Numerous studies have explored anti-oxidants as therapeutic agents in acute lung injury (ALI), but their outcome in clinical trials has been disappointing. One explanation for this failure is that oxidants generated in ALI are not only cytotoxic, but they also function as second messengers in pathways required for lung cell proliferation and differentiation. Thus, non-selective antioxidants may disrupt signaling required for cell survival and recovery. A related possibility is that key molecule(s) integrating ROS actions on the pulmonary vasculature have yet to be identified;antioxidants may fail to protect against damage to these putative sentinel molecule(s) governing activation of cell death programs. Based on multiple lines of compelling evidence obtained from cell culture studies, herein we propose to test the concept that mitochondrial (mt) DNA is a sentinel molecule dictating lung cell fate in response to oxidant stress and that the mtDNA repair pathway is a target for intervention in ALI.
Specific Aim 1 will begin translating findings from cell culture ino practical application by testing the hypothesis that increasing mtDNA glycosylase activity using novel fusion protein constructs protects against, and reverses, ALI in rodents with either Pseudomonas aeruginosa- or ventilator- induced ALI. These experiments comprise an important step towards our longer term goal of developing mtDNA repair fusion proteins as platform drug molecules for treating ALI. Even though enhancement of mtDNA repair suppresses ROS-mediated cell death, the mechanism of this salutary effect has remained elusive. Traditional concepts hold that accelerated mtDNA repair prevents accumulation of oxidative mtDNA damage, thereby attenuating mitochondrial generation of pro-apoptotic ROS and attendant activation of mitochondrially-driven cell death, but not all currently available data support this model and some studies suggest that mtDNA repair, per se, is unimportant. Accordingly, Specific Aim 2 will use wild type and mutant Ogg1 proteins differing in their capacities to repair - but not to bind - mtDNA to determine whether repair of RS-induced mtDNA damage is required for prevention of RS-induced EC cytotoxicity, barrier dysfunction, and formation an extracellular release of injury-propagating mtDNA fragments.
There are currently no pharmaco-therapeutic interventions to treat ALI. In a related context, while reactive oxygen species play a role in these disorders, non-selective anti-oxidants have proven ineffective. Herein we will test a new concept - that repair of oxidative mtDNA damage directs cell fate decisions in ALI - which, if valid, will point to an entirely new pharmacologic strategy for treating ALI and related disorders.
|Lee, Yann-Leei; Obiako, Boniface; Gorodnya, Olena M et al. (2017) Mitochondrial DNA Damage Initiates Acute Lung Injury and Multi-Organ System Failure Evoked in Rats by Intra-Tracheal Pseudomonas Aeruginosa. Shock 48:54-60|
|Simmons, Jon D; Lee, Yann-Leei L; Pastukh, Viktor M et al. (2017) Potential contribution of mitochondrial DNA damage associated molecular patterns in transfusion products to the development of acute respiratory distress syndrome after multiple transfusions. J Trauma Acute Care Surg 82:1023-1029|
|Pastukh, Viktor M; Gorodnya, Olena M; Gillespie, Mark N et al. (2016) Regulation of mitochondrial genome replication by hypoxia: The role of DNA oxidation in D-loop region. Free Radic Biol Med 96:78-88|
|Yang, Xi-Ming; Cui, Lin; White, James et al. (2015) Mitochondrially targeted Endonuclease III has a powerful anti-infarct effect in an in vivo rat model of myocardial ischemia/reperfusion. Basic Res Cardiol 110:3|
|Pastukh, Viktor; Roberts, Justin T; Clark, David W et al. (2015) An oxidative DNA ""damage"" and repair mechanism localized in the VEGF promoter is important for hypoxia-induced VEGF mRNA expression. Am J Physiol Lung Cell Mol Physiol 309:L1367-75|
|Simmons, Jon D; Gillespie, Mark N (2015) Plasma nuclear and mitochondrial DNA levels in acute myocardial infarction patients. Coron Artery Dis 26:286-288|
|Kuck, Jamie L; Obiako, Boniface O; Gorodnya, Olena M et al. (2015) Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs. Am J Physiol Lung Cell Mol Physiol 308:L1078-85|
|Lee, Yann-Leei; King, Madelyn B; Gonzalez, Richard P et al. (2014) Blood transfusion products contain mitochondrial DNA damage-associated molecular patterns: a potential effector of transfusion-related acute lung injury. J Surg Res 191:286-9|
|Schumacker, Paul T; Gillespie, Mark N; Nakahira, Kiichi et al. (2014) Mitochondria in lung biology and pathology: more than just a powerhouse. Am J Physiol Lung Cell Mol Physiol 306:L962-74|
|Hashizume, Masahiro; Mouner, Marc; Chouteau, Joshua M et al. (2014) Mitochondrial Targeted Endonuclease III DNA Repair Enzyme Protects against Ventilator Induced Lung Injury in Mice. Pharmaceuticals (Basel) 7:894-912|
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