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Truncated Oxidized Phospholipids as a Factor Exacerbating ALI in the Aging Lungs
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A5733 - Truncated Oxidized Phospholipids as a Factor Exacerbating ALI in the Aging Lungs
Author Block: Y. Ke1, A. Sitikov2, S. Son2, P. Karki3, E. Berdyshev4, A. Birukova3, K. G. Birukov1; 1Dept of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, United States, 2Dept of Medicine, University of Chicago, Chicago, IL, United States, 3Dept of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States, 4National Jewish Health, Littleton, CO, United States.
As antioxidant defense mechanisms become impaired with aging, exaggerated oxidant stress may cause disproportional oxidation of cell membranes and circulating phospholipids leading to formation of truncated oxidized phospholipid products (TR-OxPLs) which exhibit deleterious effects. This study investigated the role of elevated TR-OxPL as a factor exacerbating inflammation and lung barrier dysfunction in the animal model of aging. Mass Spec analysis of PL species in young (2-4 m.o.) and aged (18-24 m.o.) mice revealed elevated basal levels of TR-OxPLs in the aged population accompanied by decreased levels of SOD2. Bacterial lipopolysaccharide (LPS) also caused increased generation of TR-OxPLs, with higher levels detected in the aged group. An impact of TR-OxPLs on EC barrier compromise caused by bacterial particles was further evaluated in the two-hit cell culture model of ALI. LPS-induced EC barrier dysfunction was augmented by cell co-treatment with low dose TR-OxPLs, which did not affect endothelial function when added alone. Deleterious effects of TR-OxPLs on LPS-challenged EC were associated with further weakening of cell junctions and more robust EC hyperpermeability. Biochemical and imaging analysis revealed higher levels of VE-cadherin phosphorylation and internalization in LPS/TR-OxPL treated cells vs. LPS alone. Inhibition of TR-PLs generation by ectopic expression of phopsholipid hydrolase PAFAH2 significantly reduced LPS-induced EC dysfunction. Similar results were obtained in LPS-treated EC preincubated with ROS scavenger, amifostine. Amifostine was also effective when cells were treated with TR-OxPLs alone, suggesting positive feedback mechanism of ROS production by TR-OxPLs. In vivo, amifostine administration markedly reduced parameters of LPS-induced ALI. Amifostine inhibitory properties were more pronounced in the old mouse population vs. young counterparts. These exciting results demonstrate age-dependent increase in TR-OxPLs production in basal conditions and upon inflammatory stimulation, and support the hypothesis about the role of TR-OxPLs in exacerbation of inflammation in aging lungs.
Author Block: Y. Ke1, A. Sitikov2, S. Son2, P. Karki3, E. Berdyshev4, A. Birukova3, K. G. Birukov1; 1Dept of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, United States, 2Dept of Medicine, University of Chicago, Chicago, IL, United States, 3Dept of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States, 4National Jewish Health, Littleton, CO, United States.
As antioxidant defense mechanisms become impaired with aging, exaggerated oxidant stress may cause disproportional oxidation of cell membranes and circulating phospholipids leading to formation of truncated oxidized phospholipid products (TR-OxPLs) which exhibit deleterious effects. This study investigated the role of elevated TR-OxPL as a factor exacerbating inflammation and lung barrier dysfunction in the animal model of aging. Mass Spec analysis of PL species in young (2-4 m.o.) and aged (18-24 m.o.) mice revealed elevated basal levels of TR-OxPLs in the aged population accompanied by decreased levels of SOD2. Bacterial lipopolysaccharide (LPS) also caused increased generation of TR-OxPLs, with higher levels detected in the aged group. An impact of TR-OxPLs on EC barrier compromise caused by bacterial particles was further evaluated in the two-hit cell culture model of ALI. LPS-induced EC barrier dysfunction was augmented by cell co-treatment with low dose TR-OxPLs, which did not affect endothelial function when added alone. Deleterious effects of TR-OxPLs on LPS-challenged EC were associated with further weakening of cell junctions and more robust EC hyperpermeability. Biochemical and imaging analysis revealed higher levels of VE-cadherin phosphorylation and internalization in LPS/TR-OxPL treated cells vs. LPS alone. Inhibition of TR-PLs generation by ectopic expression of phopsholipid hydrolase PAFAH2 significantly reduced LPS-induced EC dysfunction. Similar results were obtained in LPS-treated EC preincubated with ROS scavenger, amifostine. Amifostine was also effective when cells were treated with TR-OxPLs alone, suggesting positive feedback mechanism of ROS production by TR-OxPLs. In vivo, amifostine administration markedly reduced parameters of LPS-induced ALI. Amifostine inhibitory properties were more pronounced in the old mouse population vs. young counterparts. These exciting results demonstrate age-dependent increase in TR-OxPLs production in basal conditions and upon inflammatory stimulation, and support the hypothesis about the role of TR-OxPLs in exacerbation of inflammation in aging lungs.
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