Inter-alpha Inhibitors in Experimental Necrotizing Enterocolitis

实验性坏死性小肠结肠炎中的α间抑制剂

• 批准号: 10822492
• 负责人: YOW-PIN LIM
• 金额: $ 37.83万
• 依托单位: PROTHERA BIOLOGICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10822492
• 关键词: Abdomen; Ablation; Acute; Acute Disease; Address; Adult; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Attenuated; Bacteria; Binding; Body part; Cathepsin G; Clinical; Complement 5a; Complement Activation; Complex; Consumption; Control Animal; Death Rate; Development; Diagnosis; Disease; Disease Progression; Dithizone; Down-Regulation; Elastases; Etiology; Excretory function; Experimental Models; Exposure to; Family; Feasibility Studies; Functional disorder; Future; Gastrointestinal tract structure; Generations; Goals; HMGB1 gene; Histones; Histopathology; Human; Immune; Immune response; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interleukin-6; Intestines; Klebsiella; Klebsiella pneumoniae; Laboratories; Life; Medical; Modeling; Modernization; Morbidity - disease rate; Mus; Necrosis; Necrotizing Enterocolitis; Neonatal; Newborn Animals; Organ; Organ failure; Paneth Cells; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Plasma; Play; Premature Infant; Proteins; Replacement Therapy; Reporting; Research; Role; Sepsis; Serine Protease; Serine Proteinase Inhibitors; Serum Albumin; Severities; Signal Transduction; Small Intestines; TNF gene; Therapeutic Agents; Tissues; Toxic effect; Trauma; Urine; body system; comparison control; cytokine; effective therapy; extracellular; high risk infant; immunoregulation; improved; in vivo; inflammatory modulation; innovation; inter-alpha-inhibitor; intestinal barrier; intestinal epithelium; intestinal injury; mature animal; mortality; mouse model; necrotic tissue; neonatal sepsis; novel; phase 1 study; predictive test; premature; protective effect; pup; systemic inflammatory response; therapeutically effective

Necrotizing enterocolitis (NEC) is a devastating acute inflammatory condition of the gastrointestinal tract resulting in intestinal necrosis, systemic sepsis and multi-system organ failure found mostly in infants born prematurely. Despite modern medical advances in the past decade, the etiology remains elusive and morbidity and mortality are still unacceptably high. It has been concluded that the onset of an excessive and uncontrolled inflammatory response by the neonatal intestine to exposure to luminal bacteria is a unifying hypothesis that encompasses many of the factors that have been associated with the development of NEC. The development of effective therapeutic agents that can target and modulate inflammatory response might be the key to reduce the morbidity and mortality associated with this life-threatening disease. Inter-alpha inhibitor proteins (IAIP) are a family of structurally related serine protease inhibitors found in relatively high concentration in human plasma. Substantial evidence suggested that IAIP play an important anti-inflammatory and regulatory role in host response and systemic inflammation. We previously reported that circulating IAIP levels are significantly decreased in adult and neonatal sepsis and the total IAIP levels correlated inversely with mortality in adult patients with severe sepsis. As part of the innate immune response, IAIP protect against the damaging effects of proteases and ‘danger signals’ released during acute systemic inflammation following severe infections, burn, trauma and injury. As a consequence, IAIP are rapidly consumed and excreted in the urine, leading to a rapid decrease in plasma. In several adult and newborn animal models of systemic inflammation and sepsis, administration of IAIP to normalize the decrease levels demonstrated significant protective effects even when given at delayed timepoints strongly indicating that IAIP is potentially useful as an adjunctive agent in the management of systemic inflammation/sepsis. In a study to determine the role of IAIP in NEC, we found a significant decrease of IAIP in infants with clinically proven NEC (Bell’s stage II/III) compared to infants with non-specific abdominal disorders. We hypothesize that IAIP administration might have similar beneficial effects as in neonatal sepsis in reducing the morbidity and mortality associated with NEC. Preliminary studies using a model based on paneth cell ablation and Klebsiella pneumoniae exposure to induce NEC-like injury in the small intestine of immature mice confirmed that endogenous IAIP levels were rapidly depleted similar to the observation made in infants with NEC. This study will obtain proof-of-concept of a replacement therapy using human plasma derived IAIP to reduce morbidity/mortality associated with NEC. If proven, this novel and innovative IAIP treatment in conjunction with the predictive test of circulating IAIP levels to identify high risk infants would offer a rational, targeted solution in addressing a serious unmet medical need for infants suffering from this disease.

坏死性小肠结肠炎（NEC）是一种破坏性的急性炎症性疾病的胃肠道 导致肠坏死、全身性脓毒症和多系统器官衰竭的肠道，主要见于出生时的婴儿 过早地。尽管现代医学在过去十年中取得了进步，但病因仍然难以捉摸， 死亡率仍然高得令人无法接受。已经得出结论，过度和不受控制的 新生儿肠道对暴露于管腔细菌的炎症反应是一个统一的假设， 它包含了许多与NEC发展相关的因素。发展 有效的治疗药物，可以靶向和调节炎症反应可能是关键， 与这种危及生命的疾病相关的发病率和死亡率。 间-α抑制蛋白（IAIP）是在哺乳动物中发现的结构相关的丝氨酸蛋白酶抑制剂家族。 在人血浆中的浓度相对较高。大量证据表明，IAIP发挥着重要作用， 在宿主反应和全身炎症中具有抗炎和调节作用。我们之前报道过， 在成人和新生儿败血症中循环IAIP水平显著降低， 与严重脓毒症成人患者的死亡率呈负相关。作为先天免疫反应的一部分， IAIP保护免受蛋白酶的破坏作用和急性全身性疾病期间释放的“危险信号”。 严重感染、烧伤、创伤和损伤后的炎症。因此，IAIP迅速 消耗并通过尿液排出，导致血浆中的快速减少。在几个成人和新生儿 全身性炎症和脓毒症的动物模型，施用IAIP以使降低的水平正常化 即使在延迟的时间点给予，也显示出显著的保护作用，这强烈表明IAIP 作为治疗全身炎症/脓毒症的预防剂是潜在有用的。 在一项确定IAIP在NEC中作用的研究中，我们发现， 与患有非特异性腹部疾病的婴儿相比，临床证明NEC（贝尔II/III期）。我们 假设IAIP给药可能具有与新生儿败血症相似的有益作用， 与NEC相关的发病率和死亡率。基于潘氏细胞消融模型的初步研究 和肺炎克雷伯氏菌暴露诱导未成熟小鼠小肠NEC样损伤 证实内源性IAIP水平迅速耗尽，类似于在患有 NEC。本研究将获得使用人血浆衍生的IAIP的替代疗法的概念验证， 降低与NEC相关的发病率/死亡率。如果得到证实，这种新颖和创新的IAIP治疗， 结合循环IAIP水平的预测性测试来识别高风险婴儿将提供合理的， 这是一个有针对性的解决方案，以解决患有这种疾病的婴儿的严重未满足的医疗需求。