{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:21:07Z","timestamp":1768504867833,"version":"3.49.0"},"posted":{"date-parts":[[2023,1,23]]},"group-title":"Pharmacology and Toxicology","reference-count":58,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Severe lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood-brain barrier (BBB) leakage and behavioral impairment.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Pneumonia was induced in adult C57BL\/6 mice by intratracheal inoculation of\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    (PA). Solute extravasation, histology, immunofluorescence, RT-PCR, multiphoton imaging and neurological testing were performed in this study.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Lung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell-cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 hours and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1\u03b2, IL-6, and TNF-\u03b1), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b+ cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell-cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1\u03b2 induced a significant reduction of barrier function coupled with tight junction (TJ) diffusion and disorganization. Combined treatment with IL-1\u03b2 and TNF\u03b1 augmented the barrier injury.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These results suggest that lung bacterial infection causes cerebral microvascular leakage and neuroinflammation via a mechanism involving cytokine-induced BBB injury.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.01.23.524949","type":"posted-content","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T23:00:13Z","timestamp":1674514813000},"source":"Crossref","is-referenced-by-count":0,"title":["Lung infection by\n                  <i>P. aeruginosa<\/i>\n                  induces neuroinflammation and blood-brain barrier dysfunction in mice"],"prefix":"10.64898","author":[{"given":"Nuria","family":"Villalba","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yonggang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Gahan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurelie","family":"Joly-Amado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sam","family":"Spence","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Nash","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah Y.","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023012616050677000_2023.01.23.524949v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2013.07.025"},{"issue":"2","key":"2023012616050677000_2023.01.23.524949v1.2","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.imbio.2016.09.017","article-title":"The pertussis hypothesis: Bordetella pertussis colonization in the pathogenesis of Alzheimer\u2019s disease","volume":"222","year":"2017","journal-title":"Immunobiology"},{"issue":"3","key":"2023012616050677000_2023.01.23.524949v1.3","first-page":"957","article-title":"Bacterial infection and Alzheimer\u2019s disease: a meta-analysis","volume":"43","year":"2015","journal-title":"J Alzheimers Dis"},{"key":"2023012616050677000_2023.01.23.524949v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(04)00931-4"},{"key":"2023012616050677000_2023.01.23.524949v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2012.183"},{"key":"2023012616050677000_2023.01.23.524949v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccm.2004.10.015"},{"issue":"10","key":"2023012616050677000_2023.01.23.524949v1.7","first-page":"1287","article-title":"New Sepsis Definition (Sepsis-3) and Community-acquired Pneumonia Mortality","volume":"196","year":"2017","journal-title":"A Validation and Clinical Decision-Making Study. 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