Search

Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising the adaptor ASC, Caspase-1 and specific pattern recognition receptors (PRRs), promote the pathogenesis of emphysema. In the lungs of emphysematous patients, as well as spontaneous gp130 F/F and cigarette smoke (CS)-induced mouse models of emphysema, the expression (messenger RNA and protein) and activation of ASC, Caspase-1, and the inflammasome-associated PRR and DNA sensor AIM2 were up-regulated. AIM2 up-regulation in emphysema coincided with the biased production of the mature downstream inflammasome effector cytokine IL-1β but not IL-18. These observations were supported by the genetic blockade of ASC, AIM2, and the IL-1 receptor and therapy with AIM2 antagonistic suppressor oligonucleotides, which ameliorated emphysema in gp130 F/F mice by preventing elevated alveolar cell apoptosis. The functional requirement for AIM2 in driving apoptosis in the lung epithelium was independent of its expression in hematopoietic-derived immune cells and the recruitment of infiltrating immune cells in the lung. Genetic and inhibitor-based blockade of AIM2 also protected CS-exposed mice from pulmonary alveolar cell apoptosis. Intriguingly, IL-6 trans-signaling via the soluble IL-6 receptor, facilitated by elevated levels of IL-6, acted upstream of the AIM2 inflammasome to augment AIM2 expression in emphysema. Collectively, we reveal cross-talk between the AIM2 inflammasome/IL-1β and IL-6 trans-signaling axes for potential exploitation as a therapeutic strategy for emphysema.

Background Asthma epidemics associated with thunderstorms have had catastrophic impacts on individuals and emergency services. Seasonal allergic rhinitis (SAR) is present in the vast majority of people who develop thunderstorm asthma (TA), but there is little evidence regarding risk factors for TA among the SAR population. Objective We sought to identify risk factors for a history of TA and hospital presentation in a cohort of individuals with SAR. Methods This multi-centre study recruited adults from Melbourne (Australia) with a past diagnosis of TA and/or self-reported SAR. Clinical information, spirometry, white blood-cell count, ryegrass pollen specific IgE (RGP-spIgE) and fractional exhaled nitric oxide (FeNO) were measured to identify risk factors for a history of TA in individuals with SAR. Results From a total of 228 individuals with SAR, 35% (80/228) reported SAR only (I-SAR), 37% (84/228) reported TA symptoms but had not attended hospital for treatment (O-TA) and 28% (64/228) had presented to hospital for TA (H-TA). All H-TA patients reported a previous asthma diagnosis. Logistic regression analysis of factors associated with O-TA and H-TA indicated that lower forced expiratory volume in one second (FEV1) and asthma control questionnaire (ACQ) score >1.5 were associated with H-TA. Higher blood RGP-spIgE, eosinophil counts, and FeNO were significantly associated with both O-TA and H-TA. Receiver-operating curve (ROC) analysis showed RGP-spIgE >10·1 kU/L and pre-bronchodilator FEV1 ≤90% to be biomarkers of increased H-TA risk. Conclusion Clinical tests can identify risk for a history of TA in individuals with SAR and thereby inform patient-specific treatment recommendations.

Basic science has enriched our understanding of the pathophysiology of severe asthma. Clinical translation of these discoveries has resulted in biologic therapies that target key components of asth...

Oral corticosteroids (OCS) are frequently used for asthma treatment. This medication is highly effective for both acute and chronic diseases, but evidence indicates that indiscriminate OCS use is common, posing a risk of serious side effects and irreversible harm. There is now an urgent need to introduce OCS stewardship approaches, akin to successful initiatives that optimized appropriate antibiotic usage. The aim of this TSANZ (Thoracic Society of Australia and New Zealand) position paper is to review current knowledge pertaining to OCS use in asthma and then delineate principles of OCS stewardship. Recent evidence indicates overuse and over-reliance on OCS for asthma and that doses >1000 mg prednisolone-equivalent cumulatively are likely to have serious side effects and adverse outcomes. Patient perspectives emphasize the detrimental impacts of OCS-related side effects such as weight gain, insomnia, mood disturbances and skin changes. Improvements in asthma control and prevention of exacerbations can be achieved by improved inhaler technique, adherence to therapy, asthma education, smoking cessation, multidisciplinary review, optimized medications and other strategies. Recently, add-on therapies including novel biological agents and macrolide antibiotics have demonstrated reductions in OCS requirements. Harm reduction may also be achieved through identification and mitigation of predictable adverse effects. OCS stewardship should entail greater awareness of appropriate indications for OCS prescription, risk–benefits of OCS medications, side effects, effective add-on therapies and multidisciplinary review. If implemented, OCS stewardship can ensure that clinicians and patients with asthma are aware that OCS should not be used lightly, while providing reassurance that asthma can be controlled in most people without frequent use of OCS.

