Molecular Mechanisms of Hyperoxic Lung Injury

University Of South Florida, Tampa FL

Investigators

Linked publications, trials & patents

Abstract

Project Summary/Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are among the most devastating causes of fatality in critically ill patients. Recently, accumulating evidence shows that mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as an invaluable shield against oxidative stress mediated damage. During the last cycle of our grant, while studying the mechanisms by which suppressor of cytokine signaling 1 (SOCS-1) protects against ALI, we discovered that ALDH2 activity is restored in SOCS-1 overexpressed mice. Now, our efforts focus on mitochondria and mitochondrial redox regulation in ALI/ARDS. Our previous studies indicate that reactive oxygen species (ROS), produced by hyperoxia, are key factors in causing mitochondrial damage. Based on numerous studies of ROS involvement in ALI, many trials have targeted ROS for the treatment of ALI and ARDS. Unfortunately, molecular instability makes ROS challenging therapeutic targets, and treatment with anti- oxidants (which target ROS) does not rectify mitochondrial damage. However, more plausible targets may be the stable secondary ROS intermediates, such as 4-hydroxy-2-nonenal (4-HNE). 4-HNE, a toxic lipid peroxidation product that disrupts mitochondrial bioenergetics, plays a causal role in oxidative stress diseases. Therefore, clearing 4-HNE and preserving vital mitochondrial homeostasis is a logical approach for the development of new therapies. Studies in models of various oxidative stress-mediated injuries, have shown that ALDH2 is a powerful endogenous enzyme that effectively protects against oxidative stress through the clearance of 4-HNE. Despite our expanding knowledge regarding the function of ALDH2 in other diseases, there is a lack in our understanding of ALDH2 involvement in ALI and ARDS. We hypothesize that activation of ALDH2 protects against hyperoxia-induced ALI (HALI) via restoration of A-kinase anchor protein 121 (AKAP121) levels, which preserves mitochondrial function. We propose the following specific aims to investigate our hypothesis: Aim 1: Elucidate the mechanism of ALDH2 inactivation, Siah2 accumulation, and AKAP121 degradation. Aim 2: Elucidate the mechanism by which AKAP121 loss potentiates ALDH2 deficiency-induced HALI. Aim 3: Determine the therapeutic role of ALDH2 activation in hyperoxic and infectious ALI models. Our proposed studies will unveil a new molecular target (ALDH2) in ALI/ARDS pathogenesis, reveal its biological significance in regulating AKAP121 levels, and decipher its connection to mitochondrial dysfunction.