Autophagy is manifested by degradation of cytoplasmic organelles via a lysosomal pathway, involving rearrangement of intracellular membranes to sequester damaged proteins or organelles within formed membrane vesicles, or autophagosomes. Autophagosomes then fuse with lysosomes where the content is degraded and recycled to become an endogenous source of energy and nutrients. Autophagy has been described in the yeast system for decades;however, we have witnessed the explosion of this field in the mammalian system in recent years. Little is known on the role of autophagy in lung disease, and the role of autophagy in pulmonary hypertension (PH) has not been rigorously explored. We have obtained intriguing preliminary data that human PH and experimental models of PH exhibit marked induction of autophagy. Our laboratory and others have started to unravel the mechanisms and signaling pathways by which carbon monoxide (CO) imparts protective effects in various models of cellular and tissue injury. Importantly, our recent study illustrates that CO can protect against hypoxia or MCT-induced PH in mice and rats, respectively, even after the development of PH suggesting that CO may affect vascular remodeling processes including vascular cell proliferation and apoptosis. Interestingly, we have obtained preliminary data that CO regulates the autophagic process both in cultured vascular cells and in the lung. We hypothesize that autophagy represents an adaptive stress response to protect against PH, and that CO prevents PH via regulating autophagy. Furthermore, we hypothesize that autophagy regulated inflammasomes can potentially serve as diagnostic biomarker in predicting severity of PH. We will test the hypothesis by addressing the following aims:
Specific Aim #1 : To determine the mechanism by which CO-induced autophagy functions to provide cytoprotection in experimental PH Specific Aim 2: To determine the mechanism by which CO dampens the inflammasome pathway in experimental PH Specific Aim #3: To determine whether CO inhibits inflammasome and its regulated cytokines in human PH

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a dreadful disease with no effective therapies. An improved understanding of the pathogenesis of PAH will potentially provide new therapeutic targets. We hope to identify new molecules involved in the autophagy pathway which potentially could represent novel targets for therapy in PAH in the future.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Ma, Kevin C; Schenck, Edward J; Pabon, Maria A et al. (2018) The Role of Danger Signals in the Pathogenesis and Perpetuation of Critical Illness. Am J Respir Crit Care Med 197:300-309
Imamura, Mitsuru; Moon, Jong-Seok; Chung, Kuei-Pin et al. (2018) RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase. JCI Insight 3:
Harrington, John S; Choi, Augustine M K; Nakahira, Kiichi (2017) Mitochondrial DNA in Sepsis. Curr Opin Crit Care 23:284-290
Polverino, Francesca; Laucho-Contreras, Maria E; Petersen, Hans et al. (2017) A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 195:1464-1476
Lee, Seonmin; Nakahira, Kiichi; Dalli, Jesmond et al. (2017) NLRP3 Inflammasome Deficiency Protects against Microbial Sepsis via Increased Lipoxin B4 Synthesis. Am J Respir Crit Care Med 196:713-726
Zhang, Ruoyu; Nakahira, Kiichi; Guo, Xiaoxian et al. (2016) Very Short Mitochondrial DNA Fragments and Heteroplasmy in Human Plasma. Sci Rep 6:36097
Ryter, Stefan W; Choi, Augustine M K (2016) Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation. Transl Res 167:7-34
Nakahira, Kiichi; Pabon Porras, Maria Angelica; Choi, Augustine M K (2016) Autophagy in Pulmonary Diseases. Am J Respir Crit Care Med 194:1196-1207
Lee, Seonmin; Suh, Gee-Young; Ryter, Stefan W et al. (2016) Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease. Am J Respir Cell Mol Biol 54:151-60
Oliveira, Rudolf K F; Waxman, Aaron B; Agarwal, Manyoo et al. (2016) Pulmonary haemodynamics during recovery from maximum incremental cycling exercise. Eur Respir J 48:158-67

Showing the most recent 10 out of 129 publications