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Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that target pathogenic immune processes. Polymorphonuclear leukocytes (PMNs) are essential for infection control but can also promote tissue damage and pathogen spread. The major\n              <jats:italic>Sp<\/jats:italic>\n              virulence factor, pneumolysin, triggers acute inflammation by stimulating the 12-lipoxygenase (12-LOX) eicosanoid synthesis pathway in epithelial cells. This pathway is required for systemic spread in a mouse pneumonia model and produces a number of bioactive lipids, including hepoxilin A3 (HXA\n              <jats:sub>3<\/jats:sub>\n              ), a hydroxy epoxide PMN chemoattractant that has been hypothesized to facilitate breach of mucosal barriers. To understand how 12-LOX-dependent inflammation promotes dissemination during\n              <jats:italic>Sp<\/jats:italic>\n              lung infection and dissemination, we utilized bronchial stem cell-derived air\u2013liquid interface cultures that lack this enzyme to show that HXA\n              <jats:sub>3<\/jats:sub>\n              methyl ester (HXA\n              <jats:sub>3<\/jats:sub>\n              -ME) is sufficient to promote basolateral-to-apical PMN transmigration, monolayer disruption, and concomitant\n              <jats:italic>Sp<\/jats:italic>\n              barrier breach. In contrast, PMN transmigration in response to the non-eicosanoid chemoattractant N-formyl-L-methionyl-L-leucyl-phenylalanine (fMLP) did not lead to epithelial disruption or bacterial translocation. Correspondingly, HXA\n              <jats:sub>3<\/jats:sub>\n              -ME but not fMLP increased the release of neutrophil elastase (NE) from\n              <jats:italic>Sp<\/jats:italic>\n              -infected PMNs. Pharmacologic blockade of NE secretion or activity diminished epithelial barrier disruption and bacteremia after pulmonary challenge of mice. Thus, HXA\n              <jats:sub>3<\/jats:sub>\n              promotes barrier-disrupting PMN transmigration and NE release, pathological events that can be targeted to curtail systemic disease following pneumococcal pneumonia.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                (\n                <jats:italic>Sp<\/jats:italic>\n                ), a leading cause of pneumonia, can spread from the lung into the bloodstream to cause systemic disease. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that limit pathologic host immune responses to\n                <jats:italic>Sp<\/jats:italic>\n                . Excessive polymorphonuclear leukocyte (PMN) infiltration into\n                <jats:italic>Sp<\/jats:italic>\n                -infected airways promotes systemic disease. Using stem cell-derived respiratory cultures that reflect bona fide lung epithelium, we identified eicosanoid hepoxilin A3 as a critical pulmonary PMN chemoattractant that is sufficient to drive PMN-mediated epithelial damage by inducing the release of neutrophil elastase. Inhibition of the release or activity of this protease in mice limited epithelial barrier disruption and bacterial dissemination, suggesting a new host-directed treatment for\n                <jats:italic>Sp<\/jats:italic>\n                lung infection.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01856-24","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T13:00:56Z","timestamp":1723208456000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Blocking HXA\n            <sub>3<\/sub>\n            -mediated neutrophil elastase release during\n            <i>S. pneumoniae<\/i>\n            lung infection limits pulmonary epithelial barrier disruption and bacteremia"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4572-8663","authenticated-orcid":true,"given":"Shuying","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA"},{"name":"Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1093-2576","authenticated-orcid":true,"given":"Shumin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Romanos","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA"},{"name":"Program in Biotechnology, Francisco de Vitoria University, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Reedy","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8892-8695","authenticated-orcid":true,"given":"Michael K.","family":"Mansour","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9985-9565","authenticated-orcid":true,"given":"Jatin M.","family":"Vyas","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9455-6672","authenticated-orcid":true,"given":"Joan","family":"Mecsas","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Mou","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts, 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