Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis
Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis
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DOI：
10.1152/ajpgi.00169.2004
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发表时间：
2005-01-01
影响因子：
4.5
通讯作者：
Walker, WA
中科院分区：
文献类型：
--
作者：
Nanthakumar, NN;Young, C;Walker, WA
坏死性小肠结肠炎（NEC）是一种主要的炎症性疾病的过早人类肠道，可以预防糖皮质激素，如果产前给予妊娠34周前。这一观察结果表明，如在动物模型中所证明的，存在有限的类固醇反应期。人肠异种移植物用于确定在发育中的人肠中是否存在糖皮质激素反应期。通过乳糖酶活性测定发育反应性，通过内源性（IL-1 β）或外源性（LPS）促炎刺激后IL-8、IL-6和单核细胞趋化蛋白-1（MCP-1）诱导测定炎症反应性。移植后30周监测回肠异种移植物的功能发育，乳糖酶活性与子宫内发育预测一致。醋酸可的松在20周（未成熟）时加速乳糖酶的个体发生，但在移植后30周（成熟）时效果消失。伴随着加速成熟，在未成熟但不成熟的异种移植物中，糖皮质激素预处理显著抑制了IL-8对IL-1 β和LPS的反应（从6倍到3倍）。IL-8的诱导作用反映在IL-8 mRNA水平，提示转录调控。IL-8在未成熟肠道中的过度激活是由ERK和p38激酶的长期激活以及由于低水平的IkappaB引起的NF-κ B的核转位介导的。类固醇预处理在未成熟的肠道抑制所有三个信号通路的激活，以响应促炎刺激。因此，通过加速功能和炎症成熟，在反应期内通过糖皮质激素加速肠成熟可能为NEC提供有效的预防性治疗。
Necrotizing enterocolitis (NEC) is a major inflammatory disease of the premature human intestine that can be prevented by glucocorticoids if given prenatally before the 34th wk of gestation. This observation suggests that a finite period of steroid responsiveness exists as has been demonstrated in animal models. Human intestinal xenografts were used to determine whether a glucocorticoid responsive period exists in the developing human intestine. Developmental responsiveness was measured by lactase activity and inflammatory responsiveness by IL-8, IL-6, and monocyte chemotactic protein-1 (MCP-1) induction after an endogenous (IL-1beta) or exogenous (LPS) proinflammatory stimulus, respectively. Functional development of ileal xenografts were monitored for 30 wk posttransplantation, and the lactase activity recapitulated that predicted by in utero development. Cortisone acetate accelerated the ontogeny of lactase at 20 wk (immature) but the effect was lost by 30 wk (mature) posttransplant. Concomitant with accelerated maturation, the IL-8 response to both IL-1beta and LPS was significantly dampened (from 6- to 3-fold) by glucocorticoid pretreatment in the immature but not mature xenografts. The induction of IL-8 was reflected at the level of IL-8 mRNA, suggesting transcriptional regulation. The excessive activation of IL-8 in the immature gut was mediated by a prolonged activation of ERK and p38 kinases and nuclear translocation of NF-kappaB due to low levels of IkappaB. Steroid pretreatment in immature intestine dampens activation of all three signaling pathways in response to proinflammatory stimuli. Therefore, accelerating intestinal maturation by glucocorticoids within the responsive period by accelerating functional and inflammatory maturation may provide an effective preventive therapy for NEC.