title: Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury.
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.
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island 02908, USA.
authors.forename: Havovi
authors.initials: H
authors.lastname: Chichger
authors.forename: Katie L
authors.initials: KL
authors.lastname: Grinnell
authors.forename: Brian
authors.initials: B
authors.lastname: Casserly
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.forename: Julie
authors.initials: J
authors.lastname: Braza
authors.forename: Joanne
authors.initials: J
authors.lastname: Lomas-Neira
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
authors.forename: Sharon
authors.initials: S
authors.lastname: Rounds
authors.forename: James R
authors.initials: JR
authors.lastname: Klinger
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Harrington
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D015824:Blood-Air Barrier / Q000201:enzymology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D051745:Protein Kinase C-delta / Q000096:biosynthesis* / Q000235:genetics; D011654:Pulmonary Edema / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012128:Respiratory Distress Syndrome
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta