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

Chichger H, Grinnell KL, Casserly B, Chung C, Braza J, Lomas-Neira J, Ayala A, Rounds S, Klinger JR, Harrington EO. Genetic disruption of protein kinase C delta reduces endotoxin-induced lung injury. Am J Physiol Lung Cell Mol Physiol 303: L880-L888, 2012. First published September 14, 2012; doi:10.1152/ajplung.00169.2012.-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. PKC delta plays a critical role in RhoA-mediated endothelial barrier function and inflammatory responses. We used mice with genetic deletion of PKC delta (PKC delta(-/-)) to assess the role of PKC delta 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 PKC delta(-/-) and PKC delta(-/-) mice. However, at 24 h after exposure to LPS, the kf values were significantly higher in lungs isolated from PKC delta(-/-) than PKC delta(-/-) mice. In addition, bronchoalveolar lavage fluid obtained from LPS-exposed PKC delta(-/-) mice displayed increased protein and cell content compared with LPS-exposed PKC delta(-/-) mice, but similar changes in inflammatory cytokines were measured. Histology indicated elevated LPS-induced cellularity and inflammation within PKC delta(-/-) mouse lung parenchyma relative to PKC delta(-/-) mouse lungs. Transient overexpression of catalytically inactive PKC delta cDNA in the endothelium significantly attenuated LPS-induced endothelial barrier dysfunction in vitro and increased k(f) lung values in PKC delta(-/-) mice. However, transient overexpression of wild-type PKC delta cDNA in PKC delta(-/-) mouse lung vasculature did not alter the protective effects of PKC delta deficiency against LPS-induced acute lung injury. We conclude that PKC delta plays a role in the pathological progression of endotoxin-induced lung injury, likely mediated through modulation of inflammatory signaling and pulmonary vascular barrier function.