Aspiration during swallow may have devastating consequences in COPD. It is known that COPD can impair swallow efficiency and safety [1–3] and a better understanding of how patients with COPD swallow is essential to inform preventative strategies. To date, no studies have examined swallow of large liquid volumes representative of everyday fast-paced drinking in an ample number of patients with COPD. In this letter we detail swallow patterns evaluated by videofluoroscopy in patients with COPD, with and without evidence of aspiration., Few studies have examined swallow of large liquid volumes representative of everyday drinking in COPD. Swallow by cup-drinking was evaluated in COPD using videofluoroscopy. Slower swallow was linked to aspiration indicating altered swallow habits in COPD. https://bit.ly/3wpdnO3

Childhood lung infection is often associated with prominent neutrophilic airway inflammation and excess production of proteases such as neutrophil elastase (NE). The mechanisms responsible for this inflammation are not well understood. One potentially relevant pathway is the production of extracellular traps by neutrophils (NETs) and macrophages (METs). The aim of this study was to measure NET and MET expression in children and the effect of deoxyribonculease (DNase) 1 and α1-antitrypsin (AAT) on this process. We studied 76 children (median age of 4.0 years) with cystic fibrosis or chronic cough who underwent investigational bronchoscopy. NETs, METs and neutrophil elastase activity in bronchoalveolar lavage (BAL) samples were measured using confocal microscopy and functional assays. The effects of DNase 1 and AAT on NET/MET expression and neutrophil elastase activity were examined in vitro. Both subject groups had airway neutrophilia with prominent BAL production of NETs with neutrophil elastase co-expression; the mean %±standard error of the mean of neutrophils expressing NETs in the cystic fibrosis group was 23.3±2.8% and in the non-cystic fibrosis group was 28.4±3.9%. NET expression was higher in subjects who had detectable neutrophil elastase activity (p≤0.0074). The percentage of macrophages expressing METs in the cystic fibrosis group was 10.7±1.2% and in the non-cystic fibrosis group was 13.2±1.9%. DNase 1 decreased NET/MET expression (p, Prominent extracellular trap formation may be observed in young children with airway inflammation, with and without cystic fibrosis. This innate inflammatory response is down-regulated by a combination of currently available therapeutics. https://bit.ly/3bDaWyC

Purpose The Phase 3 LIBERTY ASTHMA QUEST study in patients aged ≥12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks (q2w) vs matched placebo in the overall population. This post hoc analysis assessed dupilumab efficacy by disease severity as evidenced by baseline % predicted forced expiratory volume in 1 second (FEV1) and dose of inhaled corticosteroids (ICS). Patients and Methods Severe asthma exacerbation rates, change from baseline in FEV1, asthma control, quality of life, and fractional exhaled nitric oxide (FeNO) levels over the 52-week treatment period were assessed in patients with elevated type 2 inflammation biomarkers stratified by ICS dose and FEV1% predicted at baseline. Results In patients with elevated baseline eosinophils, dupilumab 200 mg and 300 mg q2w vs placebo reduced severe exacerbation rates by 50% (P=0.06) and 67% (P=0.001), respectively, in those with medium-dose ICS/FEV1% predicted 60-90%, and by 59% (P

Heat-resistant slip coatings of the ZrB2–MoSi2–SiC system on CCCM were examined for protection of aerospace technology elements from oxidation. The following compositions (mass%) were studied as coating materials: 55 ZrB2 + 25 MoSi2 + 20 SiC (ZSM25), 50 ZrB2 + 30 MoSi2 + 20 SiC (ZSM30), and 45 ZrB2 + 35 MoSi2 + 20 SiC (ZSM35). Heat-treatment modes were elaborated for the coatings. The optimal method for producing heat-resistant coatings was selected. The ZSM25 coating was found to satisfy the heat-resistance assessment tests conditions in a Multiplaz 2500-m plasmatron for 20 sec at an angle of 45°, presumably by forming a highly viscous ZrSiO4 film.

