Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis
Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis
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DOI：
10.1183/09031936.00018215
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发表时间：
2015-10-01
影响因子：
24.3
通讯作者：
Schermuly, Ralph Theo
中科院分区：
文献类型：
--
作者：
Kosanovic, Djuro;Luitel, Himal;Schermuly, Ralph Theo
有限的文献来源暗示肥大细胞介质糜酶在肺动脉高压和肺纤维化的病理。然而，没有证据表明糜酶对肺纤维化相关的肺动脉高压的发展有贡献，肺纤维化是与已经患有危及生命的间质性肺病的患者的死亡率增加相关的重要医学病症。本研究的目的是调查糜酶在这种特殊的肺动脉高压形式中的作用，糜蛋白酶抑制导致肺动脉高压和肺纤维化的减弱，如从改善的血液动力学、减少的右心室重构/肥大、肺血管重构和肺纤维化所证明的。这些有益的效果与肥大细胞数量和活性减少的强烈趋势相关，并显著降低糜酶表达水平。从机制上讲，糜酶抑制导致肺中转化生长因子β 1和基质金属蛋白酶-2含量减少。此外，糜酶抑制剂可阻止大内皮素-1诱导的肺动脉血管收缩，因此糜酶在肺纤维化相关的肺动脉高压的发病机制中起作用，并可能成为一个有希望的治疗靶点。此外，这项研究可能会提供有价值的见解，在肺动脉高压的背景下，在一般情况下，无论肺动脉高压的形式糜酶的贡献。
Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor beta 1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form.