Section of Pulmonary, Critical Care, and Sleep Medicine, Yale Univ. School of Medicine, PO Box 208057, 300 Cedar St., New Haven, CT 06520-8057.
Am J Physiol Lung Cell Mol Physiol. 2014 Mar 15;306(6):L487-96. doi: 10.1152/ajplung.00284.2013. Epub 2014 Jan 17.
The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of these underlying mechanisms remain unknown. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of COPD. This study examines the role of MIF in the pathogenesis of COPD. Mice deficient in MIF (Mif(-/-)) or the MIF receptor CD74 (Cd74(-/-)) and wild-type (WT) controls were aged for 6 mo. Both Mif(-/-) and Cd74(-/-) mice developed spontaneous emphysema by 6 mo of age compared with WT mice as measured by lung volume and chord length. This was associated with activation of the senescent pathway markers p53/21 and p16. Following exposure to cigarette smoke, Mif(-/-) mice were more susceptible to the development of COPD and apoptosis compared with WT mice. MIF plasma concentrations were measured in a cohort of 224 human participants. Within a subgroup of older current and former smokers (n = 72), MIF concentrations were significantly lower in those with COPD [8.8, 95%CI (6.7-11.0)] compared with those who did not exhibit COPD [12.7 ng/ml, 95%CI (10.6-14.8)]. Our results suggest that both MIF and the MIF receptor CD74 are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with COPD in human subjects.
慢性阻塞性肺疾病（COPD）的发病机制仍不清楚。细胞衰老和凋亡导致 COPD 的发生；然而，这些潜在机制的关键调节因子仍不清楚。巨噬细胞移动抑制因子（MIF）是一种多效细胞因子，拮抗细胞凋亡和过早衰老，可能在 COPD 的发病机制中起重要作用。本研究探讨了 MIF 在 COPD 发病机制中的作用。缺乏 MIF（Mif(-/-)）或 MIF 受体 CD74（Cd74(-/-)）的小鼠和野生型（WT）对照小鼠在 6 个月时衰老。与 WT 小鼠相比，Mif(-/-)和 Cd74(-/-)小鼠在 6 个月时通过肺容积和弦长测量自发发展为肺气肿。这与衰老途径标志物 p53/21 和 p16 的激活有关。在接触香烟烟雾后，与 WT 小鼠相比，Mif(-/-)小鼠更容易发生 COPD 和细胞凋亡。在 224 名人类参与者的队列中测量了 MIF 血浆浓度。在一组年龄较大的当前和以前的吸烟者（n = 72）中，与未患 COPD 的人相比，患有 COPD 的人的 MIF 浓度明显较低[8.8，95%CI（6.7-11.0）] [12.7ng/ml，95%CI（10.6-14.8）]。我们的结果表明，MIF 和 MIF 受体 CD74 都需要维持小鼠正常的肺泡结构，并且 MIF 的减少与人类 COPD 有关。
