Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization.
Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization.
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DOI：
10.1016/j.trsl.2021.06.002
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Garcia JG
中科院分区：
文献类型：
--
作者：
Garcia AN;Casanova NG;Valera DG;Sun X;Song JH;Kempf CL;Moreno-Vinasco L;Burns K;Bermudez T;Valdez M;Cuellar G;Gregory T;Oita RC;Hernon VR;Barber C;Camp SM;Martin D;Liu Z;Bime C;Sammani S;Cress AE;Garcia JG
预防或减轻放射性肺炎严重程度的治疗策略是一个严重未满足的需求。我们评估了细胞外烟酰胺磷酸核糖转移酶 (eNAMPT)、一种损伤相关分子模式蛋白 (DAMP) 和 Toll 样受体 4 (TLR4) 配体作为小鼠放射性肺炎的治疗靶点。在体外、组织（IHC、生物化学、成像）和血浆中评估了辐射诱导的小鼠和人类 NAMPT 表达。野生型 C57Bl6 小鼠 (WT) 和 Nampt+/- 杂合小鼠接受 20Gy 全胸肺照射 (WTLI)，每周腹膜内注射或不注射 IgG1（对照）或 eN-AMPT 中和多克隆 (pAb) 或单克隆抗体 (mAb)。 BAL 蛋白/细胞和 H&E 染色用于生成 WTLI 严重程度评分。通过 RNA 测序和生物信息学分析鉴定差异表达基因 (DEG)/通路。辐射暴露增加肺上皮中的体外 NAMPT 表达（NAMPT 启动子活性）和 WTLI 暴露小鼠中的 NAMPT 肺组织表达。 Nampt+/- 小鼠和 eNAMPT pAb/mAb 处理的小鼠表现出 WTLI 介导的肺损伤的组织学显着减轻，BAL 蛋白和细胞水平以及 eNAMPT、IL-6 和 IL-1 β 的血浆水平降低。对 WTLI 暴露肺组织的基因组和生化研究强调了 NFkB/细胞因子和 MAP 激酶信号通路的失调，而 eNAMPT mAb 治疗可以纠正这些失调。 eNAMPT/TLR4 通路本质上参与放射病理学，而 eNAMPT 中和是降低放射性肺炎严重程度的有效治疗策略。通过常规临床放射治疗或核事故来预防或减少电离辐射暴露严重程度的治疗策略是一项严重的医学和社会未满足的需求。我们评估了细胞外烟酰胺磷酸核糖转移酶 (eNAMPT)、一种损伤相关分子模式蛋白 (DAMP) 和 Toll 样受体 4 (TLR4) 配体作为小鼠放射性肺炎的治疗靶点。临床前全胸肺照射研究支持 eNAMPT/TLR4 信号通路在放射病理学中的重要参与。事实证明，用人源化单克隆抗体靶向 eNAMPT 中和是一种有效的治疗策略，可降低放射性肺炎的严重程度和潜在的临床治疗。
Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma. Wild type C57Bl6 mice (WT) and Nampt+/− heterozygous mice were exposed to 20Gy whole thoracic lung irradiation (WTLI) with or without weekly IP injection of IgG1 (control) or an eN-AMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb). BAL protein/cells and H&E staining were used to generate a WTLI severity score. Differentially-expressed genes (DEGs)/pathways were identified by RNA sequencing and bioinformatic analyses. Radiation exposure increases in vitro NAMPT expression in lung epithelium (NAMPT promoter activity) and NAMPT lung tissue expression in WTLI-exposed mice. Nampt+/− mice and eNAMPT pAb/mAb-treated mice exhibited significant histologic attenuation of WTLI-mediated lung injury with reduced levels of BAL protein and cells, and plasma levels of eNAMPT, IL-6, and IL-1 β. Genomic and biochemical studies from WTLI-exposed lung tissues highlighted dysregulation of NFkB/cytokine and MAP kinase signaling pathways which were rectified by eNAMPT mAb treatment. The eNAMPT/TLR4 pathway is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce the severity of radiation pneumonitis. Therapeutic strategies to prevent or reduce the severity of exposure to ionizing radiation, occurring either through routine clinical radiotherapy or via nuclear accidents, are a serious medical and societal unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Preclinical whole thoracic lung irradiation studies support the essential involvement of the eNAMPT/TLR4 signaling pathway in radiation pathobiology. Targeting eNAMPT neutralization with a humanized mAb proved an effective therapeutic strategy to reduce the severity of radiation pneumonitis and potential clinical treatment.
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