Mammalian cells respond to stress by accumulating or activating a set of highly conserved proteins known as heat-shock proteins (HSPs). Several of these proteins interfere negatively with apoptosis. We show that the small HSP known as Hsp27 inhibits cytochrome-c-mediated activation of caspases in the cytosol. Hsp27 does not interfere with granzyme-B-induced activation of caspases, nor with apoptosis-inducing factor-mediated, caspase-independent, nuclear changes. Hsp27 binds to cytochrome c released from the mitochondria to the cytosol and prevents cytochrome-c-mediated interaction of Apaf-1 with procaspase-9. Thus, Hsp27 interferes specifically with the mitochondrial pathway of caspase-dependent cell death.

Background To date, influenza epidemics have been considered suitable for use as a model for the COVID-19 epidemic, given that they are respiratory diseases with similar modes of transmission. However, data directly comparing the two diseases are scarce.Methods We did a nationwide retrospective cohort study using the French national administrative database (PMSI), which includes discharge summaries for all hospital admissions in France. All patients hospitalised for COVID-19 from March 1 to April 30, 2020, and all patients hospitalised for influenza between Dec 1, 2018, and Feb 28, 2019, were included. The diagnosis of COVID-19 (International Classification of Diseases [10th edition] codes U07.10, U07.11, U07.12, U07.14, or U07.15) or influenza (J09, J10, or J11) comprised primary, related, or associated diagnosis. Comparisons of risk factors, clinical characteristics, and outcomes between patients hospitalised for COVID-19 and influenza were done, with data also stratified by age group. Findings 89 530 patients with COVID-19 and 45 819 patients with influenza were hospitalised in France during the respective study periods. The median age of patients was 68 years (IQR 52-82) for COVID-19 and 71 years (34-84) for influenza. Patients with COVID-19 were more frequently obese or overweight, and more frequently had diabetes, hypertension, and dyslipidaemia than patients with influenza, whereas those with influenza more frequently had heart failure, chronic respiratory disease, cirrhosis, and deficiency anaemia. Patients admitted to hospital with COVID-19 more frequently developed acute respiratory failure, pulmonary embolism, septic shock, or haemorrhagic stroke than patients with influenza, but less frequently developed myocardial infarction or atrial fibrillation. In-hospital mortality was higher in patients with COVID-19 than in patients with influenza (15 104 [16•9%] of 89 530 vs 2640 [5•8%] of 45 819), with a relative risk of death of 2•9 (95% CI 2•8-3•0) and an age-standardised mortality ratio of 2•82. Of the patients hospitalised, the proportion of paediatric patients (<18 years) was smaller for COVID-19 than for influenza (1227 [1•4%] vs 8942 [19•5%]), but a larger proportion of patients younger than 5 years needed intensive care support for COVID-19 than for influenza (14 [2•3%] of 613 vs 65 [0•9%] of 6973). In adolescents (11-17 years), the in-hospital mortality was ten-times higher for COVID-19 than for influenza (five [1•1% of 458 vs one [0•1%] of 804), and patients with COVID-19 were more frequently obese or overweight.Interpretation The presentation of patients with COVID-19 and seasonal influenza requiring hospitalisation differs considerably. Severe acute respiratory syndrome coronavirus 2 is likely to have a higher potential for respiratory pathogenicity, leading to more respiratory complications and to higher mortality. In children, although the rate of hospitalisation for COVID-19 appears to be lower than for influenza, in-hospital mortality is higher; however, low patient numbers limit this finding...

An ever-increasing number of drugs can reproduce variegated patterns of naturally occurring interstitial lung disease (ILD), including most forms of interstitial pneumonias, alveolar involvement and, rarely, vasculitis. Drugs in one therapeutic class may collectively produce the same pattern of involvement. A few drugs can produce more than one pattern of ILD. The diagnosis of drug-induced ILD (DI-ILD) essentially rests on the temporal association between exposure to the drug and the development of pulmonary infiltrates. The histopathological features of DI-ILD are generally consistent, rather than suggestive or specific to the drug etiology. Thus, the diagnosis of DI-ILD is mainly made by the meticulous exclusion of all other possible causes. Drug dechallenge produces measurable improvement in symptoms and imaging in the majority of patients, whereas corticosteroid therapy is indicated if symptoms are present or drug dechallenge is without an effect. Rechallenge is justified in a minority of patients, and is discouraged for diagnostic purposes only. Pneumotox^® (www.pneumotox.com) provides updated information on drug-induced respiratory disease.

