title: IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide.
abstract: Acute exacerbation of chronic obstructive pulmonary disease (COPD) is often induced by infection and often has a poor prognosis. Bacterial LPS activates innate immune receptor TLR4 followed by activation of a transcriptional factor IFN regulatory factor-3 (IRF3) as well as NF-κB, resulting in upregulation of various inflammatory mediators. To clarify the role of IRF3 in the pathogenesis of LPS-triggered COPD exacerbation, porcine pancreatic elastase (PPE) followed by LPS was administered intranasally to wild-type (WT) or IRF3-/-male mice. Sequential quantitative changes in emphysema were evaluated by microcomputed tomography, and lung histology was evaluated at the sixth week. WT mice treated with PPE and LPS exhibited enlarged alveolar spaces, whereas this feature was attenuated in similarly treated IRF3-/-mice. Moreover, LPS-induced emphysema aggravation was detected only in WT mice. Analysis of acute inflammation induced by PPE plus LPS revealed that the lungs of treated IRF3-/-mice had decreased mRNA transcripts for MCP-1, MIP-1α, TNF-α, and IFN-γ-inducible protein-10 but had increased neutrophils. IRF3 was involved in the production of mediators from macrophages, alveolar epithelial cells, and neutrophils. Furthermore, compared with isolated WT neutrophils from inflamed lung, those of IRF3-/-neutrophils exhibited impaired autophagic activation, phagocytosis, and apoptosis. These results suggest that IRF3 accelerated emphysema formation based on distinct profiles of mediators involved in LPS-induced COPD exacerbation. Regulation of the IRF3 pathway can affect multiple cell types and contribute to ameliorate pathogenesis of infection-triggered exacerbation of COPD.
authors.affiliation: Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan.|Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan.|Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hosoki
authors.affiliation: Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nikura
authors.affiliation: Department of Advanced Medical Science, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Naohide
authors.initials: N
authors.lastname: Yamashita
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.affiliation: Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan; naoyama@musashino-u.ac.jp.
authors.forename: Naomi
authors.initials: N
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004646:Emphysema / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma