The cellular and molecular responses of the lung to oxidative stress involve increased expression of antioxidant enzymes and stress-response genes, including the stress-inducible gene heme oxygenase-1 (HO-1). Heme oxygenase (HO) catalyzes the first and rate-limiting step in the degradation of heme to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and iron. Our laboratory and others have established that HO-1 provides potent cytoprotection against oxidant-induced lung injury including but not limited to hyperoxia, LPS, and ischemia/reperfusion. Accumlating data from our own laboratory and others strongly suggest that the cytoprotective effects of HO-1 are mediated by the catalytic by-products of HO-1, namely ferritin, bilirubin and CO. In particular, we have accumulated data that CO may mediate HO-1 induced cytoprotection by conferring potent anti-inflammatory, anti-apoptotic, and anti-proliferative effects. Furthermore, we have delineated several important signaling pathways by which HO-1 or CO mediate its' cytoprotection. Since the discovery of HO-1 in 1968, the scientific community up to now has accepted the dogma that HO-1 is primarily localized in the rough endoplasmic reticulum. We believe that our most recent observations (see Preliminary Studies) that HO-1 is also localized in the caveolae in pulmonary endothelial cells present a new paradigm and opens up new avenues of research in this field. Thus, for the competitive renewal of this grant, based on our published work (Progress Report) and Preliminary Studies, we have chosen to propose studies to test the following novel hypothesis: Hypothesis: Sub cellular localization of HO-1 in the caveolae plays an important role in contributing to the cytoprotection of HO-1 against oxidative stress. Furthermore, caveolin-1 in caveolae helps regulate the activity and function of HO-1, and the signaling pathways by which HO-1 or CO mediates cytoprotection against oxidative stress. We will test the hypothesis by addressing the following aims: a) To determine the regulation and function of the sub-cellular localization of HO-1 in caveolae of pulmonary endothelial cells; b) To determine the regulation and function of the sub-cellular localization of biliverdin reductase in caveolae of pulmonary endothelial cells; and c) To determine the mechanism by which caveolin-1 regulates HO-1 cytoprotective functions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
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
Pabón, Maria A; Patino, Edwin; Bhatia, Divya et al. (2018) Beclin-1 regulates cigarette smoke-induced kidney injury in a murine model of chronic obstructive pulmonary disease. JCI Insight 3:
Siempos, Ilias I; Ma, Kevin C; Imamura, Mitsuru et al. (2018) RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury. JCI Insight 3:
Harrington, John S; Choi, Augustine M K; Nakahira, Kiichi (2017) Mitochondrial DNA in Sepsis. Curr Opin Crit Care 23:284-290
Lasky-Su, Jessica; Dahlin, Amber; Litonjua, Augusto A et al. (2017) Metabolome alterations in severe critical illness and vitamin D status. Crit Care 21:193
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
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

Showing the most recent 10 out of 82 publications