Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 209, Issue 11, Pages 1953-1968Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20111355
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Funding
- National Institutes of Health [HL71794, HL84153, P01-HL60678]
- American Heart Association postdoctoral fellowship [10POST2600336]
- Intramural Research Division of the National Institutes of Health [Z01-ES-101684]
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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 Ca2+ entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca2+ signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca2+ 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 Ca2+ entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca2+ 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 inter-action of myeloid differentiation factor 88 and IL-1R-associated kinase 4, which are required for NF-kappa B activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca2+ entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin.
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