{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:10:57Z","timestamp":1790205057347,"version":"4.1.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T00:00:00Z","timestamp":1561939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Wellcome Trust Senior Clinical Fellowship","award":["076945"],"award-info":[{"award-number":["076945"]}]},{"name":"Medical Research Council SHIELD consortium","award":["MRNO2995X\/1"],"award-info":[{"award-number":["MRNO2995X\/1"]}]},{"name":"Antimicrobial Resistance Cross Council Initiative Innovation","award":["MR\/M017931\/1"],"award-info":[{"award-number":["MR\/M017931\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AMs) kill bacteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To define the role and mechanism of AM apoptosis\u2013associated bacterial killing in the lung.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated a unique CD68.hMcl-1 transgenic mouse with macrophage-specific overexpression of the human antiapoptotic Mcl-1 protein, a factor upregulated in AMs from patients at increased risk of community-acquired pneumonia, to address the requirement for apoptosis-associated killing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Wild-type and transgenic macrophages demonstrated comparable ingestion and initial phagolysosomal killing of bacteria. Continued ingestion (for \u226512 h) overwhelmed initial killing, and a second, late-phase microbicidal response killed viable bacteria in wild-type macrophages, but this response was blunted in CD68.hMcl-1 transgenic macrophages. The late phase of bacterial killing required both caspase-induced generation of mitochondrial reactive oxygen species and nitric oxide, the peak generation of which coincided with the late phase of killing. The CD68.hMcl-1 transgene prevented mitochondrial reactive oxygen species but not nitric oxide generation. Apoptosis-associated killing enhanced pulmonary clearance of Streptococcus pneumoniae and Haemophilus influenzae in wild-type mice but not CD68.hMcl-1 transgenic mice. Bacterial clearance was enhanced in vivo in CD68.hMcl-1 transgenic mice by reconstitution of apoptosis with BH3 mimetics or clodronate-encapsulated liposomes. Apoptosis-associated killing was not activated during Staphylococcus aureus lung infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Mcl-1 upregulation prevents macrophage apoptosis\u2013associated killing and establishes that apoptosis-associated killing is required to allow AMs to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel, host-based antimicrobial strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201804-0646oc","type":"journal-article","created":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T12:19:26Z","timestamp":1547641166000},"page":"84-97","source":"Crossref","is-referenced-by-count":60,"title":["Alveolar Macrophage Apoptosis\u2013associated Bacterial Killing Helps Prevent Murine Pneumonia"],"prefix":"10.1093","volume":"200","author":[{"given":"Julie A.","family":"Preston","sequence":"first","affiliation":[{"name":"The Florey Institute for Host-Pathogen Interactions and"},{"name":"Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin A.","family":"Bewley","sequence":"additional","affiliation":[{"name":"The Florey Institute for Host-Pathogen Interactions and"},{"name":"Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Marriott","sequence":"additional","affiliation":[{"name":"The Florey Institute for Host-Pathogen Interactions and"},{"name":"Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"McGarry Houghton","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, and"},{"name":"Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Mohasin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamil","family":"Jubrail","sequence":"additional","affiliation":[{"name":"MRC Centre for Inflammation Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Morris","sequence":"additional","affiliation":[{"name":"The Florey Institute for Host-Pathogen Interactions and"},{"name":"Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne L.","family":"Stephenson","sequence":"additional","affiliation":[{"name":"The Florey Institute for Host-Pathogen Interactions and"},{"name":"Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Cross","sequence":"additional","affiliation":[{"name":"The Florey Institute for Host-Pathogen Interactions and"},{"name":"Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom"},{"name":"Sheffield Teaching Hospitals, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Greaves","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth W.","family":"Craig","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Geissel School of Medicine at Dartmouth, Hanover, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"van Rooijen","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin D.","family":"Bingle","sequence":"additional","affiliation":[{"name":"The Florey Institute for Host-Pathogen Interactions and"},{"name":"Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C.","family":"Read","sequence":"additional","affiliation":[{"name":"University of Southampton Medical School, Southampton, United Kingdom"},{"name":"National Institute for Health Research Southampton Biomedical Research Centre, Southampton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom; 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