American journal of physiology. Lung cellular and molecular physiology
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Am. J. Physiol. Lung Cell Mol. Physiol. · Nov 2019
Comparative StudyCigarette smoke induces overexpression of active human cathepsin S in lungs from current smokers with or without COPD.
Cigarette smoking has marked effects on lung tissue, including induction of oxidative stress, inflammatory cell recruitment, and a protease/antiprotease imbalance. These effects contribute to tissue remodeling and destruction resulting in loss of lung function in chronic obstructive pulmonary disease (COPD) patients. Cathepsin S (CatS) is a cysteine protease that is involved in the remodeling/degradation of connective tissue and basement membrane. ⋯ Despite the presence of an oxidizing environment, CatS expression and activity were significantly higher in current smokers (both non-COPD and COPD) compared with never-smokers, and correlated positively with smoking history. Moreover, we found that the exposure of primary human bronchial epithelial cells to cigarette smoke extract triggered the activation of P2X7 receptors, which in turns drives CatS upregulation. The present data suggest that excessive CatS expression and activity contribute, beside other proteases, to the deleterious effects of cigarette smoke on pulmonary homeostasis.
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Am. J. Physiol. Lung Cell Mol. Physiol. · May 2019
Consumptive coagulopathy is associated with organ dysfunction during PICS.
Patients who survive the acute phase of sepsis can progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Although sepsis is characterized by early hypercoagulability and delayed hypocoagulability, coagulopathy during chronic critical illness is not fully understood. The objective of this study was to determine whether sepsis-induced PICS is associated with coagulation abnormalities. ⋯ Finally, PICS mice displayed delayed thrombin production and decreased overall thrombin concentrations. All together, these data demonstrate a general dysregulation of coagulation resulting in microthrombus formation and compromised lung function. On the basis of these findings, we propose that consumptive coagulopathy constitutes another cardinal feature of PICS and may contribute to the ongoing tissue damage and multiple organ failure that can occur in chronic critical illness.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Mar 2019
Apoptosis signal-regulating kinase-1 promotes inflammasome priming in macrophages.
We previously showed that mice deficient in apoptosis signal-regulating kinase-1 (ASK1) were partially protected against ventilator-induced lung injury. Because ASK1 can promote both cell death and inflammation, we hypothesized that ASK1 activation regulates inflammasome-mediated inflammation. Mice deficient in ASK1 expression (ASK1-/-) exhibited significantly less inflammation and lung injury (as measured by neutrophil infiltration, IL-6, and IL-1β) in response to treatment with inhaled lipopolysaccharide (LPS) compared with wild-type (WT) mice. ⋯ Subsequent ATP treatment stimulated an increase in cleaved caspase-1 and IL-1β in WT BMDMs compared with ASK1-/- BMDMs. Similarly, treatment of MH-S cells with LPS + ATP caused an increase in both cleaved caspase-1 and IL-1β that was diminished by the ASK-1 inhibitor NQDI1. These results demonstrate, for the first time, that ASK1 promotes inflammasome priming.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Nov 2018
Human pulmonary endothelial cell permeability after exposure to LPS-stimulated leukocyte supernatants derived from patients with early sepsis.
Systemic immune activation is the hallmark of sepsis, which can result in endothelial injury and the acute respiratory distress syndrome (ARDS). The aim of this study was to investigate heterogeneity in sepsis-mediated endothelial permeability using primary human pulmonary microvascular endothelial cells (HPMECs) and the electric cell-substrate impedance sensing (ECIS) platform. After plasma removal, cellular component of whole blood from 35 intensive care unit (ICU) patients with early sepsis was diluted with media and stimulated with either lipopolysaccharide (LPS) or control media. ⋯ Maximal permeability was associated with increased intercellular adhesion molecule-1 protein and mRNA expression and decreased vascular endothelial-cadherin mRNA expression. These findings indicate that substantial heterogeneity in pulmonary endothelial permeability is induced by supernatants of LPS-stimulated leukocytes derived from patients with early sepsis and provide insights into some of the mechanisms that induce lung vascular injury. In addition, this in vitro model of lung endothelial permeability from LPS-stimulated leukocytes may be a useful method for testing therapeutic agents that could mitigate endothelial injury in early sepsis.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Nov 2018
Comparative StudyComparison of the effects of e-cigarette vapor with cigarette smoke on lung function and inflammation in mice.
Electronic cigarettes (e-cigs) are advertised as a less harmful nicotine delivery system or as a new smoking cessation tool. We aimed to assess the in vivo effects of e-cig vapor in the lung and to compare them to those of cigarette smoke (CS). We exposed C57BL/6 mice for either 3 days or 4 wk to ambient air, CS, or e-cig vapor containing 1) propylene glycol/vegetable glycerol (PG:VG-Sol; 1:1), 2) PG:VG with nicotine (G:VG-N), or 3) PG:VG with nicotine and flavor (PG:VG-N+F) and determined oxidative stress, inflammation, and pulmonary mechanics. ⋯ Our findings suggest that exposure to e-cig vapor can trigger inflammatory responses and adversely affect respiratory system mechanics. In many cases, the added flavor in e-cigs exacerbated the detrimental effects of e-cig vapor. We conclude that both e-cig vaping and conventional cigarette smoking negatively impact lung biology.