Slip coatings of ZrB2‒MoSi2‒SiC system on CCCM of the next compostions, wt. %: 55 ZrB2 + 25 MoSi2 + 20 SiC (ZSM25), 50 ZrB2 + 30 MoSi2 + 20 SiC (ZSM30) and 45 ZrB2 + 35 MoSi2 + 20 SiC (ZSM35) are discussed in the article. The modes of the coatings’ heat treatment were worked out and the optimal method for producing heat-resistant coatings was selected. It was found that the coating of composition 1 satisfies the heat resistance assessment tests conditions on the Multiplas 2500-m plasmatron, presumably working due to the formation of a highly viscous ZrSiO4 film.

Reslizumab displays efficacy in patients with inadequately controlled eosinophilic asthma; previous reports in oral corticosteroid-dependent asthma are limited.To assess efficacy of reslizumab in oral corticosteroid-dependent patients and benefits on oral corticosteroid burden.We report post hoc analyses of pooled data from duplicate, placebo-controlled phase 3 trials. Patients aged 12 to 75 years with inadequately controlled, moderate-to-severe asthma were randomized 1:1 to receive intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 52 weeks, stratified by oral corticosteroid use at enrollment and by region. Assessments included efficacy and predictors of clinical asthma exacerbation response in oral corticosteroid-dependent patients, and systemic corticosteroids burden in the overall population.Patients were randomized to reslizumab (n = 477) or placebo (n = 476); 73 (15%) patients in each group were taking oral corticosteroids at baseline. Reslizumab was favored over placebo for all efficacy end points in oral corticosteroid-dependent patients, with numerically greater improvements in oral corticosteroid-dependent patients than the overall population. Having 2 or more versus 1 clinical asthma exacerbation in the previous 12 months was the strongest positive predictor of reduced exacerbation risk with reslizumab (risk reduction, 77.5% vs 15.2%; P ≤ .02). Significantly fewer new systemic corticosteroid prescriptions were issued per patient receiving reslizumab versus placebo (mean ± SD, 0.5 ± 1.07 vs 1.0 ± 1.52; P.0001). Total and per-patient systemic corticosteroid burdens were lower: 121,135 versus 290,977 mg and 254 versus 611 mg/patient, respectively (both P.0001).Oral corticosteroid-dependent patients benefited from reslizumab across asthma efficacy outcome measures. Reslizumab-treated patients required fewer new systemic corticosteroid prescriptions and had a lower systemic corticosteroid burden compared with placebo.

1. Precision cut lung slices (PCLS) offer a unique integrated experimental platform for investigating both inflammatory and immune responses to viral infection. 2. This study aimed to develop a protocol for robust infection of PCLS ex vivo with influenza A virus (IAV) with a view to its application for assessment of antiviral agents. 3. PCLS were prepared using agarose-inflated lungs from naive C57Bl6 mice and infected with IAV (HKx31 mouse strain). Matched slices from each mouse at 3 IAV concentrations (1x104-1x106 PFU) were assessed 24 and 48 hr post infection (n=4-8). Viral loads were assessed by plaque assay of homogenised PCLS. Conditioned media was used to measure both cell death via LDH assay and inflammatory responses to infection via TNFα ELISA. 4. A dose-dependent increase in viral load was observed at 24 hr, with a further 3-fold increase in plaque numbers at 48 hr at the lowest IAV concentration only (1x104PFU, p 5. Treatment of mouse PCLS with IAV ex vivo elicits dose- and time-dependent infection and release of inflammatory cytokines. Further studies assessing immune responses and sensitivity to viral treatment are required. PCLS may be a viable screening tool for pre-clinical assessment of mechanisms of infection and validation of new therapeutic targets.

Background and objective Right ventricular (RV) volumes are crucial outcome determinants in pulmonary diseases. Little is known about the associations of RV volumes during hospitalized acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We aimed to ascertain associations of RV end-diastolic volume indexed to body surface area (RVEDVI) during hospitalized AECOPD and its relationship with mortality in long-term follow-up. Methods This is a prospective observational cohort study (December 2013-November 2019, ACTRN12617001562369) using dynamic retrospective ECG-gated computed tomography during hospitalized AECOPD. RVEDVI was defined as normal or high using Framingham Offspring Cohort values. Cox regression determined the prognostic relevance of RVEDVI for death. Results A total of 148 participants (70 ± 10 years [mean ± SD], 88 [59%] men) were included, of whom 75 (51%) had high RVEDVI. This was associated with more frequent hospital admissions in the 12 months before admission (52/75 [69%] vs. 38/73 [52%], p = 0.04) and higher breathlessness (modified Medical Research Council score, 2.9 ± 1.3 vs. 2.4 ± 1.2, p = 0.007). During follow-up, high RVEDVI was associated with greater mortality (log-rank p = 0.001). In univariable Cox regression, increasing RVEDVI was associated with higher mortality (hazard ratio [HR]: 1.02 per ml/m2 ; 95% CI: 1.01, 1.03; p = 0.001). In multivariable Cox regression, RVEDVI was independently associated with mortality (HR: 1.01 per ml/m2 ; 95% CI: 1.00, 1.03; p = 0.050) at a borderline significance level. Adding RVEDVI to three COPD mortality prediction systems improved model fit (pooled chi-square test [BODE: p = 0.05, ADO: p = 0.04, DOSE: p = 0.02]). Conclusion In patients with hospitalized AECOPD, higher RV end-diastolic volume was associated with worse acute clinical parameters and greater mortality.

