title: CCR2-antagonist prophylaxis reduces pulmonary immune pathology and markedly improves survival during influenza infection.
abstract: 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-treated 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-neutralizing 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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kaifeng Lisa
authors.initials: KL
authors.lastname: Lin
authors.forename: Shari
authors.initials: S
authors.lastname: Sweeney
authors.forename: Brian Donghoon
authors.initials: BD
authors.lastname: Kang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ramsburg
authors.forename: Michael Dee
authors.initials: MD
authors.lastname: Gunn
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D010879:Piperazines / Q000008:administration & dosage* / Q000627:therapeutic use; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage* / Q000627:therapeutic use; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D016019:Survival Analysis
chemical_list: C555353:1,5-anhydro-2,3-dideoxy-3-((3-isopropyl-3-((4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)carbonyl)cyclopentyl)amino)-4-O-methylpentitol; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; C515335:Ccr2 protein, mouse; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D054390:Receptors, CCR2