provides a measure of regional ventilation heterogeneity in [Formula: see text] that is less affected by irregularities in the breathing pattern than its corresponding Phase-III slope analysis parameter Scond.

Pulmonary function testing during SARS-CoV-2: An ANZSRS/TSANZ position statement.

The Thoracic Society of Australia and New Zealand (TSANZ) and the Australian and New Zealand Society of Respiratory Science (ANZSRS) commissioned a joint position paper on pulmonary function testing during coronavirus disease 2019 (COVID-19) in July 2021. A working group was formed via an expression of interest to members of both organizations and commenced work in September 2021. A rapid review of the literature was undertaken, with a 'best evidence synthesis' approach taken to answer the research questions formed. This allowed the working group to accept findings of prior relevant reviews or societal document where appropriate. The advice provided is for providers of pulmonary function tests across all settings. The advice is intended to supplement local infection prevention and state, territory or national directives. The working group's key messages reflect a precautionary approach to protect the safety of both healthcare workers (HCWs) and patients in a rapidly changing environment. The decision on strategies employed may vary depending on local transmission and practice environment. The advice is likely to require review as evidence grows and the COVID-19 pandemic evolves. While this position statement was contextualized specifically to the COVID-19 pandemic, the working group strongly advocates that any changes to clinical/laboratory practice, made in the interest of optimizing the safety and well-being of HCWs and patients involved in pulmonary function testing, are carefully considered in light of their potential for ongoing use to reduce transmission of other droplet and/or aerosol borne diseases.

Therapeutic efficacy of IL-17A neutralization with corticosteroid treatment in a model of antigen-driven mixed-granulocytic asthma.

Many mouse models of allergic asthma exhibit eosinophil-predominant cellularity rather than the mixed-granulocytic cytology in steroid-unresponsive severe disease. Therefore, we sought to implement a novel mouse model of antigen-driven, mixed-granulocytic, severe allergic asthma to determine biomarkers of the disease process and potential therapeutic targets. C57BL/6J wild-type, interleukin-6 knockout (IL-6-/-), and IL-6 receptor knockout (IL-6R-/-), mice were injected with an emulsion of complete Freund's adjuvant and house dust mite antigen (CFA/HDM) on day 1. Dexamethasone, a lymphocyte-depleting biological, or anti-IL-17A was administered during the intranasal HDM challenge on days 19-22. On day 23, the CFA/HDM model elicited mixed bronchoalveolar lavage (BAL) cellularity (typically 80% neutrophils and 10% eosinophils), airway hyperresponsiveness (AHR) to methacholine, diffusion impairment, lung damage, body weight loss, corticosteroid resistance, and elevated levels of serum amyloid A (SAA), pro-inflammatory cytokines, and T helper type 1/ T helper type 17 (Th1/Th17) cytokines compared with eosinophilic models of HDM-driven allergic airway disease. BAL cells in IL-6- or IL-6R-deficient mice were predominantly eosinophilic and associated with elevated T helper type 2 (Th2) and reduced Th1/Th17 cytokine production, along with an absence of SAA. Nevertheless, AHR remained in IL-6-deficient mice even when dexamethasone was administered. However, combined administration of anti-IL-17A and systemic corticosteroid significantly attenuated both overall and neutrophilic airway inflammation and also reduced AHR and body weight loss. Inhibition of IL-17A combined with systemic corticosteroid treatment during antigen-driven exacerbations may provide a novel therapeutic approach to prevent the pathological pulmonary and constitutional changes that greatly impact patients with the mixed-granulocytic endotype of severe asthma.

The need for physiological phenotyping to develop new drugs for airways disease.

Asthma and COPD make up the majority of obstructive airways diseases (OADs), which affects ∼11 % of the population. The main drugs used to treat OADs have not changed in the past five decades, with advancements mainly comprising variations on existing treatments. The recent biologics are beneficial to only specific subsets of patients. Part of this may lie in our inability to adequately characterise the tremendous heterogeneity in every aspect of OAD. The field is currently moving towards the concept of personalised medicine, based on a focus on treatable traits that are objective, measurable and modifiable. We propose extending this concept via the use of emerging clinical tools for comprehensive physiological phenotyping. We describe, based on published data, the evidence for the use of functional imaging, gas washout techniques and oscillometry, as well as potential future applications, to more comprehensively assess and predict treatment response in OADs. In this way, we hope to demonstrate how physiological phenotyping tools will improve the way in which drugs are prescribed, but most importantly, will facilitate development of new drugs for OADs.

