Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China.
Signal Transduct Target Ther. 2023 Oct 11;8(1):390. doi: 10.1038/s41392-023-01634-x.
Patients with chronic obstructive pulmonary disease (COPD) who exhibit elevated blood eosinophil levels often experience worsened lung function and more severe emphysema. This implies the potential involvement of eosinophils in the development of emphysema. However, the precise mechanisms underlying the development of eosinophil-mediated emphysema remain unclear. In this study, we employed single-cell RNA sequencing to identify eosinophil subgroups in mouse models of asthma and emphysema, followed by functional analyses of these subgroups. Assessment of accumulated eosinophils unveiled distinct transcriptomes in the lungs of mice with elastase-induced emphysema and ovalbumin-induced asthma. Depletion of eosinophils through the use of anti-interleukin-5 antibodies ameliorated elastase-induced emphysema. A particularly noteworthy discovery is that eosinophil-derived cathepsin L contributed to the degradation of the extracellular matrix, thereby leading to emphysema in pulmonary tissue. Inhibition of cathepsin L resulted in a reduction of elastase-induced emphysema in a mouse model. Importantly, eosinophil levels correlated positively with serum cathepsin L levels, which were higher in emphysema patients than those without emphysema. Expression of cathepsin L in eosinophils demonstrated a direct association with lung emphysema in COPD patients. Collectively, these findings underscore the significant role of eosinophil-derived cathepsin L in extracellular matrix degradation and remodeling, and its relevance to emphysema in COPD patients. Consequently, targeting eosinophil-derived cathepsin L could potentially offer a therapeutic avenue for emphysema patients. Further investigations are warranted to explore therapeutic strategies targeting cathepsin L in emphysema patients.
患有慢性阻塞性肺疾病（COPD）且血液嗜酸性粒细胞水平升高的患者常伴有肺功能恶化和更严重的肺气肿。这表明嗜酸性粒细胞可能参与了肺气肿的发展。然而，嗜酸性粒细胞介导的肺气肿发展的确切机制仍不清楚。在这项研究中，我们使用单细胞 RNA 测序来鉴定哮喘和肺气肿小鼠模型中的嗜酸性粒细胞亚群，然后对这些亚群进行功能分析。评估嗜酸性粒细胞的积累揭示了弹性蛋白酶诱导的肺气肿和卵清蛋白诱导的哮喘小鼠肺部的不同转录组。通过使用抗白细胞介素-5 抗体耗尽嗜酸性粒细胞可改善弹性蛋白酶诱导的肺气肿。一个特别值得注意的发现是，嗜酸性粒细胞衍生的组织蛋白酶 L 有助于细胞外基质的降解，从而导致肺组织的肺气肿。组织蛋白酶 L 的抑制导致弹性蛋白酶诱导的肺气肿在小鼠模型中减少。重要的是，嗜酸性粒细胞水平与血清组织蛋白酶 L 水平呈正相关，肺气肿患者的血清组织蛋白酶 L 水平高于无肺气肿患者。COPD 患者嗜酸性粒细胞中的组织蛋白酶 L 表达与肺肺气肿直接相关。总之，这些发现强调了嗜酸性粒细胞衍生的组织蛋白酶 L 在细胞外基质降解和重塑中的重要作用，以及其与 COPD 患者肺气肿的相关性。因此，针对嗜酸性粒细胞衍生的组织蛋白酶 L 可能为肺气肿患者提供一种治疗途径。需要进一步研究来探索针对肺气肿患者的组织蛋白酶 L 的治疗策略。
