All ETDs from UAB

Advisory Committee Chair

Trent E Tipple

Advisory Committee Members

Natalia Kedishvili

Namasivayam Ambalavanan

Anupam Agarwal

Maaike Everts

Rajasekaran Namakkal Soorappan

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Endogenous antioxidant responses defend the lung against oxygen toxicity. In premature neonates, oxygen toxicity and impaired antioxidant defenses contribute to the development of bronchopulmonary dysplasia (BPD), the leading cause of long-term morbidity among premature infants. In adults, oxygen toxicity and impaired antioxidant defense contributes to the pathogenesis of acute lung injury (ALI). Acute Respiratory Distress Syndrome (ARDS), a severe form of ALI, can cause permeant lung damage and mortality. Our lab has established that pharmacologic thioredoxin reductase-1 (TXNRD1) inhibition attenuates lung injury in murine BPD and ALI models. The protective effects of TXNRD1 inhibition are mediated by the activation of nuclear factor E2-related factor 2 (Nrf2), the master regulator of antioxidant responses. We have consistently observed a disproportionate induction of heme oxygenase-1 (HO-1) following TXNRD1 inhibition when compared to other Nrf2-regulated genes in vitro and in vivo. However, HO-1 is not exclusively regulated by Nrf2 in all cell types. The work present herein defined the role of Nrf2 in HO-1 induction in lung epithelia; the contribution of epithelial HO-1 in hyperoxic responses in the adult murine lung; and the transcriptomic effects of TXNRD1 inhibition and hyperoxic exposure in a murine model of neonatal ALI/BPD. Our findings provide key information regarding the regulation of HO-1 in hyperoxic responses and provide further support for the potential of TXNRD1 as a novel therapeutic target to mitigate lung injury as a result of BPD and ALI, a significant and costly cause of morbidity in humans.

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