Scientists in pyjamas: characterising the working arrangements and productivity of Australian medical researchers during the COVID-19 pandemic.

OBJECTIVE: To characterise the working arrangements of medical research scientists and support staff in Australia during the COVID-19 pandemic, and to evaluate factors (in particular: wearing pyjamas) that influence the self-assessed productivity and mental health of medical institute staff working from home. DESIGN: Prospective cohort survey study, 30 April - 18 May 2020. SETTING, PARTICIPANTS: Staff (scientists and non-scientists) and students at five medical research institutes in Sydney, New South Wales. MAIN OUTCOME MEASURES: Self-assessed overall and task-specific productivity, and mental health. RESULTS: The proportions of non-scientists and scientists who wore pyjamas during the day were similar (3% v 11%; P = 0.31). Wearing pyjamas was not associated with differences in self-evaluated productivity, but was significantly associated with more frequent reporting of poorer mental health than non-pyjama wearers while working from home (59% v 26%; P < 0.001). Having children in the home were significantly associated with changes in productivity. Larger proportions of people with toddlers reported reduced overall productivity (63% v 32%; P = 0.008), and reduced productivity in writing manuscripts (50% v 17%; P = 0.023) and data analysis (63% v 23%; P = 0.002). People with primary school children more frequently reported reduced productivity in writing manuscripts (42% v 16%; P = 0.026) and generating new ideas (43% v 19%; P = 0.030). On a positive note, the presence of children in the home was not associated with changes in mental health during the pandemic. In contrast to established researchers, early career researchers frequently reported reduced productivity while working at home. CONCLUSIONS: Our findings are probably applicable to scientists in other countries. They may help improve work-from-home policies by removing the stigma associated with pyjama wearing during work and by providing support for working parents and early career researchers.

Ventilation heterogeneity and oscillometry predict asthma control improvement following step-up inhaled therapy in uncontrolled asthma.

BACKGROUND AND OBJECTIVE: Abnormal peripheral airway function is an important feature of asthma and relates to asthma symptoms and poor asthma control. We aimed to determine whether peripheral airway function, as measured by forced oscillatory impedance and multiple-breath nitrogen washout (MBNW), relates to symptom improvement in asthmatic participants with uncontrolled asthma, after stepping up to high-dose ICS/LABA treatment. METHODS: A total of 19 subjects (14 females, mean age: 29.9 ± 13.6 years) with uncontrolled asthma, as defined by an ACQ5 > 1.5, taking 500 µg/day fluticasone equivalent or less, underwent spirometry, plethysmography, fractional exhaled FeNO, forced oscillatory resistance (Rrs5Hz ) and reactance (Xrs5Hz ), and indices of MBNW ventilation heterogeneity (lung clearance index (LCI), diffusion-convection-dependent (Sacin) and convection-dependent (Scond)). Measurements were made before and after 8 weeks of treatment with fluticasone/formoterol combination inhaler 250/10 µg, 2 puffs twice daily. RESULTS: Treatment improved ACQ5 (P = 0.0002), FEV1 (P = 0.02), FVC (P = 0.04), FeNO (P = 0.0008), Xrs5Hz (P = 0.01), LCI (P = 0.0002), Sacin (P = 0.006) and Scond (P = 0.01). At baseline, ACQ5 correlated with Xrs5Hz (rs = 0.52, P = 0.03) and Rrs5Hz (rs = 0.55, P = 0.02). The improvement in ACQ5 was predicted by more abnormal baseline LCI (P = 0.03), Scond (P = 0.02) and Rrs5Hz (P = 0.006). Baseline Scond was the best predictor of a clinically meaningful improvement in asthma control (ΔACQ > 0.5, ROC-AUC = 0.91, P = 0.007). CONCLUSION: Step-up to high-dose combination treatment in uncontrolled asthma is associated with improved peripheral airway function as measured by Xrs5Hz and MBNW. Baseline MBNW and FOT parameters correlated with the improvement in symptoms and may predict a positive response to up-titration in uncontrolled asthmatic patients.

Reduced lung elastic recoil and fixed airflow obstruction in asthma.

