期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 314, 期 2, 页码 L298-L317出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00154.2017
关键词
cigarette smoke; COPD; emphysema; TLR2; TLR4
资金
- National Health and Medical Research Council (NHMRC) of Australia
- Australian Research Council
- NHMRC Early Career Research Fellowship
- Wellcome Trust
- NHMRC Principal Research Fellowship
- Brawn Fellowship, Faculty of Health and Medicine, University of Newcastle
- Medical Research Council [G1000758B, G1000758] Funding Source: researchfish
- Asthma UK [MRC-Asthma UK Centre, MRC-AsthmaUKCentre] Funding Source: researchfish
Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death and imposes major socioeconomic burdens globally. It is a progressive and disabling condition that severely impairs breathing and lung function. There is a lack of effective treatments for COPD, which is a direct consequence of the poor understanding of the underlying mechanisms involved in driving the pathogenesis of the disease. Toll-like receptor (TLR) 2 and TLR4 are implicated in chronic respiratory diseases, including COPD, asthma and pulmonary fibrosis. However, their roles in the pathogenesis of COPD are controversial and conflicting evidence exists. In the current study, we investigated the role of TLR2 and TLR4 using a model of cigarette smoke (CS)-induced experimental COPD that recapitulates the hallmark features of human disease. TLR2, TLR4, and associated coreceptor mRNA expression was increased in the airways in both experimental and human COPD. Compared with wild-type (WT) mice, CS-induced pulmonary inflammation was unaltered in TLR2-deficient (Tlr2(-/-)) and TLR4-deficient (Tlr4(-/-)) mice. CS-induced airway fibrosis, characterized by increased collagen deposition around small airways, was not altered in Tlr2-/-mice but was attenuated in Tlr4(-/)-mice compared with CS-exposed WT controls. However, Tlr2-/-mice had increased CS-induced emphysema-like alveolar enlargement, apoptosis, and impaired lung function, while these features were reduced in Tlr4(-/-)mice compared with CS-exposed WT controls. Taken together, these data highlight the complex roles of TLRs in the pathogenesis of COPD and suggest that activation of TLR2 and/or inhibition of TLR4 may be novel therapeutic strategies for the treatment of COPD.
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