Background The generic term “exacerbation” does not reflect the heterogeneity of acute exacerbations of COPD (AECOPD). We utilised a novel algorithmic strategy to profile exacerbation phenotypes based on underlying aetiologies. Methods Patients hospitalised for AECOPD (n=146) were investigated for aetiological contributors summarised in a mnemonic acronym ABCDEFGX (A: airway virus; B: bacterial; C: co-infection; D: depression/anxiety; E: eosinophils; F: failure (cardiac); G: general environment; X: unknown). Results from clinical investigations were combined to construct AECOPD phenotypes. Relationships to clinical outcomes were examined for both composite phenotypes and their specific aetiological components. Aetiologies identified at exacerbation were reassessed at outpatient follow-up. Results Hospitalised AECOPDs were remarkably diverse, with 26 distinct phenotypes identified. Multiple aetiologies were common (70%) and unidentifiable aetiology rare (4.1%). If viruses were detected (29.5%), patients had longer hospitalisation (7.7±5.6 versus 6.0±3.9 days, p=0.03) despite fewer “frequent exacerbators” (9.3% versus 37%, p=0.001) and lower mortality at 1 year (p=0.03). If bacterial infection was found (40.4%), patients were commonly “frequent exacerbators” (44% versus 18.4%, p=0.001). Eosinophilic exacerbations (28%) were associated with lower pH (7.32±0.06 versus 7.36±0.09, p=0.04), higher venous carbon dioxide tension (PvCO2) (53.7±10.5 versus 48.8±12.8, p=0.04), greater noninvasive ventilation (NIV) usage (34.1% versus 18.1%) but shorter hospitalisation (4 (3–5) versus 6 (4–9) days, p, Hospitalised #AECOPD present as complex multidimensional clinical phenotypes, often comprising multiple distinct aetiologies. Profiling AECOPDs according to their multifactorial aetiological components has important prognostic and therapeutic implications. https://bit.ly/3nIHEnO

Background Clinicians are increasingly recognizing severe asthma patients in whom biologics and other add-on therapies lead to dramatic improvement. Currently, there is no agreed-upon super-responder (SR) definition. Objective To survey severe asthma experts using a modified Delphi process, to develop an international consensus-based definition of a severe asthma SR. Methods The Delphi panel was composed of 81 participants (94% specialist pulmonologists or allergists) from 24 countries and consisted of three iterative online voting rounds. Consensus on individual items, whether acceptance or rejection, required at least 70% agreement by panel members. Results Consensus was achieved that the SR definition should be based on improvement across three or more domains assessed over 12 months. Major SR criteria included exacerbation elimination, a large improvement in asthma control (two or more times the minimal clinically important difference), and cessation of maintenance of oral steroids (or weaning to adrenal insufficiency). Minor SR criteria were composed of a 75% exacerbation reduction, having well-controlled asthma, and 500 mL or greater improvement in FEV1. The SR definition requires improvement in at least two major criteria. In the future, the SR definition should be expanded to incorporate quality of life measures, although current tools can be difficult to implement in a clinical setting and further research is needed. Conclusions This international consensus-based definition of severe asthma SRs is an important prerequisite for better understanding SR prevalence, predictive factors, and the mechanisms involved. Further research is needed to understand the patient's perspective and to measure quality of life more precisely in SRs.

