Dichotomous Role of Tumor Necrosis Factor in Pulmonary Barrier Function and Alveolar Fluid Clearance.
Dichotomous Role of Tumor Necrosis Factor in Pulmonary Barrier Function and Alveolar Fluid Clearance.
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DOI：
10.3389/fphys.2021.793251
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发表时间：
2021
影响因子：
4
通讯作者：
Hamacher J
中科院分区：
文献类型：
--
作者：
Lucas R;Hadizamani Y;Enkhbaatar P;Csanyi G;Caldwell RW;Hundsberger H;Sridhar S;Lever AA;Hudel M;Ash D;Ushio-Fukai M;Fukai T;Chakraborty T;Verin A;Eaton DC;Romero M;Hamacher J
肺泡-毛细血管渗漏是急性呼吸窘迫综合征（ARDS）的标志，是严重脓毒症、创伤和肺炎（包括COVID-19）的潜在致命并发症。除了屏障功能障碍外，ARDS的特征在于炎症过度和肺泡液体清除率（AFC）受损，这促进了肺渗透性水肿的发展并阻碍了气体交换。肿瘤坏死因子（TNF）是一种进化上保守的多效性细胞因子，参与宿主对病原体和癌症的免疫防御。TNF以膜结合和可溶形式存在，并且其主要（但不排他）促炎和细胞溶解作用由位于同源三聚体中相邻亚基之间界面处的部分重叠TNFR 1和TNFR 2结合位点介导。而TNFR 1信号传导可以介导肺中的过度炎症和受损的屏障功能和AFC，TNFR 2的配体刺激可以保护免于通气诱导的肺损伤。与TNFR结合位点在空间上不同，TNF在其结构内具有凝集素样结构域，其在ARDS中保护肺功能。由17个残基TIP肽模拟的TNF的凝集素样结构域代表肺泡-毛细血管屏障保护的生理介质。并增加流体静力学和渗透性肺水肿动物模型中的AFC。TIP肽在与其α亚基结合后直接激活上皮钠通道（ENaC）-液体和血压控制的关键介质，α亚基也是非选择性阳离子通道（NSC）的一部分。TNF的凝集素样结构域的活性在TNF及其可溶性TNFR之间的复合物中被保留，并且在肺炎中可能是生理相关的。基于抗体和可溶性TNFR的治疗策略在类风湿性关节炎、银屑病和炎症性肠病等疾病中显示出相当大的成功，但它们的长期使用会增加对感染的易感性。由于TNF的凝集素样结构域不干扰TNF的抗菌作用，同时在肺泡-毛细血管隔室中发挥保护作用，因此目前在ARDS和COVID-19的临床试验中对其进行了评估。更全面地了解TNFR结合位点与TNF凝集素样结构域在肺损伤、组织缺氧、修复和重塑中的确切作用，可能会促进ARDS新疗法的开发。
Alveolar-capillary leak is a hallmark of the acute respiratory distress syndrome (ARDS), a potentially lethal complication of severe sepsis, trauma and pneumonia, including COVID-19. Apart from barrier dysfunction, ARDS is characterized by hyper-inflammation and impaired alveolar fluid clearance (AFC), which foster the development of pulmonary permeability edema and hamper gas exchange. Tumor Necrosis Factor (TNF) is an evolutionarily conserved pleiotropic cytokine, involved in host immune defense against pathogens and cancer. TNF exists in both membrane-bound and soluble form and its mainly -but not exclusively- pro-inflammatory and cytolytic actions are mediated by partially overlapping TNFR1 and TNFR2 binding sites situated at the interface between neighboring subunits in the homo-trimer. Whereas TNFR1 signaling can mediate hyper-inflammation and impaired barrier function and AFC in the lungs, ligand stimulation of TNFR2 can protect from ventilation-induced lung injury. Spatially distinct from the TNFR binding sites, TNF harbors within its structure a lectin-like domain that rather protects lung function in ARDS. The lectin-like domain of TNF -mimicked by the 17 residue TIP peptide- represents a physiological mediator of alveolar-capillary barrier protection. and increases AFC in both hydrostatic and permeability pulmonary edema animal models. The TIP peptide directly activates the epithelial sodium channel (ENaC) -a key mediator of fluid and blood pressure control- upon binding to its α subunit, which is also a part of the non-selective cation channel (NSC). Activity of the lectin-like domain of TNF is preserved in complexes between TNF and its soluble TNFRs and can be physiologically relevant in pneumonia. Antibody- and soluble TNFR-based therapeutic strategies show considerable success in diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease, but their chronic use can increase susceptibility to infection. Since the lectin-like domain of TNF does not interfere with TNF’s anti-bacterial actions, while exerting protective actions in the alveolar-capillary compartments, it is currently evaluated in clinical trials in ARDS and COVID-19. A more comprehensive knowledge of the precise role of the TNFR binding sites versus the lectin-like domain of TNF in lung injury, tissue hypoxia, repair and remodeling may foster the development of novel therapeutics for ARDS.
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影响因子：
4
作者：
Xiong, Chenling;Yang, Guang;Kumar, Sanjiv;Aggarwal, Saurabh;Leustik, Martin;Snead, Connie;Hamacher, Juerg;Fischer, Bernhard;Umapathy, Nagavedi S.;Hossain, Hamid;Wendel, Albrecht;Catravas, John D.;Verin, Alexander D.;Fulton, David;Black, Stephen M.;Chakraborty, Trinad;Lucas, Rudolf
通讯作者：
Lucas, Rudolf
影响因子：
158.5
作者：
Amato, MBP;Barbas, CSV;Carvalho, CRR
通讯作者：
Carvalho, CRR
影响因子：
3.5
作者：
Amour, A;Slocombe, PM;Murphy, G
通讯作者：
Murphy, G
影响因子：
158.5
作者：
Ackermann, Maximilian;Verleden, Stijn E.;Jonigk, Danny
通讯作者：
Jonigk, Danny
DOI：
10.1073/pnas.1821401116
发表时间：
2019-07-02
影响因子：
11.1
作者：
Cao, Yapeng;Zhang, Xiaoyu;Huo, Yuqing
通讯作者：
Huo, Yuqing