MURINE STRAIN DIFFERENCES IN ACUTE LUNG INJURY AND ACTIVATION OF POLY(ADP-RIBOSE) POLYMERASE BY IN-VITRO EXPOSURE OF LUNG SLICES TO BLEOMYCIN
MURINE STRAIN DIFFERENCES IN ACUTE LUNG INJURY AND ACTIVATION OF POLY(ADP-RIBOSE) POLYMERASE BY IN-VITRO EXPOSURE OF LUNG SLICES TO BLEOMYCIN
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DOI：
10.1165/ajrcmb/7.6.645
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发表时间：
1992-12-01
影响因子：
6.4
通讯作者：
LAZO, JS
中科院分区：
文献类型：
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作者：
HOYT, DG;LAZO, JS
切割DNA的抗肿瘤抗生素博莱霉素（BLM）可引起肺纤维化，但启动纤维化状态的基本早期事件尚未得到很好的表征。因此，我们直接检查了BLM介导的肺细胞损伤，通过监测乳酸脱氢酶（LDH）的释放和核聚（ADP-核糖）聚合酶（PAP）的活性，这是刺激DNA断裂，使用肺切片分离BLM敏感（C57 B1/6）和BLM耐药（BALB/c）小鼠。肺切片连续孵育或不与PAP抑制剂，3-氨基苯甲酰胺（3-AB），并暴露于BLM 45分钟。LDH释放从C57 B1/6肺切片增加2倍，8.5小时后，与BLM治疗。相反，BLM不能增加BALB/c小鼠肺片累积LDH释放。C57 B1/6肺切片与3-AB的共孵育阻止了BLM诱导的LDH释放。在C57 B1/6肺切片暴露于BLM后1.25 h，核PAP活化3- 4倍，但在3.75 h时恢复到对照水平。在BALB/c肺切片中，核PAP在这些时间仅受到轻微影响。C57 B1/6切片与3-AB的共孵育防止了PAP活性的早期增加。这些结果表明，小鼠品系对急性细胞损伤和肺切片中BLM早期PAP活化的敏感性与肺的体内敏感性平行。此外，3-AB抑制肺切片中的PAP活化和急性细胞损伤。PAP的差异活化似乎支配小鼠品系变化，响应于BLM，并且与PAP活化参与急性肺细胞损伤，启动BLM诱导的纤维化过程的假设一致。
The DNA-cleaving, antitumor antibiotic bleomycin (BLM) causes pulmonary fibrosis, but the essential early events initiating the fibrotic state have not been well characterized. Thus, we have directly examined BLM-mediated pulmonary cell injury by monitoring lactate dehydrogenase (LDH) release and nuclear poly(ADP-ribose) polymerase (PAP) activity, which is stimulated by DNA breakage, using lung slices isolated from BLM-sensitive (C57B1/6) and BLM-resistant (BALB/c) mice. Lung slices were incubated continuously with or without the PAP inhibitor, 3-aminobenzamide (3-AB), and exposed to BLM for 45 min. LDH release from C57B1/6 lung slices increased 2-fold by 8.5 h after treatment with BLM. In contrast, BLM failed to enhance cumulative LDH release by BALB/c mouse lung slices. Co-incubation of C57B1/6 lung slices with 3-AB prevented BLM-induced LDH release. Nuclear PAP was activated 3- to 4-fold 1.25 h after exposure of C57B1/6 lung slices to BLM but returned to control levels by 3.75 h. Nuclear PAP was only marginally affected at these times in BALB/c lung slices. Co-incubation of C57B1/6 slices with 3-AB prevented the early increases in PAP activity. These results demonstrate that murine strain sensitivity to acute cell injury and early PAP activation by BLM in lung slices parallels the in vivo sensitivity of lungs. In addition, 3-AB suppresses PAP activation and acute cell injury in lung slices. Differential activation of PAP appears to govern murine strain variation in response to BLM and is consistent with the hypothesis that activation of PAP participates in acute pneumocyte injury, initiating the process of BLM-induced fibrosis.