Gene knockout or pharmacological inhibition of Poly(ADP-Ribose) polymerase-1 prevents lung inflammation in a murine model of asthma
Gene knockout or pharmacological inhibition of Poly(ADP-Ribose) polymerase-1 prevents lung inflammation in a murine model of asthma
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DOI：
10.1165/rcmb.2001-0015oc
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发表时间：
2003-03-01
影响因子：
6.4
通讯作者：
Smulson, ME
中科院分区：
文献类型：
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作者：
Boulares, AH;Zoltoski, AJ;Smulson, ME
呼吸道炎症是哮喘和慢性阻塞性肺疾病的主要特征。活性氧物种(ROS)通过破坏DNA而导致炎症，进而导致多(ADP-核糖)聚合酶-1(PARP-1)的激活及其底物烟酰胺腺嘌呤二核苷酸的耗尽。在这里，我们表明，PARP-1激活的预防在体外可以保护ROS诱导的呼吸道上皮细胞损伤，在体内可以保护呼吸道炎症。H_2O_2诱导A549人呼吸道上皮细胞产生ROS，PARP-1激活，伴随烟酰胺腺嘌呤二核苷酸耗竭，乳酸脱氢酶释放。这些作用可被PARP-1抑制剂3-氨基苯甲酰胺(3-AB)阻断。此外，3-AB可抑制H_2O_2诱导的促炎转录因子核转录因子-kappaB的激活和IL-8基因的表达。在过敏原诱导的哮喘小鼠模型中，3-AB可预防卵清蛋白引起的呼吸道炎症。此外，PARP-1基因敲除小鼠对卵蛋白诱导的炎症具有抵抗力。这些保护作用与抑制诱导型一氧化氮合酶的表达有关。这些结果表明PARP-1激活与呼吸道炎症有关，并表明这种酶可能成为治疗哮喘和其他呼吸系统疾病(如慢性阻塞性肺疾病)的新治疗策略的潜在靶点。
Airway inflammation is a central feature of asthma and chronic obstructive pulmonary disease. Reactive oxygen species (ROS) contribute to inflammation by damaging DNA, which, in turn, results in the activation of poly(ADP-ribose) polymerase-1 (PARP-1) and depletion of its substrate, nicotinamide adenine dinucleotide. Here we show that prevention of PARP-1 activation protects against both ROS-induced airway epithelial cell injury in vitro and airway inflammation in vivo. H2O2 induced the generation of ROS, PARP-1 activation and concomitant nicotinamide adenine dinucleotide depletion, and release of lactate dehydrogenase in A549 human airway epithelial cells. These effects were blocked by the PARP-1 inhibitor 3-aminobenzamide (3-AB). Furthermore, 3-AB inhibited both activation of the proinflammatory transcription factor nuclear factor-kappaB and expression of the interleukin-8 gene induced by H2O2 in these cells. in a murine model of allergen-induced asthma, 3-AB prevented airway inflammation elicited by ovalbumin. Moreover, PARP-1 knockout mice were resistant to such ovalbumin-induced inflammation. These protective effects were associated with an inhibition of expression of the inducible nitric oxide synthase. These results implicate PARP-1 activation in airway inflammation, and suggest this enzyme as a potential target for the development of new therapeutic strategies in the treatment of asthma as well as other respiratory disorders such as chronic obstructive pulmonary disease.