TRPM2 channels in alveolar epithelial cells mediate bleomycin-induced lung inflammation
TRPM2 channels in alveolar epithelial cells mediate bleomycin-induced lung inflammation
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DOI：
10.1016/j.freeradbiomed.2015.11.021
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发表时间：
2016-01-01
影响因子：
7.4
通讯作者：
Shimizu, Shunichi
中科院分区：
文献类型：
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作者：
Yonezawa, Ryo;Yamamoto, Shinichiro;Shimizu, Shunichi
肺部炎症是抗肿瘤药物博莱霉素（BLM）治疗的主要不良反应。瞬时受体电位melastatin 2（TRPM 2）是一种钙离子渗透通道，通过产生ADP-核糖被氧化应激激活。我们在此研究了TRPM 2通道是否有助于BLM诱导的肺部炎症。肺内滴注BLM到野生型（WT）小鼠增加了多形核白细胞（PMN）的数量和炎症细胞因子在肺中的水平。WT小鼠中炎症标志物的增加在trpm 2敲除（KO）小鼠中显著降低，这证明TRPM 2通道的激活参与BLM诱导的肺部炎症。在肺泡巨噬细胞、肺泡上皮细胞和肺成纤维细胞中观察到TRPM 2 mRNA的表达。TRPM 2蛋白在肺组织中有表达。其中，上皮细胞中的TRPM 2通道被BLM预处理后加入H2 O2激活，导致巨噬细胞炎性蛋白-2（MIP-2）的分泌。聚腺苷二磷酸核糖聚合酶（PARP）抑制剂PJ 34和3-氨基苯甲酰胺可阻断BLM预处理对H2 O2诱导的TRPM 2的激活作用。聚（ADP-核糖）在细胞核中的积累，ADP-核糖生产的标志，强烈诱导H2 O2的BLM预处理后。此外，给WT小鼠施用PRAP抑制剂显著减少了由BLM滴注诱导的炎性细胞的募集和MIP-2的分泌。上述结果提示，BLM诱导肺泡上皮细胞分泌MIP-2可能是通过激活TRPM 2通道而实现的，而TRPM 2的激活可能是通过PARP途径产生ADP-核糖而实现的。TRPM 2通道可能成为BLM诱导的肺部炎症的新的治疗靶点。(C)2015 Elsevier Inc. All rights reserved.
Lung inflammation is a major adverse effect of therapy with the antitumor drug bleomycin (BLM). Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable channel that is activated by oxidative stress through the production of ADP-ribose. We herein investigated whether TRPM2 channels contributed to BLM-induced lung inflammation. The intratracheal instillation of BLM into wild-type (WT) mice increased the number of polymorphonuclear leukocytes (PMNs) and inflammatory cytokine levels in the lung. Increases in inflammatory markers in WT mice were markedly reduced in trpm2 knockout (KO) mice, which demonstrated that the activation of TRPM2 channels was involved in BLM-induced lung inflammation. The expression of TRPM2 mRNA was observed in alveolar macrophages, alveolar epithelial cells, and lung fibroblasts. Actually, TRPM2 protein was expressed in lung tissues. Of these, TRPM2 channels in epithelial cells were activated by the addition of H2O2 following a BLM pretreatment, resulting in the secretion of macrophage inflammatory protein-2 (MIP-2). The H2O2-induced activation of TRPM2 by the BLM pretreatment was blocked by the poly(ADP-ribose) polymerase (PARP) inhibitors PJ34 and 3-aminobenzamide. The accumulation of poly(ADP-ribose) in the nucleus, a marker for ADP-ribose production, was strongly induced by H2O2 following the BLM pretreatment. Furthermore, administration of PRAP inhibitors into WT mice markedly reduced recruitment of inflammatory cells and MIP-2 secretion induced by BLM instillation. These results suggest that the induction of MIP-2 secretion through the activation of TRPM2 channels in alveolar epithelial cells is an important mechanism in BLM-induced lung inflammation, and the TRPM2 activation is likely to be mediated by ADP-ribose production via PARP pathway. TRPM2 channels may be new therapeutic target for BLM-induced lung inflammation. (C) 2015 Elsevier Inc. All rights reserved.