Department of Biochemistry, Panjab University, Chandigarh, India.
Department of Biochemistry, Panjab University, Chandigarh, India.
Biochem Pharmacol. 2018 Apr;150:24-34. doi: 10.1016/j.bcp.2018.01.027. Epub 2018 Feb 3.
COPD is associated with high morbidity and mortality and no effective treatment is available till date. We have previously reported that PARP-1 plays an important role in the establishment of airway inflammation associated with asthma and ALI. In the present work, we have evaluated the beneficial effects of PARP-1 inhibition on COPD pathogenesis utilizing elastase induced mouse model of the disease. Our data show that PARP-1 inhibition by olaparib significantly reduced the elastase-induced recruitment of inflammatory cells particularly neutrophils in the lungs of mice when administered at a dose of 5 mg/kg b.wt (i.p.). Reduction in the lung inflammation was associated with suppressed myeloperoxidase activity. Further, the drug restored the redox status in the lung tissues towards normal as reflected by the levels of ROS, GSH and MDA. Olaparib administration prior to elastase instillation blunted the phosphorylation of P65-NF-κB at Ser 536 without altering phosphorylation of its inhibitor IκBα in the lungs. Furthermore, olaparib down regulated the elastase-induced expression of NF-κB dependent pro-inflammatory cytokines (TNF-A, IL-6), chemokine (MIP-2) and growth factor (GCSF) severely both at the mRNA and protein levels. Additionally, PARP-1 heterozygosity suppressed the recruitment of inflammatory cells and production of TNF-A, IL-6, MIP-2 and GCSF in the BALF to the similar extent as exhibited by olaparib administration. Finally, PARP-1 inhibition by olaparib or gene deletion protected against elastase-induced emphysema markedly. Overall, our data strongly suggest that PARP-1 plays a critical role in elastase induced lung inflammation and emphysema, and thus may be a new drug target candidate in COPD.
COPD 与高发病率和死亡率相关，迄今为止尚无有效的治疗方法。我们之前曾报道过，PARP-1 在与哮喘和 ALI 相关的气道炎症的建立中起着重要作用。在本工作中，我们利用弹性蛋白酶诱导的 COPD 小鼠模型评估了 PARP-1 抑制对 COPD 发病机制的有益作用。我们的数据表明，PARP-1 抑制剂奥拉帕尼（olaparib）以 5mg/kg 体重（腹腔注射）的剂量给药时，可显著减少弹性蛋白酶诱导的肺部炎症细胞（尤其是中性粒细胞）的募集。肺炎症的减少与髓过氧化物酶活性的抑制有关。此外，该药物将肺组织中的氧化还原状态恢复至正常水平，反映为 ROS、GSH 和 MDA 的水平。弹性蛋白酶注入前给予奥拉帕尼可使 NF-κB 的 P65 亚基 Ser536 磷酸化减弱，而不改变其抑制剂 IκBα在肺中的磷酸化。此外，奥拉帕尼下调了 NF-κB 依赖性促炎细胞因子（TNF-α、IL-6）、趋化因子（MIP-2）和生长因子（GCSF）在肺部的弹性酶诱导表达，在 mRNA 和蛋白水平均严重下调。此外，PARP-1 杂合性以与奥拉帕尼给药相似的程度抑制了 BALF 中炎症细胞的募集和 TNF-α、IL-6、MIP-2 和 GCSF 的产生。最后，奥拉帕尼或基因缺失抑制 PARP-1 可显著防止弹性蛋白酶诱导的肺气肿。总的来说，我们的数据强烈表明，PARP-1 在弹性蛋白酶诱导的肺炎症和肺气肿中起着关键作用，因此可能是 COPD 的一个新的药物靶点候选物。
