Paneth cells-derived IL-17A and liver ischemia reperfusion injury

潘氏细胞源性IL-17A与肝脏缺血再灌注损伤

• 批准号: 10274320
• 负责人: Adam David Griesemer
• 金额: $ 69.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274320
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Ankylosing spondylitis; Apoptosis; Attenuated; Autoimmune Diseases; Cell Degranulation; Cell model; Clinical; Coupled; Data; Excision; Extrahepatic; Functional disorder; Genetic; Goals; Hepatic; Human; In Vitro; Incidence; Inflammation; Inflammatory; Injury; Injury to Kidney; Interleukin-17; Intestines; Ischemia; Kidney; Liver; Macaca fascicularis; Mediating; Modeling; Monkeys; Mus; Necrosis; Operative Surgical Procedures; Organ; Paneth Cells; Patients; Portal vein structure; Postoperative Period; Procedures; Psoriasis; Psoriatic Arthritis; Reconstructive Surgical Procedures; Reperfusion Injury; Reperfusion Therapy; Sepsis; Small Intestines; Source; Systemic Inflammatory Response Syndrome; Testing; base; clinical translation; clinically significant; cytokine; in vivo; inflammatory disease of the intestine; intestinal barrier; intestinal crypt; intestinal injury; intrahepatic; ischemic injury; liver injury; liver ischemia; liver transplantation; lung injury; multiorgan injury; neutralizing antibody; nonhuman primate; novel; organ injury; prevent; reconstruction; targeted treatment; therapy development; translational approach

Liver ischemia and reperfusion (IR) injury is a clinically significant problem during and after liver transplantation, hepatic resection and portal vein reconstruction surgery. Unfortunately, there is no therapy to prevent or treat hepatic IR injury. Furthermore, it is becoming increasingly clear that liver IR injury frequently results in significant extra-hepatic remote organ injury including kidney, intestinal and lung injury as well as a systemic inflammatory response syndrome and sepsis. In particular, the incidence of acute kidney injury after liver resection is extremely high and approaches ~50-80% after major hepatic resection or liver transplantation. Our previous studies implicate small intestinal crypt Paneth cells as the initiator of extra-hepatic remote organ injury after liver IR in mice. Furthermore, small intestinal Paneth cells are the predominant source of pro- inflammatory cytokine IL-17A required for generating hepatic and extra-hepatic injury in mice. However, for clinical translation of these studies leading to therapy, it is critical that we determine whether Paneth cell dysregulation and degranulation as well as Paneth cell release of IL-17A also occur after hepatic IR in human and nonhuman primate liver IR injury models. In this proposal, we will elucidate whether small intestinal Paneth cells dysregulate and release pro-inflammatory IL-17A after human and nonhuman primate liver IR injury and whether IL-17A neutralization attenuates liver injury as well as extra-hepatic organ injury after nonhuman primate IR. Exciting preliminary data suggest that cynomolgus monkey liver IR causes profound Paneth cell degranulation and Paneth cell IL-17A induction coupled with rapid kidney and small intestine injury. Furthermore, our preliminary data suggest that cynomolgus monkeys treated with IL-17A neutralizing antibody had markedly less hepatic IR injury as well as reduced post-operative AKI. Preliminary data also suggest that human small intestine Paneth cells degranulate after ischemic injury. Based on these preliminary findings, we hypothesize that hepatic IR injury leads to intestinal Paneth cell dysregulation/degranulation and Paneth cell- derived IL-17A induction leading to intestinal inflammation and apoptosis, subsequent exacerbation of hepatic injury and induction of acute kidney injury. We also hypothesize that IL-17A neutralization will attenuate hepatic, intestinal and kidney injury after liver IR in nonhuman primates. We will utilize both in vivo (highly translational cynomolgus monkey liver IR and human liver transplant studies) and in vitro (freshly isolated cynomolgus monkey and human Paneth cells) models to further elucidate the mechanisms and potential therapy for intestinal and renal injury after hepatic IR by testing the following three specific aims. Aim #1: To demonstrate remote organ injury and Paneth cell degranulation after liver IR injury. Aim #2: To demonstrate Paneth cell-mediated IL-17A release after liver IR injury. Aim #3: To develop therapies to reduce non-human primate liver IR injury induced hepatic and extra-hepatic organ injury.

肝脏缺血再灌流(IR)损伤是肝脏手术中和术后的重要临床问题。 肝移植、肝切除、门静脉重建术。不幸的是，目前还没有治疗方法 预防或治疗肝脏IR损伤。此外，越来越明显的是，肝脏IR损伤频繁。 导致严重的肝外远隔器官损伤，包括肾、肠和肺损伤，以及 全身炎症反应综合征和脓毒症。尤其是术后急性肾损伤的发生率 肝大部切除或肝移植后肝切除率极高，接近50-80%。 我们先前的研究表明小肠隐窝潘氏细胞是肝外远隔器官的始动细胞。 小鼠肝脏缺血再灌注后的损伤。此外，小肠潘氏细胞是前体细胞的主要来源。 炎症细胞因子IL-17A在小鼠肝和肝外损伤中的作用。然而，对于 这些研究的临床转化导致治疗，关键是我们确定潘斯细胞 人肝缺血再灌注后IL-17A的调节失调、脱颗粒和潘氏细胞释放 非人灵长类动物肝脏IR损伤模型。在这项建议中，我们将澄清小肠是否 人和非人灵长类动物肝脏IR后Paneth细胞调节和释放促炎性IL-17A IL-17A中和对肝损伤及肝外器官损伤的影响 非人灵长类IR。令人振奋的初步数据表明，食蟹猴肝脏IR导致深远的 潘氏细胞脱颗粒和潘氏细胞IL-17A诱导，再加上肾脏和小肠的快速损伤。 此外，我们的初步数据表明，用IL-17A中和抗体治疗食蟹猴 术后肝脏IR损伤明显减轻，AKI明显减少。初步数据还表明， 人小肠潘氏细胞缺血损伤后脱颗粒。根据这些初步调查结果，我们 假设肝脏IR损伤导致肠道潘氏细胞失调/脱颗粒，潘氏细胞... 衍生的IL-17A诱导导致肠道炎症和细胞凋亡，继而加重肝脏 损伤与急性肾损伤的诱导。我们还假设IL-17A的中和作用将减弱 非人灵长类动物肝脏缺血再灌注后的肝、肠、肾损伤。我们将在体内利用这两者(高度 翻译食蟹猴肝脏IR和人肝移植研究)和体外(新鲜分离的 食蟹猴和人Paneth细胞)模型进一步阐明其机制和潜力 肝缺血再灌注后肠和肾损伤的治疗通过测试以下三个特定目标。 目的1：探讨肝脏IR损伤后远隔器官损伤和潘氏细胞脱颗粒的情况。 目的#2：证实肝脏IR损伤后潘氏细胞介导的IL-17A的释放。 目的#3：开发减少非人灵长类肝脏IR损伤的治疗方法 器官损伤。