Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-delta (delta-PKC)

Inflammation and proinflammatory mediators are activators of delta-PKC. In vitro, delta-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 delta-PKC TAT peptide inhibitor was used to test the hypothesis that inhibition of delta-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 delta-PKC TAT inhibitory peptide (2CLP+delta-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 delta-PKC phosphorylation in the lung within 24 h. Treatment with the delta-PKC TAT inhibitory peptide significantly decreased pulmonary delta-PKC phosphorylation, indicating effective inhibition of delta-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 delta-PKC TAT reduced 2CLP-induced elevations in chemokine levels in BALF and plasma, suggesting that delta-PKC modulated chemokine expression. Most importantly, intratracheal administration of delta-PKC TAT peptide significantly attenuated inflammatory cell infiltration, disruption of lung architecture, and pulmonary edema associated with 2CLP. Thus, delta-PKC is an important regulator of proinflammatory events in the lung. Targeted inhibition of delta-PKC exerted a lung-protective effect 24 h after 2CLP. J. Leukoc. Biol. 89: 3-10; 2011.