Faculté de Médecine, Université Paris-Est, UMR U955, Créteil, France.
Am J Respir Crit Care Med. 2013 Apr 1;187(7):703-14. doi: 10.1164/rccm.201208-1361OC.
Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by the irreversible loss of replicative capacity associated with the secretion of inflammatory mediators. However, the mechanisms of this phenomenon remain poorly defined.
The aim of this study was to analyze the role of prostaglandin E2 (PGE2), a prostaglandin known to be increased in COPD lung fibroblasts, in inducing senescence and related inflammation in vitro in lung fibroblasts and in vivo in mice.
Fibroblasts were isolated from patients with COPD and from smoker and nonsmoker control subjects. Senescence markers and inflammatory mediators were investigated in fibroblasts and in mice.
Lung fibroblasts from patients with COPD exhibited higher expression of PGE2 receptors EP2 and EP4 as compared with nonsmoker and smoker control subjects. Compared with both nonsmoker and smoker control subjects, during long-term culture, COPD fibroblasts displayed increased senescent markers (increased senescence associated-β galactosidase activity, p16, and p53 expression and lower proliferative capacity), and an increased PGE2, IL-6, IL-8, growth-regulated oncogene (GRO), CX3CL1, and matrix metalloproteinase-2 protein and cyclooxygenase-2 and mPGES-1 mRNA expression. Using in vitro pharmacologic approaches and in vivo experiments in wild-type and p53(-/-) mice we demonstrated that PGE2 produced by senescent COPD fibroblasts is responsible for the increased senescence and related inflammation. PGE2 acts either in a paracrine or autocrine fashion by a pathway involving EP2 and EP4 prostaglandin receptors, cyclooxygenase-2-dependent reactive oxygen species production and signaling, and consecutive p53 activation.
PGE2 is a critical component of an amplifying and self-perpetuating circle inducing senescence and inflammation in COPD fibroblasts. Modulating the described PGE2 signaling pathway could provide a new basis to dampen senescence and senescence-associated inflammation in COPD.
慢性阻塞性肺疾病（COPD）与肺成纤维细胞衰老有关，这是一个过程，其特征是与炎症介质分泌相关的复制能力的不可逆转丧失。然而，这种现象的机制仍未得到明确界定。
本研究旨在分析前列腺素 E2（PGE2）在体外诱导肺成纤维细胞衰老及相关炎症中的作用，以及在 COPD 小鼠模型中的作用。
从 COPD 患者和吸烟及非吸烟对照者中分离出成纤维细胞。在成纤维细胞和小鼠中检测衰老标志物和炎症介质。
与非吸烟对照者和吸烟者对照者相比，COPD 患者的肺成纤维细胞表现出更高的 PGE2 受体 EP2 和 EP4 的表达。与非吸烟对照者和吸烟者对照者相比，COPD 成纤维细胞在长期培养过程中表现出更高的衰老标志物（衰老相关-β半乳糖苷酶活性增加、p16 和 p53 表达增加以及增殖能力降低），以及更高的 PGE2、IL-6、IL-8、生长调节致癌基因（GRO）、CX3CL1 和基质金属蛋白酶-2 蛋白和环氧化酶-2 和 mPGES-1mRNA 表达。我们通过体外药理学方法和野生型及 p53（-/-）小鼠的体内实验证明，由衰老的 COPD 成纤维细胞产生的 PGE2 是导致衰老和相关炎症增加的原因。PGE2 通过涉及 EP2 和 EP4 前列腺素受体、环氧化酶-2 依赖性活性氧产生和信号转导以及随后的 p53 激活的旁分泌或自分泌途径发挥作用。
PGE2 是 COPD 成纤维细胞衰老和炎症的一个关键组成部分。调节所述的 PGE2 信号通路可能为抑制 COPD 中的衰老和衰老相关炎症提供新的基础。