OCS play an important role in the management of asthma. However, steroid‐related AE are common and represent a leading cause of morbidity. Limited published studies suggest OCS usage varies across countries and recent registry data indicate that at least 25–60% of patients with severe asthma in developed countries may at some stage be prescribed OCS. Recent evidence indicate that many patients do not receive optimal therapy for asthma and are often prescribed maintenance OCS or repeated steroid bursts to treat exacerbations. Given the recent progress in adult severe asthma and new treatment options, judicious appraisal of steroid use is merited. A number of strategies and add‐on therapies are now available to treat severe asthma. These include increasing specialist referral for multidisciplinary assessments and implementing OCS‐sparing interventions, such as improving guideline adherence and add‐on tiotropium and macrolides. Biologics have recently become available for severe asthma; these agents reduce asthma exacerbations and lower OCS exposure. Further research, collaboration and consensus are necessary to develop a structured stewardship approach including realistic OCS‐weaning programmes for patients with severe asthma on regular OCS; education and public health campaigns to improve timely access to specialized severe asthma services for treatment optimization; and implementing targeted strategies to identify patients who warrant OCS use using objective biomarker‐based strategies.

Background Characterizing acute exacerbations of COPD (AECOPD) and individualizing therapy is challenging. Key exacerbation therapies include antibiotics and systemic corticosteroids. Blood eosinophils, when either low or high, may offer a simple, inexpensive distinction to predict beneficial responses to these therapies. Methods We conducted derivation (n = 242) and validation (n = 99) cohort studies of patients hospitalized for AECOPD. Patients who received oral corticosteroids before ED presentation were excluded. The derivation cohort was identified by individual case file review. The validation cohort was prospectively recruited during hospital admission. Exacerbations were grouped according to blood eosinophil count as low ( 150/μL). Exacerbations were classified as being associated with infection if either virus testing was positive or C-reactive protein was ≥20 mg/L. Associations of eosinophil groups with infection, hospital length of stay, and 12-month survival were compared using appropriate statistical methods. Results There were no significant differences in baseline characteristics between patients with low, normal, or high blood eosinophils in either cohort. Eosinophil counts 150/μL. Conclusions Low and high blood eosinophil counts in hospitalized patients with AECOPD provide a practical clinical distinction that can potentially be used to inform management strategies. Prospective studies are needed to evaluate if this strategy can guide discriminate use of antibiotics and/or corticosteroids.

Severe asthma leads to debilitating symptoms for patients and excessive socioeconomic burden for the community. Comprehensive models of care are required to address complex issues, risk factors and comorbidities in patients with severe asthma, and to identify patients most appropriate for specialised treatments. Dedicated severe asthma services improve asthma control, reduce asthma exacerbations and hospital admissions, and improve quality of life. Currently, diverse models of care exist for managing severe asthma across Australia. Most referrals to severe asthma services are from respiratory physicians seeking a second opinion or from primary care for poorly controlled asthma. Despite benefits of specialised severe asthma services, many patients are not referred and resources are limited, often resulting in long waiting times. Patient referral is often unstructured and there are considerable variations in the management of severe asthma with limited access to other health care professionals such as speech pathologists and dieticians, and restricted scope to optimise patient work-up before referral. Ongoing communication between the specialist and referring clinician is essential for continuity of care but is often lacking. Referral pathways can be optimised by developing referral criteria and guidelines to triage patients with severe asthma and to improve resource efficiency. Additional education and tools for assessing and managing severe asthma are needed, and mechanisms should be developed for involving primary care in the management of stabilised patients. Strategies to increase patient access to multidisciplinary services are recommended.

We report the prevalence of reduced levels of carbon monoxide transfer factor (TLCO) in middle-aged current or ex-smokers with normal spirometry. Spirometry and TLCO measurements were performed and we identified 391 subjects aged 40-60 years, with a significant smoking history and normal spirometry. In this group, 96 subjects (24%) had TLCO measuremements below the lower limit of normal when using the newly established Global Lung Initiative (GLI) reference equations. The measurement of TLCO should be considered as part of the standard assessment of smokers.

