Department of Respiratory Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo, 060-8638, Japan.
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America.
Respir Res. 2023 Aug 17;24(1):201. doi: 10.1186/s12931-023-02508-0.
Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear.
We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD.
Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality.
AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD.
This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).
肺泡巨噬细胞（AMs）和 AM 产生的基质金属蛋白酶（MMP）-12 已知在慢性阻塞性肺疾病（COPD）的发病机制中发挥关键作用。巨噬细胞凋亡抑制剂（AIM）/CD5 分子样（CD5L）是一种由巨噬细胞分泌的多功能蛋白，主要以与免疫球蛋白（Ig）M 五聚体结合的形式存在于血液中。尽管 AIM 在各种疾病中具有促进和抑制作用，但它在 COPD 中的作用尚不清楚。
我们使用猪胰弹性蛋白酶（PPE）诱导和香烟烟雾诱导的肺气肿小鼠模型以及 AM 体外模型研究了 AIM 在 COPD 发病机制中的作用。我们还分析了非吸烟者、健康吸烟者和 COPD 患者之间血液中 AIM/IgM 比值的差异，并研究了 COPD 患者血液 AIM/IgM 比值与 COPD 加重和死亡率之间的关系。
与野生型（WT）小鼠相比，PPE 和香烟烟雾诱导的肺气肿模型中 AIM 小鼠的肺气肿形成、炎症和细胞死亡减轻。在 AIM 小鼠中，PPE 诱导的 MMP-12 增加在 mRNA 和蛋白质水平上均减弱。根据用香烟烟雾提取物刺激的 AM 进行的体外实验，与 WT 小鼠相比，AIM 小鼠中的 MMP-12 水平降低。通过添加重组 AIM，这种降低得到了逆转。此外，对临床样本的分析表明，与健康吸烟者相比，COPD 患者的血液 AIM/IgM 比值更高。此外，血液 AIM/IgM 比值与 COPD 患者的疾病严重程度呈正相关。更高的 AIM/IgM 比值也与首次 COPD 加重的时间缩短以及全因和呼吸死亡的风险增加有关。
AIM 通过上调 MMP-12 促进 COPD 的发展。此外，较高的血液 AIM/IgM 比值与 COPD 患者的不良预后相关。
本包括非吸烟者、健康吸烟者和 COPD 吸烟者的临床研究获得了北海道大学医院伦理委员会的批准（012-0075，注册日期：2012 年 9 月 5 日）。北海道 COPD 队列研究获得了北海道大学医学院伦理委员会的批准（med02-001，注册日期：2002 年 12 月 25 日）。
