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.
■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。