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Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen species\n                  <jats:italic>in vitro<\/jats:italic>\n                  and ameliorated ALI-induced alveolar neutrophilia and NETs\n                  <jats:italic>in vivo<\/jats:italic>\n                  . We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.\n                <\/jats:p>","DOI":"10.1101\/2024.05.23.595575","type":"posted-content","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T05:10:17Z","timestamp":1716873017000},"source":"Crossref","is-referenced-by-count":1,"title":["Loss of neutrophil Shp1 produces hemorrhagic and lethal acute lung injury"],"prefix":"10.64898","author":[{"given":"SF","family":"Moussavi-Harami","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SJ","family":"Cleary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Magnen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Seo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Conrad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4531-8808","authenticated-orcid":false,"given":"BC","family":"English","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"KM","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"CL","family":"Abram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"CA","family":"Lowell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MR","family":"Looney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"1","key":"2024053009300721000_2024.05.23.595575v1.1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41572-019-0069-0","article-title":"Acute respiratory distress syndrome","volume":"5","year":"2019","journal-title":"Nat Rev Dis Primers"},{"issue":"19","key":"2024053009300721000_2024.05.23.595575v1.2","doi-asserted-by":"crossref","first-page":"502","DOI":"10.21037\/atm.2019.09.31","article-title":"Definition and global epidemiology of pediatric acute respiratory distress syndrome","volume":"7","year":"2019","journal-title":"Ann Transl Med"},{"key":"2024053009300721000_2024.05.23.595575v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198712173172504"},{"key":"2024053009300721000_2024.05.23.595575v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa033181"},{"issue":"6","key":"2024053009300721000_2024.05.23.595575v1.5","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/S2213-2600(17)30188-1","article-title":"Clinical trials in acute respiratory distress syndrome: challenges and opportunities","volume":"5","year":"2017","journal-title":"Lancet Respir Med"},{"key":"2024053009300721000_2024.05.23.595575v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00676-0"},{"issue":"10285","key":"2024053009300721000_2024.05.23.595575v1.7","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1016\/S0140-6736(21)00712-1","article-title":"Tocilizumab in COVID-19: some clarity amid controversy","volume":"397","year":"2021","journal-title":"Lancet"},{"issue":"10297","key":"2024053009300721000_2024.05.23.595575v1.8","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/S0140-6736(21)01422-7","article-title":"Tocilizumab in COVID-19 therapy: who benefits, and how? - Authors\u2019 reply","volume":"398","year":"2021","journal-title":"Lancet"},{"issue":"11","key":"2024053009300721000_2024.05.23.595575v1.9","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1093\/cid\/ciab536","article-title":"Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. 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