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Kevin Nelson Dissertation.pdf (5.56 MB)

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MICRORNA REGULATION OF VENTILATOR INDUCED LUNG INJURY AND PRESSURE-INDUCED LUNG INFLAMMATION

Nelson, Kevin Joseph
http://rave.ohiolink.edu/etdc/view?acc_num=osu1462276463

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biomedical Engineering.
Acuter respiratory distress syndrome (ARDS) is a very serious lung disorder where infection/inflammation in the lung leads to breakdown of alveolar-capillary barrier and fluid accumulation in the lungs. As a result inadequate gas exchange leads to severe hypoxemia [1] and ARDS patients must be mechanically ventilated for survival. Unfortunately, mechanical ventilation often leads to additional lung injury and inflammation and as a result mortality rates for ARDS are very high [2]. An improved understanding of ARDS pathogenesis over the past three decades has led to important new treatments, particularly in the area of ventilator induced lung injury (VILI). Unfortunately, only one approach, reduced tidal volume ventilation, has had a significant impact on mortality rates [3]. Therefore, the development of new therapeutic approaches for ARDS is a major public health issue. In this dissertation we studied how normal oscillatory pressure affect inflammation and miRNA expression. We also studied how the up or down-regulation of specific miRNAs can affect pressure induced inflammation. We have developed an in-vitro model for VILI by applying a normal oscillatory force to primary human small airway epithelial cells (HSAEpCs). Our results highlight the novel use of miRNAs as a way to regulate pressure induced inflammation. We also explored the use of ex-vivo lung perfusion (EVLP) as a way to model VILI by using male Sprague Dawley rats. We then investigated the use of negative pressure EVLP as a way to recondition lungs and therefore increase the donor lung pool. Finally, we explore the effects of shear stress and the complex spatial and temporal forces associated with airway reopening on inflammation and miRNA expression. We also explore the potential protective effects of Rho-kinase pathway inhibitors on pressure-induced inflammation. Some of the major findings of the work inhere described include the following: ¿ MicroRNAs have a potential application as therapeutic targets for pressure-induced inflammation in the lung. Specifically, miR-146a, 155, 33a, and 181a are significant negative regulators of normal oscillatory pressure-induced inflammation and microRNA-146a can regulate pressure-induced inflammation in-vitro in as little as 12 hr. ¿ EVLP can be used to model VILI and to illicit an inflammatory response in as little as 1 hr. ¿ Negative pressure EVLP may better recondition lungs compared to positive pressure EVLP via significantly improved compliance and decreased inflammatory response, however arterial oxygenation was not significantly different from positive pressure EVLP after 2 hr. ¿ The use of Rho inhibitor Y-27632 may render the cells less susceptible to normal oscillatory-pressure induced inflammation.
Samir Ghadiali (Advisor)
Bryan Whitson (Advisor)
Thomas Hund (Committee Member)
171 p.
Biomedical Engineering
microRNA; miRNA; miR; EVLP; ARDS; VILI; Inflammation

Recommended Citations

Citations

  • Nelson, K. J. (2016). MICRORNA REGULATION OF VENTILATOR INDUCED LUNG INJURY AND PRESSURE-INDUCED LUNG INFLAMMATION [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1462276463

    APA Style (7th edition)

  • Nelson, Kevin. MICRORNA REGULATION OF VENTILATOR INDUCED LUNG INJURY AND PRESSURE-INDUCED LUNG INFLAMMATION. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1462276463.

    MLA Style (8th edition)

  • Nelson, Kevin. "MICRORNA REGULATION OF VENTILATOR INDUCED LUNG INJURY AND PRESSURE-INDUCED LUNG INFLAMMATION." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1462276463

    Chicago Manual of Style (17th edition)

osu1462276463
459
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This open access ETD is published by The Ohio State University and OhioLINK.