Browsing by Author "Birnbaumer, Lutz"

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    TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation
    (Rockefeller University Press, 2012) Tauseef, Mohammad; Knezevic, Nebojsa; Chava, Koteswara R.; Smith, Monica; Sukriti, Sukriti; Gianaris, Nicholas; Obukhov, Alexander G.; Vogel, Stephen M.; Schraufnagel, Dean E.; Dietrich, Alexander; Birnbaumer, Lutz; Malik, Asrar B.; Mehta, Dolly; Cellular and Integrative Physiology, School of Medicine
    Lung vascular endothelial barrier disruption and the accompanying inflammation are primary pathogenic features of acute lung injury (ALI); however, the basis for the development of both remains unclear. Studies have shown that activation of transient receptor potential canonical (TRPC) channels induces Ca(2+) entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca(2+) signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca(2+) entry in ECs in a TLR4-dependent manner. Moreover, deletion of TRPC6 renders mice resistant to endotoxin-induced barrier dysfunction and inflammation, and protects against sepsis-induced lethality. TRPC6 induces Ca(2+) entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca(2+) entry mediated by TRPC6, in turn, activates the nonmuscle myosin light chain kinase (MYLK), which not only increases lung vascular permeability but also serves as a scaffold to promote the interaction of myeloid differentiation factor 88 and IL-1R-associated kinase 4, which are required for NF-κB activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca(2+) entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin.