Abstract
Cardiovascular disease (CVD) is a major comorbidity in chronic obstructive pulmonary disease (COPD). Although the mechanism of its development remains largely unknown, it appears to be associated with cigarette consumption and reduced lung function. Therefore, the aim of this study was to investigate the potential link between water-soluble cigarette smoke extract (CSE)-induced endothelial dysfunction and the function of CXCL16/CXCR6 axis on the initial attachment of leukocytes, in addition to its possible impact on COPD-associated systemic inflammation. To do this, we employed several experimental approaches, including RNA silencing and flow cytometry analysis, the dynamic flow chamber technique, and intravital microscopy in the cremasteric arterioles of animals exposed to cigarette smoke (CS). CSE-induced arterial CXCL16 expression, leading to increased platelet–leukocyte and mononuclear cell adhesiveness. CSE-induced CXCL16 expression was dependent on Nox5 expression and subsequent RhoA/p38 MAPK/NF-κB activation. Flow cytometry analysis revealed that COPD patients (n = 35) presented greater numbers of activated circulating platelets (PAC-1+ and P-selectin+) expressing CXCL16 and CXCR6 as compared with age-matched controls (n = 17), with a higher number of CXCR6+-platelets in the smoking COPD group than in ex-smokers. This correlated with enhanced circulating CXCR6+-platelet–leukocyte aggregates in COPD patients. The increase in circulating numbers of CXCR6-expressing platelets and mononuclear cells resulted in enhanced platelet–leukocyte and leukocyte adhesiveness to CSE-stimulated arterial endothelium, which was greater than that found in age-matched controls and was partly dependent on endothelial CXCL16 upregulation. Furthermore, CS exposure provoked CXCL16-dependent leukocyte–arteriolar adhesion in cremasteric arterioles, which was significantly reduced in animals with a nonfunctional CXCR6 receptor. In conclusion, we provide the first evidence that increased numbers of CXCR6-expressing circulating platelets and mononuclear leukocytes from patients with COPD might be a marker of systemic inflammation with potential consequences in CVD development. Accordingly, CXCL16/CXCR6 axis blockade might constitute a new therapeutic approach for decreasing the risk of CVD in COPD patients.
Highlights
Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder characterized by the progressive and largely irreversible decrement in lung function associated with an abnormal chronic inflammatory response of the lungs to noxious particles and gases, mostly from cigarette smoke (CS)
Flow cytometry analysis of Human umbilical arterial endothelial cells (HUAEC) after 24 h exposure to cigarette smoke extract (CSE), INF-γ, or TNF-α revealed a significant increase in protein levels of CXCL16 (Figure 1C), which was confirmed by immunocytochemistry (Figure 1D)
While mononuclear cell adhesion was still evident in CSE-stimulated HUAEC when platelets were dissociated from leukocytes (EDTA), impaired mononuclear leukocyte attachment was detected after CXCL16 HUAEC neutralization (72% inhibition, Figure 1F)
Summary
Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder characterized by the progressive and largely irreversible decrement in lung function associated with an abnormal chronic inflammatory response of the lungs to noxious particles and gases, mostly from cigarette smoke (CS). COPD is considered a multisystem disease characterized by both pulmonary and systemic inflammation [1,2,3]. The latter is believed to be responsible for many COPD comorbidities [1, 3, 4], one of the most relevant of which is cardiovascular disease (CVD) [1, 3, 4]. Vascular dysfunction in smokers has been widely described [7]
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