BACKGROUND AND OBJECTIVE: Fixed airflow obstruction (FAO) in asthma occurs despite optimal inhaled treatment and no smoking history, and remains a significant problem, particularly with increasing age and duration of asthma. Increased lung compliance and loss of lung elastic recoil has been observed in older people with asthma, but their link to FAO has not been established. We determined the relationship between abnormal lung elasticity and airflow obstruction in asthma. METHODS: Non-smoking asthmatic subjects aged >40 years, treated with 2 months of high-dose inhaled corticosteroid/long-acting beta-agonist (ICS/LABA), had FAO measured by spirometry, and respiratory system resistance at 5 Hz (Rrs5 ) and respiratory system reactance at 5 Hz (Xrs5 ) measured by forced oscillation technique. Lung compliance (K) and elastic recoil (B/A) were calculated from pressure-volume curves measured by an oesophageal balloon. Linear correlations between K and B/A, and forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC), Rrs5 and Xrs5 were assessed. RESULTS: Eighteen subjects (11 males; mean ± SD age: 64 ± 8 years, asthma duration: 39 ± 22 years) had moderate FAO measured by spirometry ((mean ± SD z-score) post-bronchodilator FEV1 : -2.2 ± 0.5, FVC: -0.7 ± 1.0, FEV1 /FVC: -2.6 ± 0.7) and by increased Rrs5 (median (IQR) z-score) 2.7 (1.9 to 3.2) and decreased Xrs5 : -4.1(-2.4 to -7.3). Lung compliance (K) was increased in 9 of 18 subjects and lung elastic recoil (B/A) reduced in 5 of 18 subjects. FEV1 /FVC correlated negatively with K (rs = -0.60, P = 0.008) and Rrs5 correlated negatively with B/A (rs = -0.52, P = 0.026), independent of age. Xrs5 did not correlate with lung elasticity indices. CONCLUSION: Increased lung compliance and loss of elastic recoil relate to airflow obstruction in older non-smoking asthmatic subjects, independent of ageing. Thus, structural lung tissue changes may contribute to persistent, steroid-resistant airflow obstruction. CLINICAL TRIAL REGISTRATION: ACTRN126150000985583 at anzctr.org.au (UTN: U1111-1156-2795).

Electronic cigarettes: A position statement from the Thoracic Society of Australia and New Zealand.

The TSANZ develops position statements where insufficient data exist to write formal clinical guidelines. In 2018, the TSANZ addressed the question of potential benefits and health impacts of electronic cigarettes (EC). The working party included groups focused on health impacts, smoking cessation, youth issues and priority populations. The 2018 report on the Public Health Consequences of E-Cigarettes from the United States NASEM was accepted as reflective of evidence to mid-2017. A search for papers subsequently published in peer-reviewed journals was conducted in August 2018. A small number of robust and important papers published until March 2019 were also identified and included. Groups identified studies that extended, modified or contradicted the NASEM report. A total of 3793 papers were identified and reviewed, with summaries and draft position statements developed and presented to TSANZ membership in April 2019. After feedback from members and external reviewers, a collection of position statements was finalized in December 2019. EC have adverse lung effects and harmful effects of long-term use are unknown. EC are unsuitable consumer products for recreational use, part-substitution for smoking or long-term exclusive use by former smokers. Smokers who require support to quit smoking should be directed towards approved medication in conjunction with behavioural support as having the strongest evidence for efficacy and safety. No specific EC product can be recommended as effective and safe for smoking cessation. Smoking cessation claims in relation to EC should be assessed by established regulators.

BMI but not central obesity predisposes to airway closure during bronchoconstriction.

BACKGROUND AND OBJECTIVE: Obesity produces restrictive effects on lung function. We previously reported that obese patients with asthma exhibit a propensity towards small airway closure during methacholine challenge which improved with weight loss. We hypothesized that increased abdominal adiposity, a key contributor to the restrictive effects of obesity on the lung, mediates this response. This study investigates the effect of body mass index (BMI) versus waist circumference (WC) on spirometric lung function, sensitivity to airway narrowing and closure, and airway closure during bronchoconstriction in patients with asthma. METHODS: Participants underwent spirometry and methacholine challenge. Sensitivity to airway closure and narrowing was assessed from the dose-response slopes of the forced vital capacity (FVC) and the ratio of forced expiratory volume in 1 s (FEV1 ) to FVC, respectively. Airway closure during bronchoconstriction (closing index) was computed as the percent reduction in FVC divided by the percent reduction in FEV1 at maximal bronchoconstriction. RESULTS: A total of 116 asthmatic patients (56 obese) underwent methacholine challenge. Spirometric lung function was inversely related to WC (P < 0.05), rather than BMI. Closing index increased significantly during bronchoconstriction in obese patients and was related to increasing BMI (P = 0.01), but not to WC. Sensitivity to airway closure and narrowing was not associated with BMI or WC. CONCLUSION: Although WC is associated with restrictive effects on baseline lung function, increased BMI, rather than WC, predisposes to airway closure during bronchoconstriction. These findings suggest that obesity predisposes to airway closure during bronchoconstriction through mechanisms other than simple mass loading.

