Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody.
Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody.
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DOI：
10.1183/13993003.02536-2020
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Garcia JGN
中科院分区：
文献类型：
--
作者：
Quijada H;Bermudez T;Kempf CL;Valera DG;Garcia AN;Camp SM;Song JH;Franco E;Burt JK;Sun B;Mascarenhas JB;Burns K;Gaber A;Oita RC;Reyes Hernon V;Barber C;Moreno-Vinasco L;Sun X;Cress AE;Martin D;Liu Z;Desai AA;Natarajan V;Jacobson JR;Dudek SM;Bime C;Sammani S;Garcia JGN
2019年严重急性呼吸综合征冠状病毒/冠状病毒病大流行凸显了对降低急性呼吸窘迫综合征（ARDS）死亡率的有效治疗的严重未满足需求。我们探讨了细胞外烟酰胺磷酸核糖基转移酶（eNAMPT）是否是一个潜在的ARDS治疗靶点，该酶是toll样受体（TLR）4的配体，也是先天免疫和炎症的主要调节剂。野生型C57BL/6J或内皮细胞(EC)-cNAMPT - / -敲除小鼠（靶向EC NAMPT缺失）暴露于脂多糖（LPS）诱导的（“一击”）或LPS/呼吸机联合（“二击”）诱导的急性炎性肺损伤模型。采用NAMPT特异性单克隆抗体（mAb）成像探针（99mTc-ProNamptor）检测肺组织中NAMPT的表达。在体外和体内分别使用enampt中和山羊多克隆抗体（pAb）或人源化单克隆抗体（ALT-100 mAb）。免疫组织化学、生化和影像学研究证实，在两种临床前ARDS模型中，NAMPT肺组织表达呈时间依赖性增加。在两种临床前模型中，静脉给予enampt中和的pAb或mAb均可显著减轻炎性肺损伤（血红素和伊红染色、支气管肺泡灌洗（BAL）蛋白、BAL多形核细胞、血浆白细胞介素-6）。体外人肺EC研究表明，enampt中和抗体（pAb, mAb）可以强烈消除enampt诱导的TLR4通路激活和EC屏障破坏。在野生型和EC-cNAMPT - / -小鼠的体内研究证实，在两种临床前ARDS模型中，ec来源的NAMPT对炎症性肺损伤的严重程度有非常显著的贡献。这些发现强调了ec衍生的eNAMPT的作用以及eNAMPT/TLR4炎症途径的生物靶向潜力。结合预测的eNAMPT生物标志物和NAMPT基因分型分析，这为识别高风险ARDS受试者提供了个性化治疗的机会。在这些双重互补的ARDS临床前模型中，人源化的eNAMPT中和单克隆抗体（mAb）在降低ARDS的严重程度方面非常有效，强调了在ARDS/VILI中靶向eNAMPT/TLR4途径的治疗潜力https://bit.ly/3ljEhBD
The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target. Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT−/− knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced (“one-hit”) or a combined LPS/ventilator (“two-hit”)-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo. Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT−/− mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models. These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine. Underscoring the therapeutic potential for targeting the eNAMPT/TLR4 pathway in ARDS/VILI, a humanised eNAMPT-neutralising monoclonal antibody (mAb) was highly effective in reducing the severity of ARDS in these dual complementary pre-clinical ARDS models https://bit.ly/3ljEhBD
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影响因子：
8.3
作者：
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