未经证实:对乙酰氨基酚(APAP)诱导的急性肝损伤(AILI)是急性肝衰竭(ALF)的主要原因。N-乙酰半胱氨酸(NAC)仅在APAP中毒后24小时内有效,迫切需要治疗这种疾病的替代方法。本研究旨在测试卡萨利菌素(Camp)是否,这是慢性肝病的保护因素,保护小鼠免受APAP诱导的肝损伤和ALF。
未经证实:在小鼠中产生临床相关的AILI模型和APAP诱导的ALF模型。使用遗传和药理学方法来干扰体内cathelicidin的水平。
未经证实:在APAP中毒的小鼠中观察到肝前CRAMP/CRAMP(小鼠cathelicidin的前体和成熟形式)的增加。上调的cathelicidin源自肝脏浸润的中性粒细胞。与野生型同窝相比,camp敲除对肝损伤没有影响,但抑制了AILI的肝修复,并降低了APAP诱导的ALF的生存率。在APAP攻击的Camp敲除小鼠中观察到CRAMP施用逆转了受损的肝脏恢复。延迟崩溃,CRAMP(1-39)(CRAMP的扩展形式),或LL-37(人导管素的成熟形式)治疗表现出对于AILI的治疗益处。在AILI中联合治疗cathelicidin和NAC显示出比单独的NAC更强的肝保护作用。在APAP诱导的ALF中观察到CRAMP(1-39)/LL-37和NAC的类似累加效应。cathelicidin在APAP受损肝脏中的修复作用归因于肝脏修复开始时炎症的加速消退。可能通过自分泌方式增强中性粒细胞吞噬坏死细胞碎片。
UNASSIGNED:Cathelicidin通过促进炎症消退促进肝脏恢复,从而减少APAP诱导的小鼠肝损伤和ALF,提示晚期AILI伴或不伴ALF患者的治疗潜力。
未经证实:对乙酰氨基酚诱导的急性肝损伤是急性肝衰竭的主要原因。N-乙酰半胱氨酸的功效,唯一的临床批准的药物对乙酰氨基酚诱导的急性肝损伤,对于晚期出现的患者显着降低。我们发现cathelicidin在对乙酰氨基酚诱导的肝损伤或急性肝衰竭的小鼠中表现出巨大的治疗潜力。通过特异性促进对乙酰氨基酚中毒后的肝脏修复,弥补了N-乙酰半胱氨酸治疗的局限性。cathelicidin的促修复作用,作为中性粒细胞的关键效应分子,在APAP损伤的肝脏中,炎症在肝脏修复开始时加速消退,可能通过自分泌方式增强中性粒细胞的吞噬功能。
UNASSIGNED: Acetaminophen (APAP)-induced acute liver injury (AILI) is a leading cause of acute liver failure (ALF). N-acetylcysteine (NAC) is only effective within 24 h after APAP intoxication, raising an urgent need for alternative approaches to treat this disease. This study aimed to test whether cathelicidin (Camp), which is a protective factor in chronic liver diseases, protects mice against APAP-induced liver injury and ALF.
UNASSIGNED: A clinically relevant AILI model and an APAP-induced ALF model were generated in mice. Genetic and pharmacological approaches were used to interfere with the levels of cathelicidin in vivo.
UNASSIGNED: An increase in hepatic pro-CRAMP/CRAMP (the precursor and mature forms of mouse cathelicidin) was observed in APAP-intoxicated mice. Upregulated cathelicidin was derived from liver-infiltrating neutrophils. Compared with wild-type littermates, Camp knockout had no effect on hepatic injury but dampened hepatic repair in AILI and reduced survival in APAP-induced ALF. CRAMP administration reversed impaired liver recovery observed in APAP-challenged Camp knockout mice. Delayed CRAMP, CRAMP(1-39) (the extended form of CRAMP), or LL-37 (the mature form of human cathelicidin) treatment exhibited a therapeutic benefit for AILI. Co-treatment of cathelicidin and NAC in AILI displayed a stronger hepatoprotective effect than NAC alone. A similar additive effect of CRAMP(1-39)/LL-37 and NAC was observed in APAP-induced ALF. The pro-reparative role of cathelicidin in the APAP-damaged liver was attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced neutrophil phagocytosis of necrotic cell debris in an autocrine manner.
UNASSIGNED: Cathelicidin reduces APAP-induced liver injury and ALF in mice by promoting liver recovery via facilitating inflammation resolution, suggesting a therapeutic potential for late-presenting patients with AILI with or without ALF.
UNASSIGNED: Acetaminophen-induced acute liver injury is a leading cause of acute liver failure. The efficacy of N-acetylcysteine, the only clinically approved drug against acetaminophen-induced acute liver injury, is significantly reduced for late-presenting patients. We found that cathelicidin exhibits a great therapeutic potential in mice with acetaminophen-induced liver injury or acute liver failure, which makes up for the limitation of N-acetylcysteine therapy by specifically promoting liver repair after acetaminophen intoxication. The pro-reparative role of cathelicidin, as a key effector molecule of neutrophils, in the APAP-injured liver is attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced phagocytic function of neutrophils in an autocrine manner.