Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury

Chichger, Havovi, Grinnell, Katie L., Casserly, Brian, Chung, Chun-Shiang, Braza, Julie, Lomas-Neira, Joanne, Ayala, Alfred, Rounds, Sharon, Klinger, James R. and Harrington, Elizabeth O. (2012) Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury. American Journal of Physiology - Lung Cellular and Molecular Physiology, 303 (10). pp. 880-888. ISSN 1522-1504

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The pathogenesis of acute lung injury and acute respiratory distress syndrome is characterized by sequestration of leukocytes in lung tissue, disruption of capillary integrity, and pulmonary edema. PKCδ plays a critical role in RhoA-mediated endothelial barrier function and inflammatory responses. We used mice with genetic deletion of PKCδ (PKCδ−/−) to assess the role of PKCδ in susceptibility to LPS-induced lung injury and pulmonary edema. Under baseline conditions or in settings of increased capillary hydrostatic pressures, no differences were noted in the filtration coefficients (kf) or wet-to-dry weight ratios between PKCδ+/+ and PKCδ−/− mice. However, at 24 h after exposure to LPS, the kf values were significantly higher in lungs isolated from PKCδ+/+ than PKCδ−/− mice. In addition, bronchoalveolar lavage fluid obtained from LPS-exposed PKCδ+/+ mice displayed increased protein and cell content compared with LPS-exposed PKCδ−/− mice, but similar changes in inflammatory cytokines were measured. Histology indicated elevated LPS-induced cellularity and inflammation within PKCδ+/+ mouse lung parenchyma relative to PKCδ−/− mouse lungs. Transient overexpression of catalytically inactive PKCδ cDNA in the endothelium significantly attenuated LPS-induced endothelial barrier dysfunction in vitro and increased kf lung values in PKCδ+/+ mice. However, transient overexpression of wild-type PKCδ cDNA in PKCδ−/− mouse lung vasculature did not alter the protective effects of PKCδ deficiency against LPS-induced acute lung injury. We conclude that PKCδ plays a role in the pathological progression of endotoxin-induced lung injury, likely mediated through modulation of inflammatory signaling and pulmonary vascular barrier function.

Item Type: Journal Article
Keywords: endothelium, pulmonary edema, lipopolysaccharide, acute lung injury
Faculty: ARCHIVED Faculty of Science & Technology (until September 2018)
Depositing User: Repository Admin
Date Deposited: 01 Jun 2016 08:43
Last Modified: 09 Sep 2021 16:16

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