{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:44:09Z","timestamp":1791207849329,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2011,1,1]],"date-time":"2011-01-01T00:00:00Z","timestamp":1293840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Infection with influenza virus induces severe pulmonary immune pathology that leads to substantial human mortality. Although antiviral therapy is effective in preventing infection, no current therapy can prevent or treat influenza-induced lung injury. Previously, we reported that influenza-induced pulmonary immune pathology is mediated by inflammatory monocytes trafficking to virus-infected lungs via CCR2 and that influenza-induced morbidity and mortality are reduced in CCR2-deficient mice. In this study, we evaluated the effect of pharmacologically blocking CCR2 with a small molecule inhibitor (PF-04178903) on the entry of monocytes into lungs and subsequent morbidity and mortality in influenza-infected mice. Subcutaneous injection of mice with PF-04178903 was initiated 1 d prior to infection with influenza strain H1N1A\/Puerto Rico\/8\/34. Compared with vehicle controls, PF-04178903\u2013treated mice demonstrated a marked reduction in mortality (75 versus 0%) and had significant reductions in weight loss and hypothermia during subsequent influenza infection. Drug-treated mice also displayed significant reductions in bronchoalveolar lavage fluid total protein, albumin, and lactose dehydrogenase activity. Administration of PF-04178903 did not alter viral titers, severity of secondary bacteria infections (Streptococcus pneumoniae), or levels of anti-influenza\u2013neutralizing Abs. Drug-treated mice displayed an increase in influenza nucleoprotein-specific cytotoxic T cell activity. Our results suggest that CCR2 antagonists may represent an effective prophylaxis against influenza-induced pulmonary immune pathology.<\/jats:p>","DOI":"10.4049\/jimmunol.1001002","type":"journal-article","created":{"date-parts":[[2010,11,23]],"date-time":"2010-11-23T00:24:36Z","timestamp":1290471876000},"page":"508-515","source":"Crossref","is-referenced-by-count":89,"title":["CCR2-Antagonist Prophylaxis Reduces Pulmonary Immune Pathology and Markedly Improves Survival during Influenza Infection"],"prefix":"10.1093","volume":"186","author":[{"given":"Kaifeng Lisa","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Medicine, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shari","family":"Sweeney","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian Donghoon","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Ramsburg","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Dee","family":"Gunn","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center , Durham, NC 27710"},{"name":"Department of Immunology, Duke University Medical Center , Durham, NC 27710"},{"name":"Department of Pathology, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,1,1]]},"reference":[{"key":"2025032410561902300_r1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/sj.icb.7100026","article-title":"A question of self-preservation: immunopathology in influenza virus infection","volume":"85","author":"La Gruta","year":"2007","journal-title":"Immunol. 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Biol."},{"key":"2025032410561902300_r13","first-page":"273","article-title":"Significant involvement of CCL2 (MCP-1) in inflammatory disorders of the lung","volume":"10","author":"Rose","year":"2003","journal-title":"Microcirculation"},{"key":"2025032410561902300_r14","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/path.1667","article-title":"C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases","volume":"204","author":"Okuma","year":"2004","journal-title":"J. Pathol."},{"key":"2025032410561902300_r15","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1016\/S0002-9440(10)65068-7","article-title":"Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus","volume":"156","author":"Dawson","year":"2000","journal-title":"Am. J. Pathol."},{"key":"2025032410561902300_r16","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.4049\/jimmunol.180.4.2562","article-title":"CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality","volume":"180","author":"Lin","year":"2008","journal-title":"J. Immunol."},{"key":"2025032410561902300_r17","first-page":"185","article-title":"Reactive species in viral pneumonitis: lessons from animal models","volume":"16","author":"Davis","year":"2001","journal-title":"News Physiol. Sci."},{"key":"2025032410561902300_r18","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1046\/j.1365-2567.2000.00142.x","article-title":"Nitric oxide and virus infection","volume":"101","author":"Akaike","year":"2000","journal-title":"Immunology"},{"key":"2025032410561902300_r19","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1006\/mpat.1995.0056","article-title":"Tumor necrosis factor as a mediator of inflammation in influenza A viral pneumonia","volume":"19","author":"Peper","year":"1995","journal-title":"Microb. Pathog."},{"key":"2025032410561902300_r20","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1084\/jem.20080201","article-title":"Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand","volume":"205","author":"Herold","year":"2008","journal-title":"J. Exp. 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Immunol."},{"key":"2025032410561902300_r31","doi-asserted-by":"crossref","first-page":"e1691","DOI":"10.1371\/journal.pone.0001691","article-title":"Multiple dendritic cell populations activate CD4+ T cells after viral stimulation","volume":"3","author":"Mount","year":"2008","journal-title":"PLoS One"},{"key":"2025032410561902300_r32","doi-asserted-by":"crossref","first-page":"8670","DOI":"10.1073\/pnas.0402644101","article-title":"Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus","volume":"101","author":"Belz","year":"2004","journal-title":"Proc. Natl. Acad. Sci. 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Immunol."},{"key":"2025032410561902300_r36","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1084\/jem.188.8.1541","article-title":"Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice","volume":"188","author":"Karupiah","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025032410561902300_r37","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.4049\/jimmunol.151.5.2444","article-title":"Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes","volume":"151","author":"Mehrotra","year":"1993","journal-title":"J. Immunol."},{"key":"2025032410561902300_r38","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.4049\/jimmunol.136.8.2755","article-title":"Monoclonal antibodies to interferon-gamma inhibit interleukin 2-dependent induction of growth and maturation in lectin\/antigen-reactive cytolytic T lymphocyte precursors","volume":"136","author":"Simon","year":"1986","journal-title":"J. Immunol."},{"key":"2025032410561902300_r39","doi-asserted-by":"crossref","first-page":"7603","DOI":"10.4049\/jimmunol.172.12.7603","article-title":"IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection","volume":"172","author":"van der Sluijs","year":"2004","journal-title":"J. Immunol."},{"key":"2025032410561902300_r40","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1093\/infdis\/174.5.994","article-title":"Interleukin-10 impairs host defense in murine pneumococcal pneumonia","volume":"174","author":"van der Poll","year":"1996","journal-title":"J. Infect. Dis."},{"key":"2025032410561902300_r41","doi-asserted-by":"crossref","first-page":"6707","DOI":"10.1128\/IAI.00789-06","article-title":"Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection","volume":"74","author":"McNamee","year":"2006","journal-title":"Infect. Immun."},{"key":"2025032410561902300_r42","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1084\/jem.184.3.1191","article-title":"Selective induction of monocyte and not neutrophil-attracting chemokines after influenza A virus infection","volume":"184","author":"Sprenger","year":"1996","journal-title":"J. Exp. 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