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

本研究的目的是调查是否促凝状态和炎症反应的发生和管理trombomodulin（TM）防止肺动脉高压（PH）的发展在野百合碱。注射老鼠野百合碱增加mPAP、RVH、%肌化和% MWT。在注射野百合碱后19天内，TM可显著降低50-100μm外周动脉的mPAP、%肌化和% MWT，但29天后作用消失。野百合碱可增加BALF中肿瘤坏死因子α、单核细胞趋化蛋白-1和凝血酶-抗凝血酶复合物（达特）的水平，降低eNOS的表达和peNOS的表达。在TM治疗的大鼠中，eNOS表达降低，peNOS与TM未治疗的大鼠相似。Kaplan-Meier生存曲线显示有和无TM的大鼠之间没有差异。虽然TM的管理可能会稍微延迟野百合碱诱导的PH的进展，治疗的生理意义是有限的，因为TM没有改善生存。虽然外源性TM未能防止PH的发生在本研究中，治疗，以增加内皮细胞中的TM的内源性生产可能会降低PH的严重程度。进一步的调查将是必要的。

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.