Carrie L Kempf, Jin H Song, Saad Sammani, Tadeo Bermudez, Vivian Reyes Hernon, Lin Tang, Hua Cai, Sara M Camp, Carly A Johnson, Mohamed S Basiouny, Leslie A Bloomquist, Jacqueline S Rioux, Carl W White, Livia A Veress, Joe G N Garcia
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We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure.</p><p><strong>Methods: </strong>Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized.</p><p><strong>Results: </strong>Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFβ, and IL-1β expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFβ, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1β. TNFα).</p><p><strong>Conclusion: </strong>The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality.</p>","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"6 1","pages":"389-397"},"PeriodicalIF":0.0000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883439/pdf/","citationCount":"0","resultStr":"{\"title\":\"TLR4 Ligation by eNAMPT, a Novel DAMP, is Essential to Sulfur Mustard- Induced Inflammatory Lung Injury and Fibrosis.\",\"authors\":\"Carrie L Kempf, Jin H Song, Saad Sammani, Tadeo Bermudez, Vivian Reyes Hernon, Lin Tang, Hua Cai, Sara M Camp, Carly A Johnson, Mohamed S Basiouny, Leslie A Bloomquist, Jacqueline S Rioux, Carl W White, Livia A Veress, Joe G N Garcia\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Human and preclinical studies of sulfur mustard (SM)-induced acute and chronic lung injuries highlight the role of unremitting inflammation. We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure.</p><p><strong>Methods: </strong>Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized.</p><p><strong>Results: </strong>Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFβ, and IL-1β expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFβ, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1β. TNFα).</p><p><strong>Conclusion: </strong>The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality.</p>\",\"PeriodicalId\":72981,\"journal\":{\"name\":\"European journal of respiratory medicine\",\"volume\":\"6 1\",\"pages\":\"389-397\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883439/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European journal of respiratory medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of respiratory medicine","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/8 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
目的:对硫芥子气(SM)诱导的急性和慢性肺损伤进行的人体和临床前研究强调了持续炎症的作用。我们评估了利用人源化 mAb(ALT-100)靶向新型 DAMP 和 TLR4 配体 eNAMPT(细胞外烟酰胺磷酸核糖基转移酶)在大鼠 SM 暴露模型中的效用:方法:利用急性(SM 4.2 毫克/千克,24 小时)、亚急性(SM 0.8 毫克/千克,第 7 天)、亚急性(SM 2.1 毫克/千克,第 14 天)和慢性(SM 1.2 毫克/千克,第 29 天)SM 模型:结果:每种 SM 模型的 eNAMPT 表达(肺匀浆)都明显增加,磷酸化 NFkB 和 NOX4 的水平也有所提高。在亚急性和慢性 SM 模型中均可观察到肺纤维化(三色染色),同时平滑肌肌动蛋白(SMA)、TGFβ 和 IL-1β 的表达也升高。接受 ALT-100(1 或 4 毫克/千克,每周一次)治疗的 SM 暴露大鼠存活率提高,肺部炎症和纤维化的组织学/生化证据(Trichrome 染色、pNFkB、SMA、TGFβ、NOX4 减少)显著减少,气道狭窄减少,血浆细胞因子水平(ENAMPT、IL-6、IL-1β、TNFα)降低:结论:高度可药用的 eNAMPT/TLR4 信号通路是 SM 诱导的 ROS 生成、肺部炎症损伤和纤维化的关键因素。ALT-100 mAb 是一种潜在的医疗对策,可满足减少 SM 相关肺部病理生物学/死亡率的未满足需求。
TLR4 Ligation by eNAMPT, a Novel DAMP, is Essential to Sulfur Mustard- Induced Inflammatory Lung Injury and Fibrosis.
Objective: Human and preclinical studies of sulfur mustard (SM)-induced acute and chronic lung injuries highlight the role of unremitting inflammation. We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure.
Methods: Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized.
Results: Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFβ, and IL-1β expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFβ, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1β. TNFα).
Conclusion: The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality.