RRC ID 19140
Author Chichger H, Grinnell KL, Casserly B, Chung CS, Braza J, Lomas-Neira J, Ayala A, Rounds S, Klinger JR, Harrington EO.
Title Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury.
Journal Am J Physiol Lung Cell Mol Physiol
Abstract 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.
Volume 303(10)
Pages L880-8
Published 2012-11-15
DOI 10.1152/ajplung.00169.2012
PII ajplung.00169.2012
PMID 22983354
PMC PMC3517673
MeSH Acute Lung Injury / chemically induced Acute Lung Injury / enzymology* Acute Lung Injury / genetics Acute Lung Injury / pathology Animals Blood-Air Barrier / enzymology* Blood-Air Barrier / pathology Cytokines / genetics Cytokines / metabolism Gene Expression Regulation, Enzymologic / drug effects* Inflammation Mediators / metabolism Lipopolysaccharides / toxicity* Mice Mice, Knockout Protein Kinase C-delta / biosynthesis* Protein Kinase C-delta / genetics Pulmonary Edema / chemically induced Pulmonary Edema / enzymology Pulmonary Edema / genetics Pulmonary Edema / pathology Respiratory Distress Syndrome, Adult
IF 4.06
Times Cited 22
WOS Category RESPIRATORY SYSTEM PHYSIOLOGY
Resource
Mice B6.129P2-Prkcd<tm1Kin>(RBRC00457)