Toll-like receptor 2 and 4 have Opposing Roles in the Pathogenesis of Cigarette Smoke-induced Chronic Obstructive Pulmonary Disease

Abstract

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.

Enhancing tristetraprolin activity reduces the severity of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

“…[18][19][20][21][22][23] As expected, chronic CS exposure of wild-type mice increased collagen deposition around the airways compared to normal air-exposed wild-type controls (Figure 3a). [18][19][20][21][22][23] As expected, chronic CS exposure of wild-type mice increased collagen deposition around the airways compared to normal air-exposed wild-type controls (Figure 3a).…”

“…We previously showed that mice develop small airway remodelling characterised by increases in collagen deposition, epithelial cell area and numbers of nuclei around and in the small airways in experimental COPD. [18][19][20][21][22][23] As expected, chronic CS exposure of wild-type mice increased collagen deposition around the airways compared to normal air-exposed wild-type controls (Figure 3a). CS-exposed Zfp36 aa/aa mice were protected against collagen deposition with no differences compared to normal air-exposed Zfp36 aa/aa controls and had significantly reduced deposition compared to CS-exposed wild-type controls.…”

“…[18][19][20][21][22][23][24] In this study, chronic CS exposure of wild-type mice for 8 weeks resulted in increased alveolar diameter and septal damage, which were assessed using the mean linear intercept and destructive index methods, respectively, compared to air-exposed wild-type controls ( Figure 3b). [18][19][20][21][22][23][24] In this study, chronic CS exposure of wild-type mice for 8 weeks resulted in increased alveolar diameter and septal damage, which were assessed using the mean linear intercept and destructive index methods, respectively, compared to air-exposed wild-type controls ( Figure 3b).…”

“…18,21,22,27 These include pulmonary inflammation (chronic bronchitis), small airway remodelling, emphysema-like alveolar enlargement and impaired lung function. 18,21,22,27 These include pulmonary inflammation (chronic bronchitis), small airway remodelling, emphysema-like alveolar enlargement and impaired lung function.…”

“…[18][19][20][21][22][23][24]30,50,51,[68][69][70] Exposures are equivalent to a pack-aday smoker. [18][19][20][21][22][23][24]30,50,51,[68][69][70] Exposures are equivalent to a pack-aday smoker.…”