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  • hmg-coa reductase Emphysema is an important component of COP


    Emphysema is an important component of COPD, which is responsible for airflow limitation. In the present study, a significant airspace enlargement was observed 21 days after elastase administration. Interestingly, daily administration of olaparib provided greater protection against emphysema as compared to when the drug was given on alternate days. Since the half-life of the drug is 11.9 ± 4.8 h [49], [90], it appears that the continuous PARP-1 inhibition is requisite for protection against elastase-induced emphysema.
    Declaration of interest
    Acknowledgements The present work was supported by funds from Department of Biotechnology, Government of India (BT/RLF/Re-entry/36/2012), DST-PURSE and UGC-SAP to ASN. We also acknowledge the Senior Research Fellowships to Vivek Dharwal from CSIR. The corresponding author was previously affiliated with Louisiana State University Health Sciences Center(LSUHSC), New Orleans, LA and the studies using PARP-1 deficient mice were conducted by him. The facilities provided by LSUHSC for conducting part of the work are highly acknowledged.
    Introduction Chronic obstructive pulmonary disease (COPD) causes irreversible damage to lung structures, leading to progressive disability and death. Emphysema and chronic bronchitis are included in the group of diseases named COPD, but with differences in pathophysiology and symptoms [1]. Emphysema is the major cause of morbidity and mortality in COPD patients worldwide. It is characterized by chronic and permanent inflammation and destruction of the alveolar walls due to the breakdown of the extracellular matrix in the parenchyma. The parenchymal breakdown leads to enlargement of the alveoli, loss of elastic recoil, reduction of the gas exchange capacity, and pulmonary hyperinflation [2]. Inflammatory cells migrate to hmg-coa reductase and, in addition to resident lung macrophages, release proteases that lead to an imbalance between them and proteinase inhibitory defenses or antiproteases [3]. Also associated with this condition are activated macrophages and neutrophils that release oxidants that, under conditions of oxidative stress, lead to a redox imbalance and consequent cellular damage [4]. Cigarette smoking is the main risk factor for pulmonary emphysema because it leads to a respiratory burst and consequent predominance of oxidants compared with antioxidants [5]. Studies using animal models of cigarette smoke-induced emphysema have demonstrated the importance of metalloproteinases, especially matrix metalloproteinase-12 (MMP-12). MMP-12 plays a pivotal role in the inflammatory process that leads to lung injury [6,7]. Genetic deficiency of α1-antitrypsin (α1-ATP) also causes pulmonary emphysema due to an elastolytic imbalance [8,9]. Both conditions cause destruction of lung tissue, yet the morphologies of these lesions differ, as emphysema is caused by cigarette smoke with a centrilobular characteristic, and emphysema is caused by α1-ATP deficiency with a panacinar characteristic [10]. Experimental investigations are being conducted using cigarette smoke or elastolytic enzymes to propose new treatment strategies since morphological emphysema in patients is similar in those mouse models [11,12]. Pharmacological treatment for emphysema is limited, but clinical symptoms improve, thus leading to an improved quality of life [13]. Long-term inhaled bronchodilators are used, which are effective for relieving symptoms [14], while corticosteroids have limited effectiveness [15]. To date, no drug can repair the lung damage caused by cigarette smoking or α1-ATP deficiency. Recent studies [[16], [17], [18], [19]] have reported the pleiotropic effects of statins (inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase), going beyond their ability to lower cholesterol, including anti-inflammatory effects (suppression of pro-inflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteinases) and antioxidant effects (including reactive oxygen species (ROS) scavengers). Our group recently published a study in which we used two inhaled statins (atorvastatin and simvastatin) to repair the emphysematous lesions in the lungs of mice that were chronically exposed to cigarette smoke and found that repair occurred in both treated groups [20]. Our objective in the present study was to evaluate whether treatment with inhaled atorvastatin could promote lung repair in a mouse model of severe emphysema caused by elastase.