Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Emory University, Atlanta, Georgia, USA.
Am J Respir Cell Mol Biol. 2012 Jun;46(6):748-56. doi: 10.1165/rcmb.2011-0224OC. Epub 2012 Jan 6.
The incidence of idiopathic pulmonary fibrosis (IPF) increases with age. The mechanisms that underlie the age-dependent risk for IPF are unknown. Based on studies that suggest an association of IPF and γherpesvirus infection, we infected young (2-3 mo) and old (≥18 mo) C57BL/6 mice with the murine γherpesvirus 68. Acute murine γherpesvirus 68 infection in aging mice resulted in severe pneumonitis and fibrosis compared with young animals. Progressive clinical deterioration and lung fibrosis in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-β during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, CXCL12, in bronchoalveolar lavage. Analyses of lytic virus infection and virus reactivation indicate that old mice were able to control chronic infection and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up-regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and fibrosis associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways.
特发性肺纤维化 (IPF) 的发病率随年龄增长而增加。导致 IPF 随年龄增长而发生的机制尚不清楚。基于提示 IPF 与γ疱疹病毒感染之间存在关联的研究，我们用鼠γ疱疹病毒 68 感染年轻（2-3 月龄）和年老（≥18 月龄）C57BL/6 小鼠。与年轻动物相比，衰老小鼠急性鼠γ疱疹病毒 68 感染导致严重的肺炎和纤维化。在感染的慢性晚期，仅在潮气量减少的老年小鼠中观察到进行性临床恶化和肺纤维化。感染的衰老小鼠在感染的急性期表现出更高的转化生长因子-β表达。此外，衰老、感染的小鼠在支气管肺泡灌洗液中显示出促炎细胞因子和纤维母细胞募集趋化因子 CXCL12 的升高。对裂解病毒感染和病毒再激活的分析表明，老年小鼠能够控制慢性感染并引发抗病毒免疫反应。然而，感染的老年小鼠显示出凋亡反应显著增加，这通过原位末端脱氧核苷酸转移酶 dUTP 缺口末端标记测定、caspase-3 水平和促凋亡分子 Bcl-2 相互作用介质的表达来确定。衰老肺中 II 型肺上皮细胞的凋亡伴随着内质网应激标志物结合免疫球蛋白蛋白的上调和 X 盒结合蛋白 1 的剪接。这些结果表明，衰老的肺更容易受到与内质网应激、II 型肺上皮细胞凋亡和促纤维化途径激活相关的损伤和纤维化的影响。
