Angiotensin II and the fibroproliferative response to acute lung injury
Angiotensin II and the fibroproliferative response to acute lung injury
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DOI：
10.1152/ajplung.00313.2002
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发表时间：
2004-01-01
影响因子：
4.9
通讯作者：
Laurent, GJ
中科院分区：
文献类型：
--
作者：
Marshall, RP;Gohlke, P;Laurent, GJ
血管紧张素II(Ang II)是由局部肾素-血管紧张素系统激活产生的，被认为在组织修复和重塑中发挥重要作用，部分是通过转化生长因子-β(TGF-β)。血管紧张素转换酶(ACE)抑制剂已被证明通过一些潜在的机制来消除实验性肺损伤；然而，Ang II在肺中潜在的纤维增殖作用尚未被表征。我们推测，肺损伤后，血管紧张素Ⅱ可刺激成纤维细胞合成前胶原，促进肺组织胶原沉积。在体外，Ang II通过激活1型受体和至少部分地通过转化生长因子-β的自分泌作用，有效地诱导人肺成纤维细胞产生前胶原。博莱霉素诱导的肺损伤后，肺血管紧张素II浓度在肺胶原增加之前的第3天出现升高，并一直维持到第21天死亡。给予血管紧张素转换酶抑制剂(雷米普利)可降低血管紧张素转换酶活性、血管紧张素Ⅱ浓度、转化生长因子-β表达和胶原沉积。氯沙坦(一种血管紧张素II 1型受体拮抗剂)也减轻了转化生长因子-β的表达和肺组织胶原沉积的增加。这些观察表明，可能在肺内局部产生的Ang II可能在急性肺损伤的纤维化反应中发挥重要作用，至少部分是通过转化生长因子-β的作用。血管紧张素转换酶抑制剂和受体拮抗剂已广泛应用于临床，应被评估为治疗纤维化肺疾病的潜在新疗法。
Angiotensin II (ANG II), generated by activation of local renin-angiotensin systems, is believed to play an important role in tissue repair and remodeling, in part via transforming growth factor-beta (TGF-beta). Angiotensin-converting enzyme (ACE) inhibitors have been shown to abrogate experimental lung injury via a number of potential mechanisms; however, the potentially fibroproliferative role for ANG II in the lung has not been characterized. We hypothesized that, after lung injury, ANG II would stimulate fibroblast procollagen synthesis and promote lung collagen deposition in rats. In vitro, ANG II was a potent inducer of procollagen production in human lung fibroblasts via activation of the type 1 receptor and, at least in part, via the autocrine action of TGF-beta. After bleomycin-induced lung injury, an increase in lung ANG II concentration was observed by day 3 that preceded increases in lung collagen and was maintained until death at day 21. Administration of an ACE inhibitor (ramipril) reduced ACE activity, ANG II concentration, TGF-beta expression, and collagen deposition. Losartan ( an ANG II type 1 receptor antagonist) also attenuated the increase in TGF-beta expression and lung collagen deposition. These observations suggest that ANG II, possibly generated locally within the lung, may play an important role in the fibrotic response to acute lung injury, at least in part via the action of TGF-beta. ACE inhibitors and receptor antagonists, already widely used clinically, should be assessed as potential new therapies for fibrotic lung disease.