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Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject's lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar-capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.

Thoracic surgeries involving resection of lung tissue pose a risk of severe postoperative pulmonary complications, including acute respiratory distress syndrome (ARDS) and respiratory failure. Lung resections require one-lung ventilation (OLV) and, thus, are at higher risk of ventilator-induced lung injury (VILI) attributable to barotrauma and volutrauma in the one ventilated lung, as well as hypoxemia and reperfusion injury on the operated lung. Further, we also aimed to assess the differences in localized and systemic markers of tissue injury/inflammation in those who developed respiratory failure after lung surgery versus matched controls who did not develop respiratory failure. We aimed to assess the different inflammatory/injury marker patterns induced in the operated and ventilated lung and how this compared to the systemic circulating inflammatory/injury marker pattern. A case–control study nested within a prospective cohort study was performed. Patients with postoperative respiratory failure after lung surgery (n = 5) were matched with control patients (n = 6) who did not develop postoperative respiratory failure. Biospecimens (arterial plasma, bronchoalveolar lavage separately from ventilated and operated lungs) were obtained from patients undergoing lung surgery at two timepoints: (1) just prior to initiation of OLV and (2) after lung resection was completed and OLV stopped. Multiplex electrochemiluminescent immunoassays were performed for these biospecimen. We quantified 50 protein biomarkers of inflammation and tissue injury and identified significant differences between those who did and did not develop postoperative respiratory failure. The three biospecimen types also display unique biomarker patterns. [ABSTRACT FROM AUTHOR]

Airway smooth muscle (ASM) contraction controls the airway caliber. Airway narrowing is exaggerated in obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The mechanism by which ASM tone is dysregulated in disease is not clearly understood. Recent research on ion channels, particularly transient receptor potential cation channel, subfamily A, member 1 (TRPA1), is uncovering new understanding of altered airway function. TRPA1, a member of the TRP channel superfamily, is a chemo-sensitive cation channel that can be activated by a variety of external and internal stimuli, leading to the influx of [Ca.sup.2+]. Functional TRPA1 channels have been identified in neuronal and non-neuronal tissues of the lung, including ASM. In the airways, these channels can regulate the release of mediators that are markers of airway inflammation in asthma and COPD. For, example, TRPA1 controls cigarette-smoke-induced inflammatory mediator release and [Ca.sup.2+] mobilization in vitro and in vivo, a response tied to disease pathology in COPD. Recent work has revealed that pharmacological or genetic inhibition of TRPA1 inhibits the allergen-induced airway inflammation in vitro and airway hyper-responsiveness (AHR) in vivo. Collectively, it appears that TRPA1 channels may be determinants of ASM contractility and local inflammation control, positioning them as part of novel mechanisms that control (patho)physiological function of airways and ASM. Key words: asthma, COPD, AHR. La contraction du muscle lisse respiratoire (MLR) controle le calibre des voies respiratoires. Le retrecissement des voies respiratoires est excessif dans les cas de maladies pulmonaires obstructives comme l'asthme et les MPOC. Le mecanisme par lequel le tonus du MLR est deregule dans la maladie n'est pas clairement compris. Les travaux de recherche recents realises sur les canaux ioniques, particulierement TRPA1, presentent de nouvelles donnees qui expliquent la deterioration de la fonction respiratoire. TRPA1, un membre de la superfamille des canaux TRP, est un canal cationique chimio-sensible qui peut etre active par une variete de stimuli externes et internes, menant a un influx de [Ca.sup.2+]. Des canaux TRPA1 fonctionnels ont ete identifies dans des tissus neuronaux et non-neuronaux du poumon, incluant le MLR. Dans les voies respiratoires, ces canaux peuvent reguler la liberation de mediateurs qui sont des marqueurs de l'inflammation respiratoire dans l'asthme et les MPOC. Par exemple, TRPA1 controle la liberation de mediateurs inflammatoires et la mobilisation du [Ca.sup.2+] in vitro et in vivo induites par la fumee de cigarette, des reponses liees a la pathologie des MPOC. Des travaux recents ont revele que l'inhibition pharmacologique ou genetique de TRPA1 inhibe l'inflammation respiratoire provoquee par un allergene in vitro et l'hyperreactivite bronchique (HRB) in vivo. Dans l'ensemble, il semble que les canaux TRPA1 peuvent etre des determinants de la contractilite du MLR et du controle de l'inflammation locale, ce qui les place parmi les constituants de nouveaux mecanismes qui controlent la fonction (patho)physiologique des voies respiratoires et du MLR. [Traduit par la Redaction] Mots-cles: asthme, MPOC, HRB., Introduction Airway smooth muscle (ASM) controls the caliber of airways by facilitating the contraction and relaxation of the airways. In disease states such as asthma and chronic obstructive pulmonary disease [...]