Older age and obesity are associated with increased airway closure in response to methacholine in patients with asthma.

BACKGROUND AND OBJECTIVE: The reduction of forced expiratory volume in 1 s (FEV1 ) in response to methacholine challenge in asthma may reflect two components: airway narrowing, assessed by the change in FEV1 /forced vital capacity (FVC), and airway closure, assessed by the change in FVC. The purpose of this study was to determine the degree and determinants of airway closure in response to methacholine in a large group of asthmatic patients participating in studies conducted by the American Lung Association-Airways Clinical Research Centers (ALA-ACRC). METHODS: We used the methacholine challenge data from participants in five studies of the ALA-ACRC to determine the closing index, defined as the contribution of airway closure to the decrease in FEV1 , and calculated as %ΔFVC/%ΔFEV1 . RESULTS: There were a total of 936 participants with asthma, among whom the median closing index was 0.67 relative to that of a published healthy population of 0.54. A higher closing index was associated with increased age (10-year increments) (0.04, 95% CI = 0.02, 0.05, P < 0.005) and obesity (0.07, 95% CI = 0.03, 0.10, P < 0.001). There was no association between the closing index and asthma control. CONCLUSION: Our findings confirm that airway closure in response to methacholine occurs in a large, diverse population of asthmatic participants, and that increased airway closure is associated with older age and obesity. These findings suggest that therapies targeting airway closure may be important in patients with a high closing index.

IL-1/inhibitory κB kinase ε-induced glycolysis augment epithelial effector function and promote allergic airways disease.

BACKGROUND: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma. OBJECTIVES: We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma. METHODS: We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis. RESULTS: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1ß into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1ß or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1ß- or IL-1α-mediated proinflammatory responses and the stimulatory effects of IL-1ß on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1ß and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1ß levels, and lactate content correlated negatively with lung function. CONCLUSIONS: Collectively, these findings demonstrate that IL-1ß/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.

Maternal E-Cigarette Exposure in Mice Alters DNA Methylation and Lung Cytokine Expression in Offspring.

E-cigarette usage is increasing, especially among the young, with both the general population and physicians perceiving them as a safe alternative to tobacco smoking. Worryingly, e-cigarettes are commonly used by pregnant women. As nicotine is known to adversely affect children in utero, we hypothesized that nicotine delivered via e-cigarettes would negatively affect lung development. To test this, we developed a mouse model of maternal e-vapor (nicotine and nicotine-free) exposure and investigated the impact on the growth and lung inflammation in both offspring and mothers. Female Balb/c mice were exposed to e-fluid vapor containing nicotine (18 mg/ml nicotine E-cigarette [E-cig18], equivalent to two cigarettes per treatment, twice daily,) or nicotine free (E-cig0 mg/ml) from 6 weeks before mating until pups weaned. Male offspring were studied at Postnatal Day (P) 1, P20, and at 13 weeks. The mothers were studied when the pups weaned. In the mothers' lungs, e-cigarette exposure with and without nicotine increased the proinflammatory cytokines IL-1ß, IL-6, and TNF-α. In adult offspring, TNF-α protein levels were increased in both E-cig18 and E-cig0 groups, whereas IL-1ß was suppressed. This was accompanied by global changes in DNA methylation. In this study, we found that e-cigarette exposure during pregnancy adversely affected maternal and offspring lung health. As this occurred with both nicotine-free and nicotine-containing e-vapor, the effects are likely due to by-products of vaporization rather than nicotine.

Peripheral airway dysfunction and relationship with symptoms in smokers with preserved spirometry.

