Dr. Augustine M.K. Choi, the Sanford I. Weill Chairman of the Weill Department of Medicine, and his laboratory have published findings in the Journal of Clinical Investigation (JCI) that suggest a new pathway for targeting novel therapies for the treatment of COPD.
Dr. Choi (center) with investigators in the Choi Lab
COPD (Chronic Obstructive Pulmonary Diseases) are the fourth leading cause of mortality worldwide, and cigarette smoke is the major risk factor. Although the pathogenesis of COPD is not completely understood, it may involve aberrant inflammatory and cellular responses in the lung that are in response to cigarette smoke. In previous research conducted by the Choi Lab and colleagues, it was found that the process of selective autophagy (mitophagy), which involves the removal of mitochondria, has a role in the pathogenesis of COPD. It has also been reported that exposure to CS causes cell death via apoptosis and necrosis; the first (apoptosis) being a genetically programmed pathway to cell death, and the latter (necrosis) being due to extreme physical or chemical stress (such as cigarette smoke).
In previous research, the Choi Lab and colleagues showed that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to cigarette smoke. With their latest paper in JCI, entitled "Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD," the team has furthered their line of discovery on mitophagy as it relates to the pathogenesis of COP. Specifically, their new findings have implicated mitophagy-dependent necroptosis in lung emphysematous changes in response to cigarette smoke. It is this particular finding, involving necroptosis (or programmed necrosis), that has opened a new line of investigation for targeting novel therapies for COPD.
As reported in the JCI paper, Dr. Choi's team employed a variety of state of the art techniques in a mechanistic study that has explained how cigarette smoke can regulate cell death through the initiation of mitophagy and necroptosis. To that end, the researchers delivered data demonstrating that increased expression of the mitophagy protein PINK1, the necroptosis regulator RIP3, and the fission regulator Drp1 in COPD lung tissues supports their hypothesis, which is: mitophagy and necroptosis contribute to COPD. Additionally, the study showed in a mouse model that Mdivi-1 (a mitochondrial division/mitophagy inhibitor), in conjunction with a genetic deficiency of PINK1, played a role in protection against cigarette smoke-induced cell death. The researchers, therefore, suggest at the end of their discussion that treatment with Mdivi-1 may lead to novel therapies for COPD.