Thursday, April 25, 2024
4/25/2024
ABSTRACT Acute respiratory distress syndrome (ARDS) is a severe form of lung injury that kills 114,000 Americans annually with estimated treatment costs exceeding $5 billion. While much is known about the pathophysiology of ARDS, our treatments are not curative. As a result, mortality rates remain unacceptably high at 40%-60%. ARDS is characterized by profound inflammation and non-cardiogenic pulmonary edema that culminate in respiratory failure, and studies show sepsis and alcohol abuse disorder increase the risk of ARDS. Although the exact mechanism is unknown, perhaps specific derangements involving critical signaling proteins (that regulate inflammation and lung fluid balance) account for increased risk and the high mortality in ARDS. Our long-term goal is to improve outcomes in ARDS. To achieve this goal, we will use a proteomics approach to first elucidate the molecular underpinnings of ARDS and establish the effect of curcumin, a compound found in turmeric, in reversing molecular derangements. This information is critical for the development of personalized health strategies as it will provide vital insight into how the injured epithelium responds such that effective therapies can be developed. Our preliminary data show that protein glutathionylation (S-SG), the addition of oxidized glutathione to a protein, occurs in response to lipopolysaccharide (LPS) exposure, and that curcumin reverses S-SG of critical signaling proteins. LPS is a known ligand for the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily that functions to amplify and perpetuate the inflammatory response. RAGE is abundantly expressed on the alveolar epithelium and we have shown that RAGE signaling regulates lung fluid balance. The purpose of this proposed research is to show that RAGE ligation promotes S-SG of critical signaling proteins and that curcumin reverses S-SG in a mouse model. Because infection and alcohol are known risk factors, we will use well-established mouse models fed either an alcohol or isocaloric control diet with and without exposure to LPS. Specific Aim 1 is to translate our cell culture findings to an in vivo model of chronic alcohol consumption to determine if RAGE ligation results in S- SG of critical signaling proteins in isolated primary alveolar epithelial cells. Specific Aim 2 is to determine the effect of RAGE-ligand exposure on S-SG of critical signaling proteins to affect lung fluid clearance in an animal model of chronic alcohol consumption over time. Specific Aim 3 is to determine if curcumin supplementation reverses S-SG of critical signaling proteins to restore lung fluid balance in an animal model of chronic alcohol consumption. The aims will be achieved by using animal models (RAGE-/-, RAGE+/-, RAGE+/+) of acute lung injury; models will also serve as a source for isolated primary alveolar epithelial cells. Proteomics combined with sophisticated molecular and biochemical techniques will be used to definitely demonstrate S-SG of critical signaling proteins and the potential of curcumin to treat ARDS. The work proposed here is foundational for subsequent work designed to personalize health strategies to decrease morbidity and mortality from ARDS.
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