Inter-alpha Inhibitors in Experimental Necrotizing Enterocolitis

点击翻译按钮获取中文摘要

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.