JOURNAL ARTICLE

Cigarette smoke-induced pulmonary inflammation, but not airway remodelling, is attenuated in chemokine receptor 5-deficient mice

K R Bracke, A I D'hulst, T Maes, I K Demedts, K B Moerloose, W A Kuziel, G F Joos, G G Brusselle
Clinical and Experimental Allergy 2007, 37 (10): 1467-79
17883726

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory response of the airways and lungs to noxious particles and gases, mostly cigarette smoke (CS). Pathological changes characteristic of COPD include airway wall thickening, peribronchial fibrosis, peribronchial lymphoid follicles and destruction of lung parenchyma (emphysema). The recruitment of inflammatory cells into the lung in response to CS is thought to play an important role in the development of COPD.

OBJECTIVE: Our aim was to study the contribution of chemokine receptor 5 (CCR5) to the pathogenesis of COPD and specifically whether the development of airway remodelling is a direct result of airway inflammation or rather occurs through an independent mechanism.

METHODS: In this study, C57BL/6 wild-type mice and CCR5-deficient mice were subjected to sub-acute (4 weeks) and chronic (24 weeks) CS exposure.

RESULTS: Both sub-acute and chronic CS exposure significantly increased CCR5 mRNA expression and protein levels of CCR5 ligands [macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta and regulated upon activation, normal T expressed and secreted (RANTES)], and induced the recruitment of neutrophils, macrophages, dendritic cells, and lymphocytes to the bronchoalveolar lavage (BAL) of wild-type mice. Chronic CS exposure also increased the number and extent of peribronchial lymphoid follicles. In CCR5 knockout (KO) mice, these CS-induced increases in CCR5 ligands, inflammatory cells in BAL and peribronchial lymphoid follicles were all significantly attenuated compared with wild-type animals. Importantly, chronic CS exposure induced airspace enlargement in wild-type mice, while CCR5 KO mice were partially protected against the development of emphysema. However, CCR5 deficiency did not affect CS-induced airway wall remodelling, because chronic CS exposure induced a similar increase in airway wall thickness, smooth muscle mass and peribronchial deposition of collagen and fibronectin in both wild-type and CCR5 KO mice.

CONCLUSION: Our data suggest that CCR5 contributes to pulmonary inflammation and to the development of emphysema in response to CS. CCR5 is, however, not implicated in CS-induced airway wall remodelling, suggesting that the mechanisms that lead to airway inflammation are distinct to those responsible for airway remodelling.

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