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• W2310040892 abstract "Hypercapnia, with its associated acidosis (HCA), is a consequence of respiratory failure and is also seen in critically ill patients managed with conventional “protective” ventilation strategies. Nuclear factor kappa-B (NF-κB), a pivotal transcription factor, is activated in the setting of injury and repair and is central to innate immunity. We have previously established that HCA protects against ventilation-induced lung injury in vivo, potentially via a mechanism involving inhibition of NF-κB signaling. We wished to further elucidate the role and mechanism of HCA-mediated inhibition of the NF-κB pathway in attenuating stretch-induced injury in vitro. Initial experiments examined the effect of HCA on cyclic stretch-induced inflammation and injury in human bronchial and alveolar epithelial cells. Subsequent experiments examined the role of the canonical NF-κB pathway in mediating stretch-induced injury and the mechanism of action of HCA. The contribution of pH versus CO2 in mediating this effect of HCA was also examined. Pulmonary epithelial high cyclic stretch (22 % equibiaxial strain) activated NF-κB, enhanced interleukin-8 (IL-8) production, caused cell injury, and reduced cell survival. In contrast, physiologic stretch (10 % strain) did not activate inflammation or cause cell injury. HCA reduced cyclic mechanical stretch-induced NF-κB activation, attenuated IL-8 production, reduced injury, and enhanced survival, in bronchial and alveolar epithelial cells, following shorter (24 h) and longer (120 h) cyclic mechanical stretch. Pre-conditioning with HCA was less effective than when HCA was applied after commencement of cell stretch. HCA prevented the stretch-induced breakdown of the NF-κB cytosolic inhibitor IκBα, while IκBα overexpression “occluded” the effect of HCA. These effects were mediated by a pH-dependent mechanism rather than via CO2 per se. HCA attenuates adverse mechanical stretch-induced epithelial injury and death, via a pH-dependent mechanism that inhibits the canonical NF-κB activation by preventing IκBα breakdown." @default.
• W2310040892 created "2016-06-24" @default.
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• W2310040892 date "2016-03-22" @default.
• W2310040892 modified "2023-10-17" @default.
• W2310040892 title "Hypercapnic acidosis attenuates pulmonary epithelial stretch-induced injury via inhibition of the canonical NF-κB pathway" @default.
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• W2310040892 doi "https://doi.org/10.1186/s40635-016-0081-6" @default.
• W2310040892 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4801837" @default.
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