Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis
Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis
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DOI：
10.1073/pnas.97.11.6043
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发表时间：
2000-05-23
影响因子：
11.1
通讯作者：
Walker, WA
中科院分区：
文献类型：
--
作者：
Nanthakumar, NN;Fusunyan, RD;Walker, WA
坏死性小肠结肠炎（NEC）是早产儿发病和死亡的主要原因，发生在经口喂养后，与肠道的初始细菌定植有关，并假设是由于不成熟（不适当）的肠上皮细胞对细菌刺激的反应。为了验证这一假设，我们比较了未成熟与成熟人小肠中肠细胞IL-8对炎症刺激[脂多糖（LPS）和IL-1 β]的反应。比较融合的Caco-2细胞（成熟人肠上皮细胞的模型）与原代人胎儿肠细胞系（H4细胞）的初始体外研究表明，在炎症刺激后，胎儿细胞比Caco-2细胞分泌更多的IL-8（LPS，8倍; IL-1 β，20倍）。与Caco-2细胞相比，胎儿中的IL-8 mRNA活性在两种刺激下以相同的幅度成比例地增加。为了验证体外观察结果，将来自胎儿与较大儿童的小肠器官培养物暴露于LPS和IL-1 β。同样，在来自胎儿的人体器官培养物中，与年龄较大的儿童相比，IL-8分泌更大（LPS，2.5倍; IL-1 β，200倍），刺激后mRNA活性更高，表明IL-8基因转录增加可能是过度反应的原因。使用免疫组织化学染色来鉴定IL-8的细胞来源，主要在绒毛和隐窝上皮中注意到活性，但也在一些免疫应答淋巴样细胞中注意到活性。观察到未成熟的人肠细胞在炎症刺激后与过度的促炎细胞因子产生反应，这可能有助于部分解释为什么暴露于初始定植细菌的早产儿发展为坏死性小肠结肠炎。
Necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in premature infants, occurs after the introduction of oral feedings in conjunction with initial bacterial colonization of the gut and is hypothesized to be due to an immature (inappropriate) enterocyte response to bacterial stimuli. To test this hypothesis, we compared the enterocyte IL-8 response to inflammatory stimuli [lipopolysaccharide (LPS) and IL-1 beta] in immature vs. mature human small intestine. Initial in vitro studies comparing confluent Caco-2 cells, a model for mature human enterocytes, with a primary human fetal intestinal cell line (H4 cells) demonstrated that after inflammatory stimulation fetal cells secreted more IL-8 (LPS, 8-fold; IL-1 beta, 20-fold) than Caco-2 cells. IL-8 mRNA activity in fetal compared to Caco-2 cells was proportionately increased by the same magnitude with both stimuli. To validate the in vitro observations, small intestinal organ cultures from fetuses vs. older children were exposed to LPS and IL-1 beta. Again in human organ cultures from fetuses compared to older children, IL-8 secretion was greater (LPS, 2.5-fold; IL-1 beta, 200-fold) and mRNA activity after stimulation was comparably higher, suggesting that increased transcription of the IL-8 gene may account for the excessive response. Using immunohistochemical staining to identify the cellular source of IL-8, activity was noted predominantly in villous and crypt epithelium but also in a few immunoresponsive lymphoid cells, The observation that immature human enterocytes react with excessive pro-inflammatory cytokine production after inflammatory stimulation may help in part explain why prematures exposed to initial colonizing bacteria develop necrotizing enterocolitis.