Phospholipase C-{varepsilon} signaling mediates endothelial cell inflammation and barrier disruption in acute lung injury

Phospholipase C- (PLC-) is a unique PLC isoform that can be regulated by multiple signaling inputs from both Ras family GTPases and heterotrimeric G proteins and has primary sites of expression in the heart and lung. Whereas the role of PLC- in cardiac function and pathology has been documented, its relevance in acute lung injury (ALI) is unclear. We used PLC-–/– mice to address the role of PLC- in regulating lung vascular inflammation and injury in an aerosolized bacterial LPS inhalation mouse model of ALI. PLC-–/– mice showed a marked decrease in LPS-induced proinflammatory mediators (ICAM-1, VCAM-1, TNF-α, IL-1β, IL-6, macrophage inflammatory protein 2, keratinocyte-derived cytokine, monocyte chemoattractant protein 1, and granulocyte-macrophage colony-stimulating factor), lung neutrophil infiltration and microvascular leakage, and loss of VE-cadherin compared with PLC-+/+ mice. These data identify PLC- as a critical determinant of proinflammatory and leaky phenotype of the lung. To test the possibility that PLC- activity in endothelial cells (EC) could contribute to ALI, we determined its role in EC inflammation and barrier disruption. RNAi knockdown of PLC- inhibited NF-B activity in response to diverse proinflammatory stimuli, thrombin, LPS, TNF-α, and the nonreceptor agonist phorbol 13-myristate 12-acetate (phorbol esters) in EC. Depletion of PLC- also inhibited thrombin-induced expression of NF-B target gene, VCAM-1. Importantl...
Source: AJP: Lung Cellular and Molecular Physiology - Category: Respiratory Medicine Authors: Tags: ARTICLES Source Type: research