{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:05:26Z","timestamp":1793361926051,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T00:00:00Z","timestamp":1590969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Respiratory syncytial virus (RSV) bronchiolitis causes significant infant mortality. Bronchiolitis is characterized by airway epithelial cell (AEC) death; however, the mode of death remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine whether necroptosis contributes to RSV bronchiolitis pathogenesis via HMGB1 (high mobility group box 1) release.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Nasopharyngeal samples were collected from children presenting to the hospital with acute respiratory infection. Primary human AECs and neonatal mice were inoculated with RSV and murine Pneumovirus, respectively. Necroptosis was determined via viability assays and immunohistochemistry for RIPK1 (receptor-interacting protein kinase-1), MLKL (mixed lineage kinase domain-like pseudokinase) protein, and caspase-3. Necroptosis was blocked using pharmacological inhibitors and RIPK1 kinase-dead knockin mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased phosphorylated RIPK1 and phosphorylated MLKL but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSV-induced HMGB1 translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8\/9\u2013dependent manner. In susceptible mice, Pneumovirus infection upregulated RIPK1 and MLKL expression in the airway epithelium at 8 to 10 days after infection, coinciding with AEC sloughing, HMGB1 release, and neutrophilic inflammation. Genetic or pharmacological inhibition of RIPK1 or MLKL attenuated these pathologies, lowered viral load, and prevented type 2 inflammation and airway remodeling. Necroptosis inhibition in early life ameliorated asthma progression induced by viral or allergen challenge in later life.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Pneumovirus infection induces AEC necroptosis. Inhibition of necroptosis may be a viable strategy to limit the severity of viral bronchiolitis and break its nexus with asthma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201906-1149oc","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T10:35:26Z","timestamp":1582799726000},"page":"1358-1371","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":119,"title":["Respiratory Syncytial Virus Infection Promotes Necroptosis and HMGB1 Release by Airway Epithelial Cells"],"prefix":"10.1093","volume":"201","author":[{"given":"Jennifer","family":"Simpson","sequence":"first","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Herston, Australia"},{"name":"School of Biomedical Science, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixuan","family":"Loh","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Ashik","family":"Ullah","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Herston, Australia"},{"name":"School of Biomedical Science, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason P.","family":"Lynch","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Herston, Australia"},{"name":"School of Biomedical Science, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhiannon B.","family":"Werder","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Herston, Australia"},{"name":"School of Biomedical Science, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Collinson","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Herston, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Zhang","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Herston, Australia"},{"name":"School of Biomedical Science, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Dondelinger","sequence":"additional","affiliation":[{"name":"VIB Center for Inflammation Research, Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu J. M.","family":"Bertrand","sequence":"additional","affiliation":[{"name":"VIB Center for Inflammation Research, Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark L.","family":"Everard","sequence":"additional","affiliation":[{"name":"School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Blyth","sequence":"additional","affiliation":[{"name":"School of Medicine and"},{"name":"Department of Infectious Diseases, Perth Children\u2019s Hospital, Perth, Western Australia, Australia"},{"name":"Department of Microbiology, PathWest Laboratory Medicine WA, QEII Medical Centre, Perth, Western Australia, Australia"},{"name":"Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, 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