Tumor Necrosis Factor-α Accelerates the Resolution of Established Pulmonary Fibrosis in Mice by Targeting Profibrotic Lung Macrophages
Tumor Necrosis Factor-α Accelerates the Resolution of Established Pulmonary Fibrosis in Mice by Targeting Profibrotic Lung Macrophages
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DOI：
10.1165/rcmb.2013-0386oc
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发表时间：
2014-04-01
影响因子：
6.4
通讯作者：
Riches, David W. H.
中科院分区：
文献类型：
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作者：
Redente, Elizabeth F.;Keith, Rebecca C.;Riches, David W. H.
特发性肺纤维化（IPF）是一种持续的纤维化实质性肺疾病，其中交替编程的巨噬细胞产生促进肌成纤维细胞存活和胶原合成的促纤维化分子。缺乏治疗IPF患者的有效疗法，常规疗法可能有害。我们测试了一个假设，即治疗性肺递送促炎细胞因子肿瘤坏死因子（TNF）-α到野生型纤维化小鼠将减少促纤维化的环境，并加速已建立的肺纤维化的解决。通过测量羟脯氨酸水平、静态顺应性和Masson三色染色，在博莱霉素滴注的野生型和TNF-α（-/-）小鼠中评估纤维化。通过酶消化肺的流式细胞术和原位免疫染色评估巨噬细胞浸润和编程状态。发现将TNF-α经肺递送至具有已建立的肺纤维化的野生型小鼠可降低其纤维化负荷，改善肺功能和结构，并减少促纤维化替代性编程巨噬细胞的数量和编程状态。相比之下，在博来霉素滴注TNF-α（-/-）小鼠中，纤维化和替代性巨噬细胞编程延长。为了解决替代编程的巨噬细胞数量减少在TNF-α诱导的已建立的肺纤维化消退中的作用，我们有条件地耗尽MAFIA（巨噬细胞Fas诱导的凋亡）小鼠中的巨噬细胞。条件性巨噬细胞耗竭表型模拟了治疗性TNF-α递送后观察到的已建立的肺纤维化的消退。总之，我们的研究结果首次表明，TNF-α通过一种涉及促纤维化巨噬细胞数量减少和编程状态的机制参与了已建立的肺纤维化的消退。我们推测，肺部输送TNF-α或增强其信号通路代表了一种新的治疗策略，以解决已建立的肺纤维化。
Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-alpha(-/-) mice by measuring hydroxyproline levels, static compliance, and Masson's trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-alpha to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-alpha(-/-) mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-alpha-induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-alpha delivery. Taken together, our results show for the first time that TNF-alpha is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-alpha or augmenting its signaling pathway represent a novel therapeutic strategy to resolve established pulmonary fibrosis.