CC-chemokine receptors in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and disability in the world, with a prevalence that is expected to increase in the next decades. The disease is characterized by a chronic inflammatory response of the airways and lungs to noxious particles and gases, mostly cigarette smoke. The molecular and cellular mechanisms that lead to this exaggerated influx of cells belonging to both the innate and adaptive immune system are not yet completely unravelled. However, there is now growing evidence that the recruitment of these inflammatory cells in response to cigarette smoke is largely regulated by chemokines acting as ligands for chemokine receptors. Several of these receptors, which fall mainly in the CC- or CXC-category, have been implicated in the pathogenesis of COPD. In this review we will focus mainly on the CC-family, as the involvement of CXC-receptors in COPD has already been extensively reviewed. In patients with COPD, several CC-chemokines like MIP-1alpha, MIP-3alpha, RANTES and MCP-1 are upregulated, suggesting the contribution of their respective receptor in the pathogenesis of the disease. Using knock out mice, this contribution has been further confirmed for CCR5 and CCR6, evidenced by an attenuated accumulation of inflammatory cells like macrophages, dendritic cells, neutrophils and CD8(+) T-lymphocytes upon cigarette smoke-exposure. Moreover, mice deficient for CCR5 or CCR6 are partially protected from the development of pulmonary emphysema, another hallmark of COPD. These data suggest that chemokine receptors are potential therapeutic targets to reduce the chronic inflammation and parenchymal destruction in COPD.
Bracke
Ken R
KR
Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium. Ken.Bracke@UGent.be
Demedts
Ingel K
IK
Joos
Guy F
GF
Brusselle
Guy G
GG
D000818:Animals; D065100:CCR5 Receptor Antagonists; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D019713:Receptors, CCR5 / Q000235:genetics / Q000502:physiology; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D065100:CCR5 Receptor Antagonists; C498126:CCR6 protein, mouse; D019713:Receptors, CCR5; D054399:Receptors, CCR6; D019707:Receptors, Chemokine