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

基本信息

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
项目类别：
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

项目摘要

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）是胃肠道的破坏性急性炎症状况导致肠道坏死，全身性败血症和多系统器官衰竭的区域主要出现在婴儿中过早。尽管过去十年中的现代医疗进展，但病因仍然难以捉摸和发病率死亡率仍然很高。得出的结论是，多余的和不受控制的发作新生儿肠对暴露于腔细菌的炎症反应是一个统一的假设，即包括与NEC发展相关的许多因素。发展可以靶向和调节炎症反应的有效治疗剂可能是减少的关键与这种威胁生命的疾病有关的发病率和死亡率。 α抑制剂蛋白（IAIP）是在结构相关的系列蛋白抑制剂的家族中，发现人血浆中相关的高浓度。大量证据表明，IAIP发挥重要作用在宿主反应和全身炎症中的抗渗透和调节作用。我们以前报道了成人和新生儿败血症的循环IAIP水平以及IAIP总水平得到显着提高重度败血症患者的死亡率成反比。作为先天免疫反应的一部分， IAIP保护免受急性全身释放的保护酶和“危险信号”的破坏性影响严重感染，烧伤，创伤和损伤后发炎。结果，IAIP迅速在尿液中食用并超过，导致血浆迅速减少。在几个成年和新生儿全身注射和败血症的动物模型，给予IAIP以使降低水平归一化即使在延迟的时间点上给出，也表现出明显的保护作用，表明IAIP 在系统注射/败血症的管理中，有可能作为辅助药物有用。在确定IAIP在NEC中的作用的研究中，我们发现婴儿的IAIP显着降低与患有非特异性腹部疾病的婴儿相比，临床证明的NEC（贝尔的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。使用基于Paneth细胞消融的模型的初步研究肺炎的肺炎暴露在未成熟小鼠的小肠中诱导NEC样损伤证实内源性IAIP水平的迅速耗尽，类似于婴儿 NEC。这项研究将获得替代疗法的概念证明降低与NEC相关的发病率/死亡率。如果经过证明，这种新颖而创新的IAIP处理与循环IAIP水平的预测测试以识别高风险婴儿的预测测试将提供理性的，针对患有这种疾病的婴儿的严重未满足医疗需求的有针对性解决方案。