BACKGROUND AND OBJECTIVE: Smokers develop respiratory symptoms and peripheral airway dysfunction even when spirometry is preserved. Multiple breath nitrogen washout (MBNW) and impulse oscillometry system (IOS) are potentially useful measures of peripheral airway function but they have not been compared in such subjects. We hypothesized that MBNW and IOS are jointly abnormal in smokers with normal spirometry and that these abnormalities relate to respiratory symptoms. METHODS: Eighty smokers with normal spirometry completed a symptom questionnaire, had ventilation heterogeneity in diffusion (Sacin) and convection-dependent (Scond) airways and trapped gas volume at functional residual capacity as a percentage of vital capacity (%VtrFRC/VC) measured by MBNW. Respiratory resistance and reactance at 5 and 20 Hz were measured using IOS. RESULTS: Respiratory symptoms were reported in 55 (68%) subjects. Forty (50%) subjects had at least one abnormal MBNW parameter, predominantly in Sacin. Forty-one (51%) subjects had at least one abnormal IOS parameter, predominantly in resistance. Sixty-one (76%) subjects had an abnormality in either MBNW or IOS. Chronic bronchitis symptoms were associated with an increased Scond, while wheeze was associated with lower spirometry and an increased resistance. Abnormalities in MBNW and IOS parameters were unrelated to each other. CONCLUSIONS: Respiratory symptoms and peripheral airway dysfunction are common in smokers with normal spirometry. Symptoms of chronic bronchitis related to conductive airway abnormalities, while wheeze was related to spirometry and IOS. The clinical significance of abnormalities in peripheral airway function in smokers remains undetermined.

Airway smooth muscle tone increases airway responsiveness in healthy young adults.

Force adaptation, a process whereby sustained spasmogenic activation (viz., tone) of airway smooth muscle (ASM) increases its contractile capacity, has been reported in isolated ASM tissues in vitro, as well as in mice in vivo. The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunteers underwent methacholine challenge on two occasions. One challenge consisted of six serial doses of saline followed by a single high dose of methacholine. The other consisted of six low doses of methacholine 5 min apart followed by a higher dose. The cumulative dose was identical for both challenges. After both methacholine challenges, subjects took a deep inspiration (DI) to total lung capacity as another way to probe ASM mechanics. Responses to methacholine and the DI were measured using a multifrequency forced oscillation technique. Compared with a single high dose, the challenge preceded by tone led to an elevated response measured by respiratory system resistance (Rrs) and reactance at 5 Hz. However, there was no difference in the increase in Rrs at 19 Hz, suggesting a predominant effect on smaller airways. Increased tone also reduced the efficacy of DI, measured by an attenuated maximal dilation during the DI and an increased renarrowing post-DI. We conclude that ASM tone increases small airway responsiveness to inhaled methacholine and reduces the effectiveness of DI in healthy humans. This suggests that force adaptation may contribute to airway hyperresponsiveness and the reduced bronchodilatory effect of DI in asthma.

Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness.

BACKGROUND: Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown. OBJECTIVES: Here we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma. METHODS: We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57. RESULTS: Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis. CONCLUSIONS: Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype.

Ablation of Glutaredoxin-1 Modulates House Dust Mite-Induced Allergic Airways Disease in Mice.

Protein S-glutathionylation (PSSG) is an oxidant-induced post-translational modification of protein cysteines that impacts structure and function. The oxidoreductase glutaredoxin-1 (Glrx1) under physiological conditions catalyzes deglutathionylation and restores the protein thiol group. The involvement of Glrx1/PSSG in allergic inflammation induced by asthma-relevant allergens remains unknown. In the present study, we examined the impact of genetic ablation of Glrx1 in the pathogenesis of house dust mite (HDM)-induced allergic airways disease in mice. Wild-type (WT) or Glrx1(-/-) mice were instilled intranasally with HDM on 5 consecutive days for 3 weeks. As expected, overall PSSG was increased in Glrx1(-/-) HDM mice as compared with WT animals. Total cells in bronchoalveolar lavage fluid were similarly increased in HDM-treated WT and Glrx1(-/-) mice. However, in response to HDM, mice lacking Glrx1 demonstrated significantly more neutrophils and macrophages but fewer eosinophils as compared with HDM-exposed WT mice. mRNA expression of the Th2-associated cytokines IL-13 and IL-6, as well as mucin-5AC (Muc5ac), was significantly attenuated in Glrx1(-/-) HDM-treated mice. Conversely, mRNA expression of IFN-γ and IL-17A was increased in Glrx1(-/-) HDM mice compared with WT littermates. Restimulation of single-cell suspensions isolated from lungs or spleens with HDM resulted in enhanced IL-17A and decreased IL-5 production in cells derived from inflamed Glrx1(-/-) mice compared with WT animals. Finally, HDM-induced tissue damping and elastance were significantly attenuated in Glrx1(-/-) mice compared with WT littermates. These results demonstrate that the Glrx1-PSSG axis plays a pivotal role in HDM-induced allergic airways disease in association with enhanced type 2 inflammation and restriction of IFN-γ and IL-17A.

Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease.

Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases.