{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:45:06Z","timestamp":1787021106548,"version":"build-2736575974"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T00:00:00Z","timestamp":1473811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"publisher","award":["1RO1AI100138"],"award-info":[{"award-number":["1RO1AI100138"]}],"id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007197","name":"U.S. Public Health Service","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007197","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Respiratory infection with Francisella tularensis (Ft) is characterized by a muted, acute host response, followed by sepsis-like syndrome that results in death. Infection with Ft establishes a principally anti-inflammatory environment that subverts host-cell death programs to facilitate pathogen replication. Although the role of cytokines has been explored extensively, the role of eicosanoids in tularemia pathogenesis is not fully understood. Given that lipoxin A4 (LXA4) has anti-inflammatory properties, we investigated whether this lipid mediator affects host responses manifested early during infection. The addition of exogenous LXA4 inhibits PGE2 release by Ft-infected murine monocytes in vitro and diminishes apoptotic cell death. Tularemia pathogenesis was characterized in 5-lipoxygenase-deficient (Alox5\u2212\/\u2212) mice that are incapable of generating LXA4. Increased release of proinflammatory cytokines and chemokines, as well as increased apoptosis, was observed in Alox5\u2212\/\u2212 mice as compared with their wild-type counterparts. Alox5\u2212\/\u2212 mice also exhibited elevated recruitment of neutrophils during the early phase of infection and increased resistance to lethal challenge. Conversely, administration of exogenous LXA4 to Alox5\u2212\/\u2212 mice made them more susceptible to infection thus mimicking wild-type animals. Taken together, our results suggest that 5-LO activity is a critical regulator of immunopathology observed during the acute phase of respiratory tularemia, regulating bacterial burden and neutrophil recruitment and production of proinflammatory modulators and increasing morbidity and mortality. These studies identify a detrimental role for the 5-LO\u2013derived lipid mediator LXA4 in Ft-induced immunopathology. Targeting this pathway may have therapeutic benefit as an adjunct to treatment with antibiotics and conventional antimicrobial peptides, which often have limited efficacy against intracellular bacteria.<\/jats:p>","DOI":"10.1189\/jlb.4a0815-365rr","type":"journal-article","created":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T23:18:36Z","timestamp":1473895116000},"page":"531-542","source":"Crossref","is-referenced-by-count":11,"title":["Lipoxin A4, a 5-lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia"],"prefix":"10.1093","volume":"101","author":[{"given":"Anju","family":"Singh","sequence":"first","affiliation":[{"name":"Trudeau Institute , Saranac Lake, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabassum","family":"Rahman","sequence":"additional","affiliation":[{"name":"Center for Immunology and Microbial Disease, Albany Medical College , Albany, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose","family":"Bartiss","sequence":"additional","affiliation":[{"name":"Trudeau Institute , Saranac Lake, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Arabshahi","sequence":"additional","affiliation":[{"name":"Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham , Birmingham, Alabama , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeevan","family":"Prasain","sequence":"additional","affiliation":[{"name":"Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham , Birmingham, Alabama , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Barnes","sequence":"additional","affiliation":[{"name":"Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham , Birmingham, Alabama , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florin Marcel","family":"Musteata","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences , Albany, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J","family":"Sellati","sequence":"additional","affiliation":[{"name":"Trudeau Institute , Saranac Lake, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,9,14]]},"reference":[{"key":"2023011712050352200_B1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.micpath.2011.03.007","article-title":"Features of sepsis caused by pulmonary infection with Francisella tularensis Type A strain","volume":"51","author":"Sharma","year":"2011","journal-title":"Microb. 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Respiratory Francisella tularensis live vaccine strain infection induces Th17 cells and prostaglandin E2, which inhibits generation of gamma interferon-positive T cells","volume":"76","author":"Woolard","year":"2008","journal-title":"Infect. Immun."},{"key":"2023011712050352200_B12","doi-asserted-by":"crossref","first-page":"e37330","DOI":"10.1371\/journal.pone.0037330","article-title":"Francisella tularensis elicits IL-10 via a PGE2-inducible factor, to drive macrophage MARCH1 expression and class II down-regulation.) 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Care Med."},{"key":"2023011712050352200_B28","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.plefa.2011.04.024","article-title":"Control of experimental pulmonary tuberculosis depends more on immunostimulatory leukotrienes than on the absence of immunosuppressive prostaglandins","volume":"85","author":"Peres-Buzalaf","year":"2011","journal-title":"Prostaglandins Leukot. Essent. Fatty Acids"},{"key":"2023011712050352200_B29","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1016\/S0021-9258(19)40034-3","article-title":"MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes","volume":"265","author":"Rouzer","year":"1990","journal-title":"J. Biol. 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