Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis
Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis
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DOI：
10.1016/s0002-9440(10)62354-1
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发表时间：
2005-05-01
影响因子：
6
通讯作者：
Chambers, RC
中科院分区：
文献类型：
--
作者：
Howell, DCJ;Johns, RH;Chambers, RC
凝血级联的激活通常在患有急性和慢性炎性和纤维化肺病的患者的肺中以及在这些疾病的动物模型中观察到。本研究的目的是检查主要凝血酶受体，蛋白酶激活受体-1（PAR-1），在急性炎症和慢性纤维化阶段的肺损伤诱导博莱霉素在小鼠肺内滴注的贡献。与野生型（WT）小鼠相比，PAR-1缺陷（PAR-1（-/-））小鼠的炎性细胞募集和支气管肺泡灌洗液（BALF）蛋白增加分别减少了56 +/- 10%（P <0.05）和53 +/- 12%（P < 0.05）。PAR-1（-/-）小鼠也受到博来霉素诱导的肺纤维化的保护，总的肺胶原积累减少了59 +/- 5%（P < 0.05）。PAR-1缺乏所提供的保护作用伴随着肺内PAR-1诱导的促炎和促纤维化介质、单核细胞趋化蛋白-1（MCP-1）、转化生长因子-β-1（TGF-β 1）和结缔组织生长因子/成纤维细胞诱导分泌蛋白-12（CTGF/FISP 12）水平的显著降低。此外，帕拉在从纤维化肺病患者获得的肺切片中的炎性和纤维增生性病变中高度表达。这些数据首次表明PAR-1信号在实验诱导的肺损伤中起着关键作用，并且他们进一步确定PAR-1是参与协调凝血，炎症和重塑之间相互作用的关键受体之一，以响应组织损伤。
Activation of the coagulation cascade is commonly observed in the lungs of patients with both acute and chronic inflammatory and fibrotic lung disorders, as well as in animal models of these disorders. The aim of this study was to examine the contribution of the major thrombin receptor, proteinase-activated receptor-1 (PAR-1), during the acute inflammatory and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. inflammatory cell recruitment and increases in bronchoalveolar lavage fluid (BALF) protein were attenuated oby 56 +/- 10% (P < 0.05) and 53 +/- 12% (P < 0.05), respectively, in PAR-1-deficient (PAR-1(-/-)) mice compared with wild-type (WT) mice. PAR-1(-/-) mice were also protected from bleomycin-induced pulmonary fibrosis with total lung collagen accumulation reduced by 59 +/- 5% (P < 0.05). The protection afforded by PAR-I deficiency was accompanied by significant reductions in pulmonary levels of the potent PAR-1inducible proinflammatory and profibrotic mediators, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta-1 (TGF-beta(1)), and connective tissue growth factor/fibroblast-inducible secreted protein-12 (CTGF/FISP12). In addition, PARA was highly expressed in inflammatory and fibroproliferative lesions in lung sections obtained from patients with fibrotic lung disease. These data show for the first time that PAR-1 signaling plays a key role in experimentally induced lung injury, and they further identify PAR-1 as one of the critical receptors involved in orchestrating the interplay between coagulation, inflammation, and remodeling in response to tissue injury.