Abstract 18495: Lung Inflammation Impairs Hypoxic Pulmonary Vasoconstriction Through Activation of Nuclear Factor of Activated T-Cells

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Hypoxic pulmonary vasoconstriction (HPV) is an important physiologic mechanism that directs blood flow away from poorly ventilated regions of the lung toward well-ventilated regions in order to maintain optimal ventilation (V) and perfusion (Q) matching which supports adequate gas exchange and oxygenation. Impaired HPV has been implicated in multiple disease processes that are associated with both hypoxemia and inflammation. Nuclear factor of activated T-cells (NFAT) is a calcium-dependent transcription factor with emerging evidence to suggest an important role in inflammatory as well as cardiovascular disorders. We hypothesize that lipopolysaccharide (LPS)-induced lung inflammation leads to impaired HPV as a result of NFAT activation. In the current study we have utilized the isolated perfused mouse lung (IPL) preparation to test acute hypoxic pulmonary vasoconstriction. Murine lung inflammation is induced by intratracheal instillation of LPS (1 mcg/gm body weight) and acute hypoxic pulmonary vasoconstriction is elicited by five minute challenges of 1% inspired oxygen tension. LPS-induced lung inflammation significantly impairs HPV at 24 hours compared to sham (saline) treatment. In protein isolates from whole mouse lung lysates, LPS-induced lung inflammation is associated with significant increases in both calcineurin and NFATc3 protein expression at 24 hours. Finally, pretreatment with a calcineurin inhibitor, cyclosporin A, one hour prior to LPS treatment prevents the impaired HPV seen in LPS-induced lung inflammation in a dose dependent manner at 30 and 100 mg/kg. We conclude that LPS-induced lung inflammation impairs hypoxic pulmonary vasoconstriction in mice. This effect is mediated by NFAT activation and we show that inhibition of calcineurin, leading to decreased NFAT activation, can attenuate the impaired HPV seen in murine lung inflammation. Impaired HPV results in V/Q mismatching and worsening hypoxemia, a detrimental effect in both acute and chronic cardiopulmonary disease. These results implicate NFAT as a potential novel therapeutic target in diseases characterized by hypoxemia and impaired HPV. We plan to continue this work to determine the downstream effects of NFAT activation that lead to impaired HPV.