Therapeutic target for pulmonary hypertension based on coagulative and inflammatory cascade analysis

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The purpose of the present study was to investigate whether procoagulant state and inflammatory response occur and administration of trombomodulin(TM) prevents the development of pulmonary hypertension(PH) in monocrotaline. injected rats. Monocrotaline increased mPAP, RVH,% muscularization, and% MWT. TM treatment significantly reduced mPAP,% muscularization, and% MWT in peripheral arteries with an external diameter of 50-100μm in 19 days after monocrotaline injecton, but the effect was lost after 29 days. Monocrotaline increased the levels of tumor necrosis factor alpha, monocyte chemoattractant protein-1, and thrombin-antithrombin complex(TAT) in BALF, and expression of eNOS while peNOS was decreased. In TM-treated rats eNOS expression was decreased and peNOS was similar compared to TM-non-treated rats. A Kaplan-Meier survival curve showed no difference between rats with and without TM. Although the administration of TM might slightly delay the progression of monocrotaline-induced PH, the physiological significance for treatment is limited, since TM did not improve survival. Although exogenous TM failed to prevent the occurrence of PH in the present study, treatment to increase the endogenous production of TM in endothelial cells might reduce the severity of PH. Further investigation will be necessary.