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However, the precise mechanisms by which <jats:italic>P. multocida<\/jats:italic> compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that <jats:italic>P. multocida<\/jats:italic> causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of <jats:italic>P. multocida<\/jats:italic> pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of <jats:italic>P. multocida<\/jats:italic> into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that <jats:italic>P. multocida<\/jats:italic>-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in <jats:italic>P. multocida<\/jats:italic>-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of <jats:italic>P. multocida<\/jats:italic> as well as potential treatment options for this and other respiratory bacterial diseases.<\/jats:p>","DOI":"10.1186\/s13567-024-01298-7","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T13:02:04Z","timestamp":1712581324000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Pasteurella multocida activates apoptosis via the FAK-AKT-FOXO1 axis to cause pulmonary integrity loss, bacteremia, and eventually a cytokine storm"],"prefix":"10.1186","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0194-4604","authenticated-orcid":false,"given":"Guangfu","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruitong","family":"Dan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianci","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nengzhang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"1298_CR1","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/nature02759","volume":"430","author":"DM Morens","year":"2004","unstructured":"Morens DM, Folkers GK, Fauci AS (2004) The challenge of emerging and re-emerging infectious diseases. 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