Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor
Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor
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DOI：
10.1152/ajplung.2000.279.1.l143
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发表时间：
2000-07-01
影响因子：
4.9
通讯作者：
Uhal, BD
中科院分区：
文献类型：
--
作者：
Wang, RQ;Ibarra-Sunga, O;Uhal, BD
血管紧张素转换酶参与肺泡上皮细胞的凋亡(Wang R，Zagariya A，Ang E，Ibarra-Sunga O和Uhal BD)。Am J Physiol肺细胞分子生理学277：L1245-L1250,1999)。本研究检测了血管紧张素转换酶抑制剂卡托普利和半胱氨酸氨基转移酶抑制剂Z-Val-Ala-Asp-氟甲基酮(zVAD-fmk)对博莱霉素(Bleo)诱导的肺泡上皮细胞凋亡和肺纤维化的抑制作用。雄性Wistar大鼠气管内注射硫酸博莱霉素8U/kg或赋形剂。Bleo处理组的大鼠接受卡托普利、zVAD-fmk或单独使用赋形剂。分别于伤后1、7、14d用天狼星红或羟脯氨酸测定肺胶原蛋白含量，原位末端标记法(ISEL)检测肺组织细胞凋亡。到第14天，Bleo使肺泡间隔和支气管周围胶原分别增加了100%和133%(P均<0.01)，但不早。相反，肺泡和呼吸道细胞的ISEL在各个时间点均增加。卡托普利和zVAD-fmk分别抑制91%和85%的胶原沉积(P<；0.01)。两种药物对肺泡和呼吸道的ISEL分别抑制99%和81%，67%和63%。这些数据提示卡托普利抑制实验性肺纤维化的作用与抑制细胞凋亡有关。他们还展示了半胱氨酸天冬氨酸酶抑制剂的抗纤维化潜力。
Angiotensin-converting enzyme is involved in apoptosis of alveolar epithelial cells (Wang R, Zagariya A, Ang E, Ibarra-Sunga O, and Uhal BD. Am J Physiol Lung Cell Mol Physiol 277: L1245-L1250, 1999). This study tested the ability of the angiotensin-converting enzyme inhibitor captopril or the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone (ZVAD-fmk) to block alveolar epithelial cell apoptosis and lung fibrosis in vivo in response to bleomycin (Bleo). Male Wistar rats received 8 U/kg of Bleo (bleomycin sulfate) or vehicle intratracheally. Subgroups of Bleo-treated rats received captopril, ZVAD-fmk, or vehicle alone. Lung collagen was assessed by picrosirius red or hydroxyproline assay at 1, 7, and 14 days post-Bleo, and apoptosis was detected by in situ end labeling (ISEL). Bleo increased alveolar septal and peribronchial collagen by 100 and 133%, respectively (both P< 0.01), by day 14 but not earlier. In contrast, ISEL was increased in alveolar and airway cells at all time points. Captopril or ZVAD-fmk inhibited collagen accumulation by 91 and 85%, respectively (P< 0.01). Both agents also inhibited ISEL in alveoli by 99 and 81% and in airways by 67 and 63%, respectively. These data suggest that the efficacy of captopril to inhibit experimental lung fibrogenesis is related to inhibition of apoptosis. They also demonstrate the antifibrotic potential of a caspase inhibitor.