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Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.
摘要：
■对芥子气（SM）引起的急性和慢性肺损伤的人体和临床前研究强调了持续炎症的作用。我们评估了靶向新型DAMP和TLR4配体的实用性，eNAMPT（细胞外烟酰胺磷酸核糖转移酶），在SM暴露的大鼠模型中利用人源化mAb（ALT-100）。
■急性（SM4.2mg/kg，24小时)，亚急性（SM0.8mg/kg，第7天),亚急性（SM2.1mg/kg，第14天),和慢性（SM1.2mg/kg，第29天）使用SM模型。
■每个SM模型均表现出eNAMPT表达（肺匀浆）的显着增加以及磷酸化的NFkB和NOX4水平的增加。在亚急性和慢性SM模型中观察到肺纤维化（三色染色）与平滑肌肌动蛋白（SMA）升高，TGFβ,和IL-1β表达。接受ALT-100（1或4mg/kg，每周)表现出增加的存活率，肺部炎症和纤维化的组织学/生化证据显着减少（三色染色，pNFkB降低，SMA,TGFβ,NOX4),减少气道狭窄，和血浆细胞因子水平降低(eNAMPT，IL-6、IL-1β。TNFα）。
■高度吸毒，eNAMPT/TLR4信号通路是SM诱导的ROS产生的关键因素，炎性肺损伤和纤维化。ALT-100mAb是解决降低SM相关肺病理学/死亡率的未满足需求的潜在医学对策。
■急性（SM4.2mg/kg，24小时)，亚急性（SM0.8mg/kg，第7天),亚急性（SM2.1mg/kg，第14天),和慢性（SM1.2mg/kg，第29天）使用SM模型。
■每个SM模型均表现出eNAMPT表达（肺匀浆）的显着增加以及磷酸化的NFkB和NOX4水平的增加。在亚急性和慢性SM模型中观察到肺纤维化（三色染色）与平滑肌肌动蛋白（SMA）升高，TGFβ,和IL-1β表达。接受ALT-100（1或4mg/kg，每周)表现出增加的存活率，肺部炎症和纤维化的组织学/生化证据显着减少（三色染色，pNFkB降低，SMA,TGFβ,NOX4),减少气道狭窄，和血浆细胞因子水平降低(eNAMPT，IL-6、IL-1β。TNFα）。
■高度吸毒，eNAMPT/TLR4信号通路是SM诱导的ROS产生的关键因素，炎性肺损伤和纤维化。ALT-100mAb是解决降低SM相关肺病理学/死亡率的未满足需求的潜在医学对策。
