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Pharmacological Inhibition of Poly ADP-Ribose Polymerase Ameliorates Elastase Induced Inflammation and Emphysema in Mice
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A7151 - Pharmacological Inhibition of Poly ADP-Ribose Polymerase Ameliorates Elastase Induced Inflammation and Emphysema in Mice
Author Block: A. S. Naura, V. Dharwal; Biochemistry, Panjab University, Chandigarh, India.
Chronic obstructive pulmonary disease (COPD) is one of the leading causes responsible for global morbidity and mortality, and has no effective treatment available till date. We have previously reported that PARP plays a crucial role in the establishment of airway inflammation associated with asthma and acute lung injury. In the present work, we have evaluated the beneficial effects of PARP inhibition on COPD pathogenesis utilizing elastase (given intratracheally) induced mouse model of the disease. Dose response studies show that PARP inhibition by olaparib at a dose of 5mg/kg b.wt (i.p.) reduced the elastase induced recruitment of inflammatory cells particularly neutrophils in the lungs significantly. Interestingly, dexamethosone at 5mg/kg (i.p.) did not protect against elastase induced lung inflammation reflecting the steroid refractory nature of the condition. Reduction in the lung inflammation was associated with suppressed myeloperoxidase activity upon olaparib administration. Further, the drug restored the redox status in the lung tissues towards normal as reflected by the levels of reactive oxygen species, reduced glutathione, and malondialdehyde. Normalization of redox status in lungs was coupled with suppressed PARP activity as reduced ribosylation of proteins was observed. Western blot analysis showed that olaparib administration prior to elastase instillation blunted the phosphorylation of P65-NF-κB at Ser 536 without altering the phosphorylation of its inhibitor IκBα in the lungs. Furthermore, olaparib down regulated the elastase induced expression of NF-κB dependent pro-inflammatory cytokines (TNF-α, IL-6), chemokine (MIP-2), and growth factor (GCSF) severely both at the mRNA and protein levels. Daily administration of the drug effectively protected against as the development of emphysema, assessed 21 days after elastase instillation. Overall, our data strongly suggest that PARP play a critical role in elastase induced lung inflammation and emphysema; thus might be a new drug target in COPD.
Author Block: A. S. Naura, V. Dharwal; Biochemistry, Panjab University, Chandigarh, India.
Chronic obstructive pulmonary disease (COPD) is one of the leading causes responsible for global morbidity and mortality, and has no effective treatment available till date. We have previously reported that PARP plays a crucial role in the establishment of airway inflammation associated with asthma and acute lung injury. In the present work, we have evaluated the beneficial effects of PARP inhibition on COPD pathogenesis utilizing elastase (given intratracheally) induced mouse model of the disease. Dose response studies show that PARP inhibition by olaparib at a dose of 5mg/kg b.wt (i.p.) reduced the elastase induced recruitment of inflammatory cells particularly neutrophils in the lungs significantly. Interestingly, dexamethosone at 5mg/kg (i.p.) did not protect against elastase induced lung inflammation reflecting the steroid refractory nature of the condition. Reduction in the lung inflammation was associated with suppressed myeloperoxidase activity upon olaparib administration. Further, the drug restored the redox status in the lung tissues towards normal as reflected by the levels of reactive oxygen species, reduced glutathione, and malondialdehyde. Normalization of redox status in lungs was coupled with suppressed PARP activity as reduced ribosylation of proteins was observed. Western blot analysis showed that olaparib administration prior to elastase instillation blunted the phosphorylation of P65-NF-κB at Ser 536 without altering the phosphorylation of its inhibitor IκBα in the lungs. Furthermore, olaparib down regulated the elastase induced expression of NF-κB dependent pro-inflammatory cytokines (TNF-α, IL-6), chemokine (MIP-2), and growth factor (GCSF) severely both at the mRNA and protein levels. Daily administration of the drug effectively protected against as the development of emphysema, assessed 21 days after elastase instillation. Overall, our data strongly suggest that PARP play a critical role in elastase induced lung inflammation and emphysema; thus might be a new drug target in COPD.
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