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.
Footnotes
This study was supported in part by Ministry of Education, Culture, Sports, Science and Technology, Japan Grant-in-Aid for Scientific Research 25460660 (to Naomi Yamashita).
Abbreviations used in this article:
- BALF
- bronchoalveolar lavage fluid
- COPD
- chronic obstructive pulmonary disease
- CSE
- cigarette smoke extract
- CT
- computed tomography
- HU
- Hounsfield unit
- IP-10
- IFN-γ–inducible protein-10
- IRF3
- IFN regulatory factor-3
- MFI
- mean fluorescence intensity
- micro-CT
- microcomputed tomography
- PI
- propidium iodide
- PPE
- porcine pancreatic elastase
- TRIF
- Toll/IL-1R domain–containing adaptor inducing IFN-β
- WT
- wild-type.
- Received June 22, 2016.
- Accepted February 23, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.