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The pulmonary microvasculature plays a critical role in endotoxin-induced acute lung injury. However, the relevant signaling remain unclear. Specifically the role of endothelial Ca 2+  in the induction of endotoxin-mediated responses in lung microvessels remains undefined. Toward elucidating this, we used the isolated blood-perfused rat lung preparation. We loaded microvessels with the Ca 2+  indicator, Fura 2 AM and then determined Ca 2+  responses to infusions of lipopolysaccharide (LPS) into the microvessels. LPS induced a more than two-fold increase in the amplitude of cytosolic Ca 2+  oscillations. Inhibiting inositol 1,4,5 trisphosphate receptors on endoplasmic reticulum (ER) Ca 2+  stores with Xestospongin C (XeC), blocked the LPS-induced increase in the Ca 2+  oscillation amplitude. However, XeC did not affect entry of external Ca 2+  via plasma membrane Ca 2+  channels in lung microvascular endothelial cells. This suggested that LPS augmented the oscillations via release of Ca 2+  from ER stores. In addition, XeC also blocked LPS-mediated activation and nuclear translocation of nuclear factor-kappa B in lung microvessels. Further, inhibiting ER Ca 2+  release blunted increases in intercellular adhesion molecule-1 expression and retention of naïve leukocytes in LPS-treated microvessels. Taken together, the data suggest that LPS-mediated Ca 2+  release from ER stores underlies nuclear factor-kappa B activation and downstream inflammatory signaling in lung microvessels. Thus, we show for the first time a role for inositol 1,4,5 trisphosphate-mediated ER Ca 2+  release in the induction of LPS responses in pulmonary microvascular endothelium. Mechanisms that blunt this signaling may mitigate endotoxin-induced morbidity.

Lipopolysaccharide Induces Endoplasmic Store Ca2+-Dependent Inflammatory Responses in Lung Microvessels