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

Chichger, Havovi and Grinnell, Katie L and Casserly, Brian and Chung, Chun-Shiang and Braza, Julie and Lomas-Neira, Joanne and Ayala, Alfred and Rounds, Sharon and 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. ISSN 1522-1504 (Draft)

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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 (k(f)) or wet-to-dry weight ratios between PKCδ(+/+) and PKCδ(-/-) mice. However, at 24 h after exposure to LPS, the k(f) 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 k(f) 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
Additional Information: Citation: Chichger, H., Grinnell, K.L., Casserly, B., Chung, C.S., Braza, J., Lomas-Neira, J., Ayala, A., Rounds, S., Klinger, J.R. and Harrington, E.O., 2012. Genetic disruption of protein kinase Cdelta reduces endotoxin-induced lung injury. American journal of physiology.Lung cellular and molecular physiology, [e-journal] 303 (10), pp.L880-8.
Faculty: Faculty of Science & Technology
Depositing User: Mr I Walker
Date Deposited: 01 Jun 2016 08:43
Last Modified: 07 Jul 2016 12:54

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