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TRPC1‐Mediated Ca2+ Entry Increases Lung Microvascular Permeability
Author(s) -
Tauseef Mohammad,
Knezevic Nebojsa,
Malik Asrar B,
Abramowitz Joel,
Birnbaumer Lutz,
Mehta Dolly
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.964.9
Subject(s) - trpc1 , thapsigargin , lung , vascular permeability , transient receptor potential channel , intracellular , chemistry , receptor , endocrinology , microbiology and biotechnology , medicine , biology
Despite the evidence that transient receptor potential canonical (TRPC1) channel can mediate Ca 2+ entry in endothelial cells the role of TRPC1 activity in the mechanism of increased lung vascular permeability remains unclear. We isolated lungs from TRPC1 −/− and wild type (WT) mice and activated Ca 2+ entry by two independent mechanisms to determine the role of TRPC1 in regulating lung microvascular permeability. We perfused lungs with either thapsigargin, that activates Ca 2+ entry by depleting intracellular stores or diacylglycerol (DAG), that activate Ca 2+ entry independent of store depletion. We determined lung microvascular permeability by determining filtration co‐efficient ( K fc ), a measure of hydraulic conductivity across endothelial exchange barrier. We show that in WT lungs thapsigargin increased lung K fc whereas thapsigargin failed to increase K fc in lungs isolated from TRPC1 −/− mice. Interestingly, OAG, a cell permeable analog of DAG, increased K fc in TRPC1 −/− mice but the K fc response was significantly lower than that observed in WT mice lungs. We next determined the contribution of TRPC1 in regulating lung microvascular permeability in response to thrombin ligation of protease activating receptor 1 (PAR‐1) which activate Ca 2+ entry both by store‐dependent and DAG‐dependent manner. We show that PAR‐1 activation by specific PAR‐1 peptide increased K fc in WT lungs whereas it failed to induce a response in lungs isolated from TRPC1 −/− mice. We also address the role of TRPC1 in the lung inflammatory response to sepsis induced by i.p. injection of LPS. Prevention of lung injury in TRPC1 −/− mice was associated with decreased mortality in response to LPS challenge. Thus, TRPC1 through its ability to regulate Ca 2+ entry is a crucial determinant of increased lung microvascular permeability and inflammatory response.