title: Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-δ (δ-PKC).
abstract: Inflammation and proinflammatory mediators are activators of δ-PKC. In vitro, δ-PKC regulates proinflammatory signaling in neutrophils and endothelial and epithelial cells, cells that can contribute to lung tissue damage associated with inflammation. In this study, a specific δ-PKC TAT peptide inhibitor was used to test the hypothesis that inhibition of δ-PKC would attenuate lung injury in an animal model of ARDS. Experimental ARDS was induced in rats via 2CLP, a model of polymicrobial sepsis. Following 2CLP surgery, the δ-PKC TAT inhibitory peptide (2CLP+δ-PKC TAT in PBS) or PBS (2CLP+PBS) was administered intratracheally. Controls consisted of SO, where animals underwent a laparotomy without 2CLP. Twenty-four hours after SO or 2CLP, blood, BALF, and lung tissue were collected. 2CLP induced δ-PKC phosphorylation in the lung within 24 h. Treatment with the δ-PKC TAT inhibitory peptide significantly decreased pulmonary δ-PKC phosphorylation, indicating effective inhibition of δ-PKC activation. Plasma and BALF levels of the chemokines CINC-1 and MIP-2 were elevated in 2CLP + PBS rats as compared with SO rats. Treatment with δ-PKC TAT reduced 2CLP-induced elevations in chemokine levels in BALF and plasma, suggesting that δ-PKC modulated chemokine expression. Most importantly, intratracheal administration of δ-PKC TAT peptide significantly attenuated inflammatory cell infiltration, disruption of lung architecture, and pulmonary edema associated with 2CLP. Thus, δ-PKC is an important regulator of proinflammatory events in the lung. Targeted inhibition of δ-PKC exerted a lung-protective effect 24 h after 2CLP.
authors: Temple University School of Medicine, 3307 North Broad St., PAH-206, Philadelphia, PA 19140, USA. laurie.kilpatrick@temple.edu
authors: Laurie E
authors: LE
authors: Kilpatrick
authors: Stephen W
authors: SW
authors: Standage
authors: Haiying
authors: H
authors: Li
authors: Nichelle R
authors: NR
authors: Raj
authors: Helen M
authors: HM
authors: Korchak
authors: Marla R
authors: MR
authors: Wolfson
authors: Clifford S
authors: CS
authors: Deutschman
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D003952:Diagnostic Imaging; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications* / Q000473:pathology
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C513297:Cxcl1 protein, rat; D010455:Peptides; D047428:Protein Kinase Inhibitors; D010769:Phosphothreonine; D051745:Protein Kinase C-delta