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）是一种严重的急性胃肠道炎症