Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2.
Leukocyte migration is critical to maintaining host defense, but uncontrolled cellular infiltration into tissues can lead to chronic inflammation. In the lung, such diseases include chronic obstructive pulmonary disease (COPD), a debilitating, respiratory condition characterized by progressive and largely irreversible airflow limitation for which cigarette smoking is the major risk factor. COPD is associated with an increased inflammatory cell influx including increased macrophage numbers in the airways and tissue. Alveolar macrophages develop from immigrating blood monocytes and have the capacity to cause the pathological changes associated with COPD. This study addressed the hypothesis that increased macrophage numbers in COPD are a result of increased recruitment of monocytes from the circulation. Chemotaxis assays of peripheral blood mononuclear cells (PBMC)/monocytes from nonsmokers, smokers, and COPD patients demonstrated increased chemotactic responses for cells from COPD patients when compared with controls toward growth-related oncogene (GRO)alpha and neutrophil-activating peptide (NAP)-2 but not toward monocyte chemoattractant protein, interleukin-8, or epithelial-derived NAP(ENA)-78. The enhanced chemotactic response toward GROalpha and NAP-2 was not mediated by differences in expression of their cellular receptors, CXCR1 or CXCR2. Receptor expression studies using flow cytometry indicated that in COPD, monocyte expression of CXCR2 is regulated differently from nonsmokers and smokers, which may account for the enhanced migration toward GROalpha and NAP-2. The results highlight the potential of CXCR2 antagonists as therapy for COPD and demonstrate that an enhanced PBMC/monocyte response to specific CXC chemokines in these patients may contribute to increased recruitment and activation of macrophages in the lungs.
Traves
Suzanne L
SL
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW3 6LY, UK.
Smith
Susan J
SJ
Barnes
Peter J
PJ
Donnelly
Louise E
LE
D000328:Adult; D000368:Aged; D002465:Cell Movement / Q000502:physiology*; D019742:Chemokines, CC / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
D019742:Chemokines, CC; D019743:Chemokines, CXC; D023063:Receptors, Interleukin-8B