Shea Barry S, Probst Clemens K, Brazee Patricia L, Rotile Nicholas J, Blasi Francesco, Weinreb Paul H, Black Katharine E, Sosnovik David E, Van Cott Elizabeth M, Violette Shelia M, Caravan Peter, Tager Andrew M
Division of Pulmonary, Critical Care and Sleep Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island, USA.
Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases.
JCI Insight. 2017 May 4;2(9). doi: 10.1172/jci.insight.86608.
Fibrotic lung disease, most notably idiopathic pulmonary fibrosis (IPF), is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to lung fibrosis is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on thrombin activity and its downstream signaling pathways. Direct thrombin inhibition with dabigatran significantly inhibited protease-activated receptor-1 (PAR1) activation, integrin αvβ6 induction, TGF-β activation, and the development of pulmonary fibrosis in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time (UTE) lung magnetic resonance imaging (MRI) with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of thrombin can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/αvβ6/TGF-β axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in IPF, and the clinical availability of direct thrombin inhibitors that our data suggest could benefit these patients.
纤维化肺病，最显著的是特发性肺纤维化（IPF），被认为是由对重复性肺损伤的异常伤口愈合反应所致。血管通透性增加是对组织损伤的主要反应，但它是否在机制上与肺纤维化相关尚不清楚。我们之前描述了一种模型，其中肺损伤后血管渗漏的加剧将伤口愈合反应的结果从正常修复转变为病理性纤维化。在此我们报告，该模型中产生的纤维化高度依赖于凝血酶活性及其下游信号通路。在这个血管渗漏依赖性模型中，用达比加群直接抑制凝血酶可显著抑制蛋白酶激活受体-1（PAR1）的激活、整合素αvβ6的诱导、转化生长因子-β（TGF-β）的激活以及肺纤维化的发展。我们使用了一种潜在的新型成像方法——基于钆的、纤维蛋白特异性探针EP-2104R的超短回波时间（UTE）肺磁共振成像（MRI），以直接观察受伤小鼠肺中纤维蛋白的积聚，并将达比加群的抗纤维化作用与纤维蛋白沉积的减少相关联。我们发现，凝血酶促纤维化作用的抑制可与止血抑制相分离，因为华法林的治疗性抗凝未能下调PAR1/αvβ6/TGF-β轴，也未能显著预防纤维化。鉴于最近发现华法林治疗对IPF无益，以及我们的数据表明直接凝血酶抑制剂在临床上可用且可能使这些患者受益，这些发现具有直接且重要的临床意义。
