Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury

Abstract

The intracellular serine/threonine kinase protein kinase C (PKC) has an important role in the genesis of pulmonary edema. This review discusses the PKC-mediated mechanisms that participate in the pulmonary endothelial response to agents involved in lung injury characteristic of the respiratory distress syndrome. Thus the paradigms of PKC-induced lung injury are discussed within the context of pulmonary transvascular fluid exchange. We focus on the signal transduction pathways that are modulated by PKC and their effect on lung endothelial permeability. Specifically, α-thrombin, tumor necrosis factor (TNF)-α, and reactive oxygen species are discussed because of their well-established roles in both human and experimental lung injury. We conclude that PKC, most likely PKC-α, is a primary supporter for lung endothelial injury in response to α-thrombin, TNF-α, and reactive oxygen species.

Novel regulators of endothelial barrier function

“…The protein kinase C (PKC) family consists of isoforms with different Ca 2ϩ and phorbol ester requirements for activation: conventional (␣, ␤, ␦), novel (⑀, ␥), and atypical (, ) (85,128). PKC␣ has a crucial role in mediating IEJ disassembly either by phosphorylating IEJ components or through inducing the RhoA pathway (76,78,96).…”

Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

“…Translocation to plasma membrane and phosphorylation of PKC␣ and in vitro phosphorylation of target proteins by PKC␣ have been used as indices of PKC␣ activation (15,35). We previously showed that GDI-1, an inhibitor of Rho-GTPases, is a PKC␣ substrate (4).…”

Ezrin/Radixin/Moesin Proteins Are Phosphorylated by TNF-α and Modulate Permeability Increases in Human Pulmonary Microvascular Endothelial Cells

“…Responses of endothelial cells (ECs) 3 to TNF-␣ and IL-1␤ include up-regulation of adhesion molecules such as ICAM-1, cytoskeletal changes, and permeability increases (1). Mice genetically deficient in receptors for TNF-␣ and IL-1␤ have reduced neutrophil emigration and edema formation in Escherichia coli pneumonia, establishing an indispensable role for these two cytokines in response to this stimulus (2).…”

“…TNF-␣ induces an increase in permeability in vivo, in the isolated lungs, and in pulmonary microvascular ECs in vitro (1). TNF-␣ also induces cytoskeletal changes within ECs, and the stabilization of F-actin using phalloidin prevents TNF-␣-induced decreases in endothelial barrier functions (3).…”