Introduction Acute exacerbations of COPD (AECOPD) are accompanied by escalations in cardiac risk superimposed upon elevated baseline risk. Appropriate treatment for coronary artery disease (CAD) and heart failure with reduced ejection fraction (HFrEF) could improve outcomes. However, securing these diagnoses during AECOPD is difficult, so their true prevalence remains unknown, as does the magnitude of this treatment opportunity. We aimed to determine the prevalence of severe CAD and severe HFrEF during hospitalised AECOPD using dynamic computed tomography (CT). Methods A cross-sectional study of 148 patients with hospitalised AECOPD was conducted. Dynamic CT was used to identify severe CAD (Agatston score ≥400) and HFrEF (left ventricular ejection fraction ≤40% and/or right ventricular ejection fraction ≤35%). Results Severe CAD was detected in 51 of 148 patients (35%), left ventricular systolic dysfunction was identified in 12 cases (8%) and right ventricular systolic dysfunction was present in 18 (12%). Clinical history and examination did not identify severe CAD in approximately one-third of cases and missed HFrEF in two-thirds of cases. Elevated troponin and brain natriuretic peptide did not differentiate subjects with severe CAD from nonsevere CAD, nor distinguish HFrEF from normal ejection fraction. Undertreatment was common. Of those with severe CAD, only 39% were prescribed an antiplatelet agent, and 53% received a statin. Of individuals with HFrEF, 50% or less received angiotensin blockers, beta blockers or antimineralocorticoids. Conclusion Dynamic CT detects clinically covert CAD and HFrEF during AECOPD, identifying opportunities to improve outcomes via well-established cardiac treatments., Severe, treatable cardiac disease is present during hospitalised #AECOPD exacerbations, and is often clinically unsuspected. This cardiac disease can be detected with dynamic CT. Appropriate treatment could change outcomes. https://bit.ly/2Is45wO

Rationale Swallow may be compromised in COPD leading to aspiration and adverse respiratory consequences. However, prevalence and consequences of detectable aspiration in stable COPD are not known. Objectives We tested the hypothesis that a significant number of patients with stable COPD will have detectable aspiration during swallow (prandial aspiration) and that they would experience more frequent severe acute exacerbations of COPD (AECOPD) over the subsequent 12 months. Methods Patients (n=151) with verified and stable COPD of all severities were recruited at a tertiary care hospital. Videofluoroscopy was conducted to evaluate aspiration using Rosenbek's scale for penetration–aspiration during 100-mL cup drinking. AECOPD was documented as moderate (antibiotics and/or corticosteroid treatment) or severe (emergency department admission or hospitalisation) over the ensuing 12 months. Measurements and main results Aspiration was observed in 30 out of 151 patients (19.9%, 18 males, 12 females; mean age 72.4 years). Patients with aspiration had more overall AECOPD events (3.03 versus 2 per patient; p=0.022) and severe AECOPD episodes (0.87 versus 0.39; p=0.032). Severe AECOPD occurred in more patients with aspiration (50% of patients versus 18.2%; OR 4.5, CI 1.9–10.5; p=0.001) and with silent aspiration (36.7% versus 18.2%; OR 2.6, CI 1.1–6.2; p=0.045). Aspiration was related to a shorter exacerbation-free period during the 12-month follow-up period (p=0.038). Conclusions Prandial aspiration is detectable in a subset of patients with COPD and was predictive of subsequent severe AECOPD. Studies to examine if the association is causal are essential to direct strategies aimed at prevention of aspiration and AECOPD., This study demonstrates that prandial aspiration occurs in ∼20% of patients with stable COPD and portends severe COPD exacerbations over the next 12 months https://bit.ly/2Tx5btj

Pirfenidone (PFD) is a pharmacological compound with therapeutic efficacy in idiopathic pulmonary fibrosis. It has been chiefly characterized as an antifibrotic agent, although it was initially developed as an antiinflammatory compound because of its ability to diminish the accumulation of inflammatory cells and cytokines. Despite recent studies that have elucidated key mechanisms, the precise molecular activities of PFD remain incompletely understood. PFD modulates fibrogenic growth factors, thereby attenuating fibroblast proliferation, myofibroblast differentiation, collagen and fibronectin synthesis, and deposition of extracellular matrix. This effect is mediated by suppression of TGF-β1 (transforming growth factor-β1) and other growth factors. Here, we appraise the impact of PFD on TGF-β1 production and its downstream pathways. Accumulating evidence indicates that PFD also downregulates inflammatory pathways and therefore has considerable potential as a viable and innovative antiinflammatory compound. We examine the effects of PFD on inflammatory cells and the production of pro- and antiinflammatory cytokines in the lung. In this context, recent evidence that PFD can target inflammasome pathways and ensuing lung inflammation is highlighted. Finally, the antioxidant properties of PFD, such as its ability to inhibit redox reactions and regulate oxidative stress-related genes and enzymes, are detailed. In summary, this narrative review examines molecular mechanisms underpinning PFD and its recognized benefits in lung fibrosis. We highlight preclinical data that demonstrate the potential of PFD as a nonsteroidal antiinflammatory agent and outline areas for future research.