title: Resolvin D1 Dampens Pulmonary Inflammation and Promotes Clearance of Nontypeable Haemophilus influenzae.
abstract: Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative, opportunistic pathogen that frequently causes ear infections, bronchitis, pneumonia, and exacerbations in patients with underlying inflammatory diseases, such as chronic obstructive pulmonary disease. In mice, NTHi is rapidly cleared, but a strong inflammatory response persists, underscoring the concept that NTHi induces dysregulation of normal inflammatory responses and causes a failure to resolve. Lipid-derived specialized proresolving mediators (SPMs) play a critical role in the active resolution of inflammation by both suppressing proinflammatory actions and promoting resolution pathways. Importantly, SPMs lack the immunosuppressive properties of classical anti-inflammatory therapies. On the basis of these characteristics, we hypothesized that aspirin-triggered resolvin D1 (AT-RvD1) would dampen NTHi-induced inflammation while still enhancing bacterial clearance. C57BL/6 mice were treated with AT-RvD1 and infected with live NTHi. AT-RvD1-treated mice had lower total cell counts and neutrophils in bronchoalveolar lavage fluid, and had earlier influx of macrophages. In addition, AT-RvD1-treated mice showed changes in temporal regulation of inflammatory cytokines and enzymes, with decreased KC at 6 h and decreased IL-6, TNF-α, and cyclooxygenase-2 expression at 24 h post infection. Despite reduced inflammation, AT-RvD1-treated mice had reduced NTHi bacterial load, mediated by enhanced clearance by macrophages and a skewing toward an M2 phenotype. Finally, AT-RvD1 protected NTHi-infected mice from weight loss, hypothermia, hypoxemia, and respiratory compromise. This research highlights the beneficial role of SPMs in pulmonary bacterial infections and provides the groundwork for further investigation into SPMs as alternatives to immunosuppressive therapies like steroids.
authors: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and.
authors: Amanda
authors: A
authors: Croasdell
authors: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and.
authors: Shannon H
authors: SH
authors: Lacy
authors: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors: Thomas H
authors: http://orcid.org/0000-0001-7177-3041
authors: TH
authors: Thatcher
authors: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors: Patricia J
authors: PJ
authors: Sime
authors: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 Richard_Phipps@urmc.rochester.edu.
authors: Richard P
authors: http://orcid.org/0000-0002-6428-1388
authors: RP
authors: Phipps
mesh_terms: D000818:Animals; D001241:Aspirin / Q000378:metabolism; D058491:Bacterial Load / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D005260:Female; D006192:Haemophilus Infections / Q000188:drug therapy / Q000276:immunology*; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D012119:Respiration / Q000187:drug effects
chemical_list: D016207:Cytokines; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D001241:Aspirin