Oxidant injury is a major contributor to the pathogenesis of many disease processes including acute lung injury. Anoxia-reoxygenation (A-R) In cells and ilschemia-reperfusion (I-R) in lungs are common models of oxidant injury. Lung I-R is likely the inciting injury during lung transplantation/surgery, thromboembolectomy, pulmonary embolism, and re-expansion pulmonary edema. These disorders have high mortalities with limited therapeutic options. This is largely due to our limited knowledge of underlying pathogenesis. We also lack appreciation of the degree to which regulatory events in vitro (A-R) are predictive of the events in vivo (I-R). Heme oxygenase (HO) catalyzes the initial and rate-limiting step in the oxidative degradation of heme to biliverdin with generation of carbon monoxide (CO) and iron. A variety of oxidant stressors strongly induce expression of HO-1, an inducible isoform of HO. Studies from our laboratory and others have demonstrated that HO-1 can protect against oxidant-induced lung injury. However, the ability of HO-1 to confer protection and the processes regulating its production in this setting has not been adequately addressed. In addition, the pivotal cell-type responsible for HO-1-mediated protection against oxidant lung injury is unknown. To begin to understand the processes that regulate A-R/I-R we examined the effects of HO-1 in these injury models. We have demonstrated that HO-1 is markedly induced in endothelial cells and mouse lung after A-R/I-R. In addition, the mitogen-activated protein kinases (MAPKs) are responsible for A-R-induced HO-1 expression. We now show that HO-1 overexpression significantly diminishes A-R/I-R-induced apoptosis in cultured lung endothelial cells and in mouse lung. Our data has led us to propose the following hypotheses: 1) in A-R, HO-1 is induced via novel activation pathways that involve MAPKs and cooperative transcription factor interactions; 2) in I-R, similar pathways are activated and are cytoprotective; and 3) in I-R, p38 MAPK activation of endothelial cell HO-1 is a critical event in cytoprotection. To test these hypotheses we will: 1) characterize the cis- and trans-acting elements that mediate HO-1 induction and define the consequences in vitro; 2) determine whether A-R regulates the relevant transcription factors via p38 or JNK MAPKs and define the consequences in vitro; 3) determine whether the processes identified in Aims I and 2 are important in vivo; and 4) define the role of endothelial cell p38 MAPK and HO-1 in HO-1-mediated cytoprotection in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071595-03
Application #
7028892
Study Section
Special Emphasis Panel (ZRG1-LBPA (02))
Program Officer
Harabin, Andrea L
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$338,268
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Srivastava, Roshni; Mannam, Praveen; Rauniyar, Navin et al. (2017) Proteomics data on MAP Kinase Kinase 3 knock out bone marrow derived macrophages exposed to cigarette smoke extract. Data Brief 13:320-325
Takyar, Seyedtaghi; Zhang, Yi; Haslip, Maria et al. (2016) An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury. FASEB J 30:1317-27
Srivastava, Anup; Shinn, Amanda S; Lam, TuKiet T et al. (2016) SILAC based protein profiling data of MKK3 knockout mouse embryonic fibroblasts. Data Brief 7:418-22
Srivastava, Anup; McGinniss, John; Wong, Yao et al. (2015) MKK3 deletion improves mitochondrial quality. Free Radic Biol Med 87:373-84
Srivastava, Anup; Shinn, Amanda S; Lee, Patty J et al. (2015) MKK3 mediates inflammatory response through modulation of mitochondrial function. Free Radic Biol Med 83:139-48
Haslip, Maria; Dostanic, Iva; Huang, Yan et al. (2015) Endothelial uncoupling protein 2 regulates mitophagy and pulmonary hypertension during intermittent hypoxia. Arterioscler Thromb Vasc Biol 35:1166-78
Sauler, Maor; Zhang, Yi; Min, Jin-Na et al. (2015) Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury. FASEB J 29:1940-9
Mannam, Praveen; Shinn, Amanda S; Srivastava, Anup et al. (2014) MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury. Am J Physiol Lung Cell Mol Physiol 306:L604-19
Zhang, Yi; Sauler, Maor; Shinn, Amanda S et al. (2014) Endothelial PINK1 mediates the protective effects of NLRP3 deficiency during lethal oxidant injury. J Immunol 192:5296-304
Zhang, Xuchen; Shan, Peiying; Homer, Robert et al. (2014) Cathepsin E promotes pulmonary emphysema via mitochondrial fission. Am J Pathol 184:2730-41

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