Chronic obstructive pulmonary disease (COPD)/pulmonary emphysema is driven by the dysregulated airway inflammation and primarily influenced by the interaction between cigarette smoking (CS) and the individual’s susceptibility. The inflammation in COPD involves both innate and adaptive immunity. By binding to its specific ligands, chemokine receptor CXCR3 plays an important role in regulating tissue inflammation and damage. In acute animal model challenged with either CS or pathogens, CXCR3 knockout (KO) attenuated lung inflammation and pathology. However, the role of CXCR3 in CS-induced chronic airway inflammation and pulmonary emphysema remains unknown. In this present study, we investigated the effect of CXCR3 in CS-induced pulmonary emphysema in an animal model, and the association between CXCR3 single nucleotide polymorphisms (SNPs) and COPD susceptibility in human subjects. We found that after chronic exposure to side stream CS (SSCS) for 24 weeks, CXCR3 KO mice demonstrated significant airspace enlargement expressed by mean linear intercept (Lm) compared with the wild-type (WT) mice. Consistently, CXCR3 KO mice had significantly higher BAL fluid macrophages and neutrophils, TNFα, and lung homogenate MMP-9 and MMP-12. Through genetic analysis of CXCR3 polymorphisms in a cohort of COPD patients with Han Chinese ethnicity, one CXCR3 SNP, rs2280964, was found to be genetically related to COPD susceptibility. Furthermore, CXCR3 SNP rs2280964 was significantly associated with the levels of serum MMP-9 in COPD patients. Our data from both animal and human studies revealed a novel role of CXCR3 possibly via influencing MMP9 production in the pathogenesis and progression of CS-associated COPD/pulmonary emphysema.

慢性阻塞性肺病 (COPD)/肺气肿是由气道炎症失调引起的，主要受吸烟 (CS) 和个人易感性之间相互作用的影响。慢性阻塞性肺病的炎症涉及先天性免疫和适应性免疫。通过与其特异性配体结合，趋化因子受体CXCR3在调节组织炎症和损伤中发挥重要作用。在受到 CS 或病原体攻击的急性动物模型中， CXCR3敲除 (KO) 减轻了肺部炎症和病理。然而， CXCR3在 CS 引起的慢性气道炎症和肺气肿中的作用仍不清楚。在本研究中，我们在动物模型中研究了CXCR3在 CS 诱导的肺气肿中的作用，以及人类受试者中CXCR3单核苷酸多态性 (SNP) 与 COPD 易感性之间的关联。我们发现，在长期暴露于侧流CS（SSCS）24周后，与野生型（WT）小鼠相比， CXCR3 KO小鼠表现出显着的空腔扩大，以平均线性截距（Lm）表示。一致的是， CXCR3 KO 小鼠的 BAL 液巨噬细胞和中性粒细胞、TNFα 以及肺匀浆 MMP-9 和 MMP-12 显着升高。通过对汉族COPD患者队列CXCR3多态性进行遗传分析，发现CXCR3 SNP rs2280964与COPD易感性存在遗传相关。此外， CXCR3 SNP rs2280964 与 COPD 患者血清 MMP-9 水平显着相关。 我们来自动物和人类研究的数据揭示了CXCR3的新作用，可能是通过影响 CS 相关 COPD/肺气肿的发病机制和进展中 MMP9 的产生。