Vascular dysfunction in aged mice contributes to persistent lung fibrosis
Vascular dysfunction in aged mice contributes to persistent lung fibrosis
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DOI：
10.1111/acel.13196
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发表时间：
2020-07-21
期刊：
影响因子：
7.8
通讯作者：
Ligresti, Giovanni
中科院分区：
文献类型：
--
作者：
Caporarello, Nunzia;Meridew, Jeffrey A.;Ligresti, Giovanni
特发性肺纤维化（IPF）是一种进行性疾病，被认为是由损伤后肺修复受损引起的，与衰老密切相关。虽然血管改变以前与IPF相关，但肺血管系统在损伤消退和纤维化过程中的作用尚不清楚。为了比较内皮细胞（EC）在肺纤维化消退和非消退模型中的作用，我们将博莱霉素应用于年轻和老年小鼠。我们发现，老年小鼠的损伤引起毛细血管稀疏，而年轻小鼠的损伤导致毛细血管密度增加。相对于年轻小鼠，来自受损老年小鼠肺的EC表现出升高的促纤维化和降低的血管稳态基因表达。在后者中，Nos3（编码酶内皮型一氧化氮合酶，eNOS）是短暂上调，在肺内皮细胞从年轻的，但不是老年小鼠受伤后。eNOS缺乏的年轻小鼠重现了在老年动物损伤后观察到的非消退性肺纤维化，表明eNOS直接参与肺纤维化消退。人肺成纤维细胞中NO受体可溶性鸟苷酸环化酶的激活降低了TGF β诱导的促纤维化基因和蛋白的表达。此外，人肺EC中eNOS的缺失减少了2D和3D共培养物中TGF β诱导的肺成纤维细胞活化的抑制。总之，我们的研究结果表明，老年小鼠持续性肺纤维化伴随着毛细血管稀疏，EC身份的损失，和eNOS表达受损。因此，靶向血管功能可能对促进肺修复和老年和IPF中的纤维化消退至关重要。
Idiopathic pulmonary fibrosis (IPF) is a progressive disease thought to result from impaired lung repair following injury and is strongly associated with aging. While vascular alterations have been associated with IPF previously, the contribution of lung vasculature during injury resolution and fibrosis is not well understood. To compare the role of endothelial cells (ECs) in resolving and non-resolving models of lung fibrosis, we applied bleomycin intratracheally to young and aged mice. We found that injury in aged mice elicited capillary rarefaction, while injury in young mice resulted in increased capillary density. ECs from the lungs of injured aged mice relative to young mice demonstrated elevated pro-fibrotic and reduced vascular homeostasis gene expression. Among the latter,Nos3(encoding the enzyme endothelial nitric oxide synthase, eNOS) was transiently upregulated in lung ECs from young but not aged mice following injury. Young mice deficient in eNOS recapitulated the non-resolving lung fibrosis observed in aged animals following injury, suggesting that eNOS directly participates in lung fibrosis resolution. Activation of the NO receptor soluble guanylate cyclase in human lung fibroblasts reduced TGF beta-induced pro-fibrotic gene and protein expression. Additionally, loss of eNOS in human lung ECs reduced the suppression of TGF beta-induced lung fibroblast activation in 2D and 3D co-cultures. Altogether, our results demonstrate that persistent lung fibrosis in aged mice is accompanied by capillary rarefaction, loss of EC identity, and impaired eNOS expression. Targeting vascular function may thus be critical to promote lung repair and fibrosis resolution in aging and IPF.