and specific aims): The lung is a major target organ for oxidant injury during exposure to hyperoxia. Many pulmonary diseases (e.g. adult respiratory distress syndrome [ARDS], emphysema) require supplemental oxygen therapy to maintain lung function which further increases the oxidant burden of the lung. Damaging effects of hyperoxia are mediated by reactive oxygen species (ROS) including superoxide and hydroxyl radicals, and hydrogen peroxide, which are generated by the incomplete reduction of oxygen. These toxic ROS can damage cellular constituents such as nucleic acids, proteins and lipids. The cellular and molecular responses of the lung to hyperoxia involve increased expression of antioxidant enzymes and stress-response genes, including the stress-inducible gene heme oxygenase-1 (HO-1). The mechanism(s) involved in the regulation of HO-1 expression after hyperoxic stress and the functional significance of HO-1 induction after hyperoxia is largely unknown. This application proposes to examine the molecular regulation of HO-1 gene expression after hyperoxia and delineate the functional significance of HO-1 induction after hyperoxia by addressing the following specific aims: 1) to determine the transcriptional regulation of HO-1 gene induction by delineating the critical cis-acting elements responsible for mediating the induction of HO-1 gene after hyperoxia; 2) to determine the role of activator protein-1 (AP-1) family of transcription factors in the induction of HO-1 gene exposure by analyzing the expression, activation and modulation of AP-1 activity after hyperoxia; 3) to determine the upstream signalling pathways involved in the activation of AP-1 and induction of the HO-1 gene after hyperoxia; and 4) to determine the functional significance of HO-1 induction in vitro and in vivo after hyperoxia.
| 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 |
| Schenck, Edward J; Oromendia, Clara; Torres, Lisa K et al. (2018) Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials. Chest : |
| Schenck, Edward J; Ma, Kevin C; Murthy, Santosh B et al. (2018) Danger Signals in the ICU. Crit Care Med 46:791-798 |
| Ryter, Stefan W; Ma, Kevin C; Choi, Augustine M K (2018) Carbon monoxide in lung cell physiology and disease. Am J Physiol Cell Physiol 314:C211-C227 |
| Harrington, John S; Schenck, Edward J; Oromendia, Clara et al. (2018) Acute respiratory distress syndrome without identifiable risk factors: A secondary analysis of the ARDS network trials. J Crit Care 47:49-54 |
| Siempos, Ilias I; Ma, Kevin C; Imamura, Mitsuru et al. (2018) RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury. JCI Insight 3: |
| Finkelsztein, Eli J; Jones, Daniel S; Ma, Kevin C et al. (2017) Comparison of qSOFA and SIRS for predicting adverse outcomes of patients with suspicion of sepsis outside the intensive care unit. Crit Care 21:73 |
| 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 |
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