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This study investigated the role of elevated Tr\u2010OxPLs as a factor exacerbating inflammation and lung barrier dysfunction in an animal model of aging. Mass spectrometry analysis of Tr\u2010OxPL species in young (2\u20134 mo) and aging (18\u201324 mo) mice revealed elevated basal levels of several products [1\u2010palmitoyl\u20102\u2010(5\u2010oxovaleroyl)\u2010\n                    <jats:italic>sn<\/jats:italic>\n                    \u2010glycero\u2010phosphocholine (POVPC), 1\u2010palmitoyl\u20102\u2010glutaroyl\u2010\n                    <jats:italic>sn<\/jats:italic>\n                    \u2010glycero\u2010phosphocholine, lysophosphocholine, 1\u2010palmitoyl\u20102\u2010(9\u2010oxo\u2010nonanoyl)\u2010\n                    <jats:italic>sn<\/jats:italic>\n                    \u2010glycero\u20103\u2010phosphocholine, 1\u2010palmitoyl\u20102\u2010azelaoyl\u2010\n                    <jats:italic>sn<\/jats:italic>\n                    \u2010glycero\u20103\u2010phosphocholine, O\u20101\u2010O\u2010palmitoyl\u20102\u2010O\u2010(5,8\u2010dioxo\u20108\u2010hydroxy\u20106\u2010octenoyl)\u2010\n                    <jats:sc>l<\/jats:sc>\n                    \u2010glycero\u20103\u2010phosphocholine, and others] in the aged lungs. An intratracheal (i.t.) injection of bacterial LPS caused increased generation of Tr\u2010OxPLs in the lungs but not in the liver, with higher levels detected in the aged group. In addition, OxPLs clearance from the lung tissue after LPS challenge was delayed in the aged group. The impact of Tr\u2010OxPLs on endothelial cell (EC) barrier compromise under inflammatory conditions was further evaluated in the 2\u2010hit cell culture model of acute lung injury (ALI). EC barrier dysfunction caused by cell treatment with a cytokine mixture (CM) was augmented by cotreatment with low\u2010dose Tr\u2010OxPLs, which did not significantly affect endothelial function when added alone. Deleterious effects of Tr\u2010OxPLs on inflamed ECs stimulated with CM were associated with further weakening of cell junctions and more robust EC hyperpermeability. Aged mice injected intratracheally with TNF\u2010\u03b1 exhibited a more pronounced elevation of cell counts and protein content in bronchoalveolar lavage (BAL) samples. Interestingly, intravenous administration of low POVPC doses\u2014which did not affect BAL parameters alone in young mice exposed to i.t. TNF\u2010\u03b1 challenge\u2014augmented lung injury to the levels observed in aged mice stimulated with TNF\u2010\u03b1 alone. Inhibition of Tr\u2010OxPL generation by ectopic expression of PL\u2010specific platelet\u2010activating factor acetylhydrolase 2 (PAFAH2) markedly reduced EC dysfunction induced by CM, whereas PAFAH2 pharmacologic inhibition augmented deleterious effects of cytokines on EC barrier function. Moreover, exacerbating effects of PAFAH2 inhibition on TNF\u2010\u03b1\u2013induced lung injury were observed\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These results demonstrate an age\u2010dependent increase in Tr\u2010OxPL production under basal conditions and augmented Tr\u2010OxPL generation upon inflammatory stimulation, suggesting a major role for elevated Tr\u2010OxPLs in more severe ALI and delayed resolution in aging lungs.\u2014Ke, Y., Karki, P., Kim, J., Son, S., Berdyshev, E., Bochkov, V. N., Birukova, A. A., Birukov, K. G. Elevated truncated oxidized phospholipids as a factor exacerbating ALI in the aging lungs. FASEB J. 33, 3887\u20133900 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201800981r","type":"journal-article","created":{"date-parts":[[2018,12,6]],"date-time":"2018-12-06T13:15:23Z","timestamp":1544102123000},"page":"3887-3900","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Elevated truncated oxidized phospholipids as a factor exacerbating ALI in the aging lungs"],"prefix":"10.1096","volume":"33","author":[{"given":"Yunbo","family":"Ke","sequence":"first","affiliation":[{"name":"Department of Anesthesiology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratap","family":"Karki","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Department of Medicine University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Son","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine Department of Medicine University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeny","family":"Berdyshev","sequence":"additional","affiliation":[{"name":"National Jewish Health  Denver Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valery N.","family":"Bochkov","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry University of Graz  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna A.","family":"Birukova","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Department of Medicine University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin G.","family":"Birukov","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(99)00507-1"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0899-5885(18)30501-X"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0007114508998445"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.11.013"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406762200"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404309101"},{"issue":"1","key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1164\/rccm.2206011","article-title":"The isoprostanes: their role as an index of oxidant stress status in human pulmonary disease","volume":"166","author":"Morrow J. 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