The dystrophin-glycoprotein complex (DGC) is an integral part of caveolae microdomains, and its interaction with caveolin-1 is essential for the phenotype and functional properties of airway smooth muscle (ASM). The sarcoglycan complex provides stability to the dystroglycan complex, but its role in ASM contraction and lung physiology in not understood. We tested whether δ-sarcoglycan (δ-SG), through its interaction with the DGC, is a determinant of ASM contraction ex vivo and airway mechanics in vivo. We measured methacholine (MCh)-induced isometric contraction and airway mechanics in δ-SG KO and wild-type mice. Last, we performed immunoblotting and transmission electron microscopy to assess DGC protein expression and the ultrastructural features of tracheal smooth muscle. Our results reveal an age-dependent reduction in the MCh-induced tracheal isometric force and significant reduction in airway resistance at high concentrations of MCh (50.0 mg/mL) in δ-SG KO mice. The changes in contraction and lung function correlated with decreased caveolin-1 and β-dystroglycan abundance, as well as an age-dependent loss of caveolae in the cell membrane of tracheal smooth muscle in δ-SG KO mice. Collectively, these results confirm and extend understanding of a functional role for the DGC in the contractile properties of ASM and demonstrate that this results in altered lung function in vivo. Key words: airway smooth muscle, caveolae, contraction, airway responsiveness, dystrophin glycoprotein complex. Le complexe DGC (<>) est une partie integrante des micro-domaines des caveoles, et son interaction avec la caveoline-1 est essentielle au phenotype et aux proprietes fonctionnelles du muscle lisse respiratoire (MLR). Le complexe sarcoglycane confere la stabilite au complexe dystroglycane mais son role dans la contraction du MLR et la physiologie pulmonaire n'est pas compris. Les auteurs ont teste si le δ-sarcoglycane (δ-SG), par son interaction avec le DGC, est un determinant de la contraction du MLR ex vivo et de la mecanique respiratoire in vivo. Ils ont mesure la contraction isometrique provoquee par la metacholine (MCh) ainsi que la mecanique respiratoire chez des souris deficientes en δ-SG et des souris sauvages. Finalement, ils ont realise des analyses par immuno-buvardage et par microscopie electronique a transmission afin d'evaluer l'expression de DGC et les caracteristiques ultrastructurales du muscle lisse tracheal. Les resultats revelent une reduction de la force isometrique induite par la MCh en fonction de l'age, ainsi qu'un reduction significative de la resistance respiratoire a de fortes concentrations de MCh (50,0 mg/mL) chez les souris deficientes en δ-SG. Les changements sur le plan de la contraction et de la fonction pulmonaire etaient en correlation avec la diminution de l'abondance de caveoline-1 et de β-dystroglycane, de meme qu'avec la perte des caveoles de la membrane cellulaire du muscle lisse tracheal des souris deficientes en δ-SG, en fonction de l'age. Dans l'ensemble, ces resultats confirment et approfondissent la comprehension du role fonctionnel du DGC dans les proprietes contractiles du MLR, et demontrent comment en resulte une deterioration de la fonction pulmonaire in vivo. [Traduit par la Redaction] Mots-cles: muscle lisse respiratoire, caveole, contraction, reactivite bronchique, complexe dystrophine glycoproteine., Introduction The dystrophin-glycoprotein complex (DGC) confers a structural link between laminin-2 in the extracellular matrix (ECM) and the F-actin cytoskeleton (Ervasti and Campbell 1993; Lapidos et al. 2004) and also [...]