Mitochondrial (mt) dysfunction is common in the Acute Respiratory Distress Syndrome and its sequel, Multiple Organ System Failure, but the potential for mt-associated pathways to serve as pharmacologic targets in ARDS and MOSF has yet to be realized. Among the discoveries originating from this project, two lines of evidence may have paradigm-shifting implications. First, modulation of mtDNA repair coordinately regulates oxidative mtDNA damage and attendant cytotoxicity. And second, fragmentation of oxidatively damaged mtDNA into Damage Associated Molecular Patterns may disseminate injury to distant organs by activating a regenerative, feed-forward pathway in which mtDNA DAMPs, themselves, damage the mitochondrial genome and promote more mtDNA DAMP formation. These considerations provide the underpinnings for our long- term goal to develop pharmacologic strategies to treat ARDS and MOSF based on the concept that mitochondrial (mt) DNA acts as a molecular sentinel governing disease progression in response to critical illness or injury. Motivated by our finding that administration of transfusion products inadvertently containing variable amounts of mtDNA DAMPs increases circulating mtDNA DAMP levels and elevates the risk of ARDS-like Transfusion Related Acute Lung Injury in severely injured patients, Aim 1 will determine if a feed-forward pathway contributes to mtDNA DAMP accumulation in massively-transfused, critically injured human subjects at risk for TRALI. Here, we will test the hypothesis that the amount of exogenous mtDNA administered during massive transfusion dictates the amount of mtDNA DAMPs mobilized from endogenous, patient-derived sources.
The second Aim i s predicated on the fact that although oxidative mtDNA damage leads to DAMP release, only scant information is available concerning mechanisms of mtDNA fragmentation and sequence characteristics of the DAMPs so formed. Indeed, such deficiencies present serious obstacles to addressing fundamental questions pertaining to which mtDNA fragments are biologically active and how they are trafficked in the intra- and extracellular environments. Accordingly, Aim 2 will test the hypothesis that sites of oxidative damage to the mitochondrial genome promote its fracture into specific mtDNA DAMP sequences and predispose the mt-genome to somatic mutation. Collectively, the proposed research is significant because it will provide insight into the mechanisms of mtDNA DAMP formation, the importance of mtDNA DAMPs in the response to injury, and their utility as a pharmacologic target. It is innovative because the postulated operation of feedforward pathway involving mtDNA damage- induced DAMP formation is a fundamentally new concept to explain the progressive pathogenesis of ARDS and MOSF.

Public Health Relevance

Observational studies in severely injured or critically ill human subjects at risk for the acute respiratory distress syndrome (ARDS) and multiple organ system failure (MOSF) show that circulating levels of pro-inflammatory mitochondrial (mt) DNA fragments, termed mtDNA Damage Associated Molecular Patterns (DAMPs), are closely associated with clinical outcomes. Research using animal models suggests that mtDNA DAMPs may, themselves, trigger a self-propagating cycle leading to more mtDNA DAMP production, which could account for the relentless progression of ARDS and MOSF despite adequate control of the initial insult. Here, we will test the hypothesis that such a feed-forward pathway driving mtDNA DAMP production is operative in human subject and provide the most thorough insight yet available on the mechanisms of formation and fundamental characteristics of mtDNA DAMPs.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Zhou, Guofei
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University of South Alabama
Schools of Medicine
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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
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