PARP inhibitor, olaparib ameliorates acute lung injury by modulating oxidative stress and NF-κB mediated inflammatory response in mice (HUM1P.265)

Abstract

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.