The mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD), primarily associated with cigarette smoking (CS), including emphysema and bronchitis, remain unclear. Our published studies have suggested that autophagy, a lysosome-dependent pathway for the degradation of organelles and proteins, represents a major cellular and tissue response to CS exposure, in both experimental and human COPD lung. Emerging studies suggest that autophagy, while well established as a cellular survival process, can exert homeostatic or detrimental effects in complex diseases. Our studies were the first to demonstrate deleterious effects of autophagy and mitochondrial autophagy (mitophagy) in experimental models of COPD. Mice genetically deficient in the mitophagy regulator PINK1 were resistant to experimental COPD. We discovered that mitophagy induced by CS in response to mitochondrial dysfunction activates programmed epithelial cell death, in particular the necroptosis mode of cell death. Our Preliminary Studies indicate that CS exposure can disrupt metabolic pathways, including dysregulation of oxidative phosphorylation (OXPHOS) and inhibition of fatty acid (FA) synthesis. Hence, we put forth the following Hypothesis: CS exposure causes epithelial cell metabolic disruption and impaired FA synthesis that causes mitochondrial dysfunction, leading to activation of PINK1-dependent mitophagy. Mitophagy in turn drives a pro-pathogenic mechanism dependent on the activation of necroptosis. Activation of this mitophagy-dependent necroptosis pathway in response to metabolic and mitochondrial dysfunction may adversely affect airway function and emphysema outcomes during CS-induced COPD pathogenesis. To test this hypothesis, we will address three Specific Aims:
Specific Aim 1 : To determine the mechanisms by which CS induces mitophagy in the lung.
Specific Aim 2 : To determine the effect of impaired OXPHOS and FA synthesis on the regulation of mitochondrial dynamics and biogenesis and their impact on experimental COPD.
Specific Aim 3 : To determine the regulation of cellular necroptosis by CS, and its impact on lung functional impairment in experimental models of COPD.

Public Health Relevance

Chronic obstructive lung disease (COPD) represents a disabling chronic lung disease that lacks effective therapies. While a past history of smoking predisposes to developing COPD, we do not understand the individual factors determining the development of this dreadful disease. We have discovered that the autophagy process is critical in the pathogenesis of COPD and a better understanding of the impact and regulation of autophagy in COPD will offer new avenues for the development of therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132198-02
Application #
9406148
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Postow, Lisa
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Ash, Samuel Y; Harmouche, Rola; Ross, James C et al. (2017) The Objective Identification and Quantification of Interstitial Lung Abnormalities in Smokers. Acad Radiol 24:941-946
Racanelli, Alexandra C; Kikkers, Sarah Ann; Choi, Augustine M K et al. (2017) Autophagy and inflammation in chronic respiratory disease. Autophagy :0
Cloonan, Suzanne M; Glass, Kimberly; Laucho-Contreras, Maria E et al. (2016) Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med 22:163-74
Moon, Jong-Seok; Nakahira, Kiichi; Chung, Kuei-Pin et al. (2016) NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat Med 22:1002-12
Nakahira, Kiichi; Pabon Porras, Maria Angelica; Choi, Augustine M K (2016) Autophagy in Pulmonary Diseases. Am J Respir Crit Care Med 194:1196-1207
Pabon, Maria A; Ma, Kevin C; Choi, Augustine M K (2016) Autophagy and Obesity-Related Lung Disease. Am J Respir Cell Mol Biol 54:636-46