We have previously shown that PARP-1 inhibition provides protection against lung inflammation in the context of asthma and acute lung injury. Olaparib is a potent new generation PARP inhibitor that has been approved for human testing. The present work was designed to evaluate its beneficial potential against LPS-induced acute lung injury and acute kidney injury upon intratracheal administration of the endotoxin in mice. Administration of olaparib at different doses, 30 min after LPS treatment showed that single intraperitoneal injection of the drug at 5 mg/kg b.wt. reduced the total number of inflammatory cells particularly neutrophils in the lungs. This was associated with reduced pulmonary edema as the total protein content in the bronchoalveolar fluid was found to be decreased substantially. Olaparib provided strong protection against LPS-mediated secondary kidney injury as reflected by restoration of serum levels of urea, creatinine, and uric acid toward normal. The drug restored the LPS-mediated redox imbalance toward normal in lung and kidney tissues as assessed by measuring malondialdehyde and GSH levels. Finally, RT-PCR data revealed that olaparib downregulates the LPS-induced expression of NF-κB-dependent genes namely TNF-α, IL-1β, and VCAM-1 in the lungs without altering the expression of total p65NF-κB. Overall, the data suggest that olaparib has a strong potential to protect against LPS-induced lung injury and associated dysfunctioning of kidney in mice. Given the fact that olaparib is approved by FDA for human testing, our findings can pave the way for testing of the drug on humans inflicted with acute lung injury.
We have previously shown that poly (ADP-ribose) polymerase (PARP)-1 gene deletion in mice provide robust protection against lung inflammation in the context of asthma and acute lung injury. Olaparib is a potent new generation PARP inhibitor that has been approved for human testing in cancer patients. The present work was designed to evaluate its beneficial potential against LPS-induced acute lung injury upon intra-tracheal administration of the endotoxin in mice. Administration of olaparib at different doses, 30 min after LPS treatment showed that single injection of the drug effectively reduced the total number of inflammatory cells particularly neutrophils in the lungs. This was associated with reduced pulmonary edema as the total protein content in bronchoalveolar fluid was found to be decreased substantially. The drug restored the LPS mediated oxidative stress toward normal in lungs as assessed by measuring malondialdehyde and GSH levels. Finally, RT-PCR data revealed that olaparib downregulates the LPS induced expression of NF-κB dependent genes namely TNF-α, IL-1β and VCAM-1 in the lungs without altering the expression of total p65NF-κB. Overall, the data suggests that olaparib possesses a strong therapeutic potential against LPS induced lung injury in mice. Given the fact that olaparib is approved by FDA for human testing, our findings can pave the way for testing of the drug on humans inflicted with acute lung injury.
Chronic Obstructive Pulmonary Disorder (COPD) is a chronic inflammatory disease, currently affecting around 328 million people worldwide. Gallic acid (GA), a naturally occurring phenolic compound is known to possess anti‐oxidant and anti‐inflammatory activities. The aim of the present work was to investigate the beneficial effects of Gallic acid against COPD linked inflammation and emphysema by utilizing Elastase (ET) and Cigarette smoke (CS) based mouse model(s) of the disease. Male Balb/c mice were treated with ET (1U/mouse) or exposed to CS (9 cigarettes/day for 4 days). GA administration was started 7 days (daily) prior to induction of injury with ET or CS exposure. Broncho‐alveolar lavage was analysed for inflammatory cells and pro‐inflammatory cytokines. Lung homogenate was assessed for oxidative stress related biochemical parameters. Further, lung tissue was subjected to semi‐quantitative RT‐PCR, Immunoblotting and histological analysis. Our data showed that GA treatment suppressed the ET induced recruitment of inflammatory cells particularly neutrophils as well as myeloperoxidase activity in lungs at 24 hrs post injury. Reduction in the inflammatory cells was associated with subdued production of pro‐inflammatory cytokines namely IL‐1β, TNF‐α and IL‐6. Additionally, GA normalized the ET induced redox imbalance in the lungs towards normal as reflected by levels of ROS, MDA, GSH and protein carbonyls. Further, GA treatment blunted the ET induced phosphorylation of p65NF‐kB and its inhibitor IκBα along with down‐regulation of mRNA expression of NF‐kB dependent pro‐inflammatory factors including IL‐1β, TNF‐α, MIP‐2, KC and GCSF. Moreover, GA suppressed the CS induced influx of neutrophils and macrophages along with blunted gene expression of pro‐inflammatory cytokines TNF‐α, MIP‐2 and KC. Finally, histological analysis of lungs at 21 days after elastase administration showed that the phytochemical blocks the development of emphysema by restoring the balance between matrix metallo‐proteinases and their inhibitor(s). Overall, our data shows that GA effectively modulates pulmonary inflammation and emphysema associated with COPD pathogenesis in mice and thus may offer a new/alternative treatment strategies in the area. Support or Funding Information Financial support from Department of Biotechnology, Government of India (BT/PR17968/MED/122/33/2016 and BT/RLF/Re‐entry/36/2012), UGC‐SAP and Senior Research Fellowship from Indian Council of Medical Research (ICMR), India
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