Mechanisms of ALI exacerbation in the aging lung

University Of Chicago, Chicago IL

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Abstract

? DESCRIPTION (provided by applicant): Mechanisms of more severe ALI and delayed recovery in older patients remain poorly understood. As antioxidant defense mechanisms in aging organism become impaired, exaggerated oxidant stress caused by increased production of reactive oxygen species during inflammation may cause increased oxidation of cell constituents and damage the host. Increased oxidation of cell membrane and circulating phospholipids generates truncated oxidized phospholipid products (TR-OxPLs) including POVPC, PGPC, lysoPC, etc., which may exhibit deleterious effects on host cells. This translational study will elucidate for the first time the role of elevated TR-OxPL as a factor exacerbating inflammation and lung barrier dysfunction in the aging population. We will investigate TR-OxPL role in propagation of ALI in the pneumonia-related model of ALI induced by heat- killed Staphylococcus aureus (HKSA). We hypothesize that increased generation of TR-OxPLs in aging group augments lung inflammation and vascular dysfunction by stimulating the expression of thioredoxin interacting protein (TXNIP), the protein known to stimulate oxidative stress by inhibition of thioredoxin antioxidant activity and enhance ongoing inflammation via stimulation of cytokine IL-1ß release. Aim-1 will determine changes in the spectrum of OxPL generated in the lungs of HKSA-challenged aging animals and link TR-OxPL generation in aging mice with severity of lung injury; Aim-2 will investigate effects of TR-OxPLs on HKSA-induced lung dysfunction and vascular endothelial inflammatory activation. Aim-3 will study molecular mechanisms of TR- OxPL-mediated exacerbation of HKSA-induced lung dysfunction. Aim-4 will use genetic and pharmacological interventions to manipulate the mechanisms of age-related modulation of lung inflammation. These studies may lead to a new direction in controlling ALI/ARDS in aging population by inactivating TXNIP or preventing the generation of deleterious oxidized phospholipid products.