Epithelial mesenchymal transition (EMT),

Transforming growth factor-β1 plays a key role in the pathogenesis of pulmonary fibrosis, mediating extracellular matrix (ECM) gene expression through a series of intracellular signaling molecules, including Smad2 and Smad3. We show that Smad3 null mice (knockout (KO)) develop progressive age-related increases in the size of alveolar spaces, associated with high spontaneous presence of matrix metalloproteinases (MMP-9 and MMP-12) in the lung. Moreover, transient overexpression of active TGF-β1 in lungs, using adenoviral vector-mediated gene transfer, resulted in progressive pulmonary fibrosis in wild-type mice, whereas no fibrosis was seen in the lungs of Smad3 KO mice up to 28 days. Significantly higher levels of matrix components (procollagen 3A1, connective tissue growth factor) and antiproteinases (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1) were detected in wild-type lungs 4 days after TGF-β1 administration, while no such changes were seen in KO lungs. These data suggest a pivotal role of the Smad3 pathway in ECM metabolism. Basal activity of the pathway is required to maintain alveolar integrity and ECM homeostasis, but excessive signaling through the pathway results in fibrosis characterized by inhibited degradation and enhanced ECM deposition. The Smad3 pathway is involved in pathogenic mechanisms mediating tissue destruction (lack of repair) and fibrogenesis (excessive repair).

BackgroundSince 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research.MethodsThe registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management.ResultsThis paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001).ConclusionsOur data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time.Trial registrationThe eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov(NCT02951416).

Selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on (1) patient empowerment, preferences, and age; (2) prominent symptoms, symptom severity, and multimorbidity; (3) efficacy and safety of treatment 1 ; (4) speed of onset of action of treatment; (5) current treatment; (6) historic response to treatment; (7) effect on sleep and work productivity 2,3 ; (8) self-management strategies; and (9) resource use. 4,5 An algorithm was devised 5 and digitalized 6 to step up or step down allergic rhinitis treatment based on control. However, its

Transient adenovirus-mediated gene transfer of IL-1β (AdIL-1β), a proinflammatory cytokine, induces marked inflammation and severe and progressive fibrosis in rat lungs. This is associated with an increase in TGF-β1 concentration in bronchoalveolar lavage (BAL) fluid. TGF-β1 is a key cytokine in the process of fibrogenesis, using intracellular signaling pathways involving Smad2 and Smad3. In this study we investigate whether inflammation induced by IL-1β is able to independently induce lung fibrosis in mice deficient in the Smad3 gene. Seven days after AdIL-1β administration, similar levels of IL-1β transgene are seen in BAL in both wild-type (WT) and knockout (KO) mice, and BAL cell profiles demonstrated a similar marked neutrophilic inflammation. Phospho-Smad2 staining was positive in areas of inflammation in both WT and KO mice at day 7. By day 35 after transient IL-1β expression, WT mice showed marked fibrosis in peribronchial areas, quantified by picrosirius red staining and morphometry. However, there was no evidence of fibrosis or collagen accumulation in IL-1β-treated KO mice, and peribronchial areas were not different from KO mice treated with the control adenovector. TGF-β1 and phospho-Smad2 were strongly positive at day 35 in fibrotic areas observed in WT mice, but no such staining was detectable in KO mice. The IL-1β-induced chronic fibrotic response in mouse lungs is dependent on Smad3. KO and WT animals demonstrated a similar inflammatory response to overexpression of IL-1β indicating that inflammation must link to the Smad3 pathway, likely through TGF-β, to induce progressive fibrosis.