Developmental origins of functional dyspepsia-like gastric hypersensitivity in rats.
Developmental origins of functional dyspepsia-like gastric hypersensitivity in rats.
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DOI：
10.1053/j.gastro.2012.11.001
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发表时间：
2013-03
期刊：
影响因子：
29.4
通讯作者：
Sarna SK
中科院分区：
文献类型：
--
作者：
Winston JH;Sarna SK
胃超敏反应（GHS）导致功能性消化不良（FD）患者的上腹痛;这种功能障碍的病因和细胞机制仍不清楚。我们调查是否炎症性损伤新生大鼠结肠诱导GHS在成年生活。我们使用细胞，分子和在体内的方法来研究GHS的机制，在成年大鼠进行新生儿结肠损伤的三硝基苯磺酸（TNBS）的腔内给药;对照组接受生理盐水。6至8周后，对大鼠进行GHS评估，并收集组织用于分子实验。出生后第10天结肠炎性损伤导致出生后第15天皮质酮异常增加，并在成年后诱导GHS。我们称之为FD样大鼠。新生儿损伤后抑制糖皮质激素受体阻断了成年大鼠GHS的诱导。新生儿血浆皮质酮异常升高可使血浆去甲肾上腺素、胃底外侧肌层神经生长因子（NGF）、胸背根神经节（DRG）和脊髓中脑源性神经营养因子（BDNF）浓度升高，胸背根神经节Kv1.1 mRNA表达下调，而不影响Kv1.4、Nav1.8、TrpA 1、TrpV 1、或P2 X3。抑制糖皮质激素受体在新生儿的侮辱或肾上腺素能受体的抑制，神经生长因子或脑源性神经营养因子在FD样大鼠抑制GHS。鞘内注射针对Kv1.1的小干扰RNA增加了幼稚大鼠的GHS。对幼鼠结肠的炎症性损伤导致成年后的GHS。GHS是由编码神经营养蛋白和离子通道的基因表达改变以及交感神经系统活动改变引起的。
Gastric hypersensitivity (GHS) contributes to epigastric pain in patients with functional dyspepsia (FD); the etiology and cellular mechanisms of this dysfunction remain unknown. We investigated whether inflammatory insult to the colons of neonatal rats induced GHS in adult life. We used cellular, molecular, and in vivo approaches to investigate the mechanisms of GHS in adult rats subjected to neonatal colonic insult by intraluminal administration of trinitrobenzene sulfonic acid (TNBS); controls received saline. Six to 8 weeks later, rats were evaluated for GHS and tissue was collected for molecular experiments.’ Inflammatory insult to the colon on post-natal day (PND) 10 caused an aberrant increase of corticosterone on PND 15 and induced GHS in adult life. We called these FD-like rats. Inhibition of glucocorticoid receptors following neonatal insult blocked the induction of GHS in adult rats. The aberrant increase of plasma corticosterone in neonates elevated the plasma concentration of norepinephrine, nerve growth factor (NGF) in the gastric fundus muscularis externae, brain-derived neurotrophic factor (BDNF) in the thoracic dorsal root ganglia (DRG) and spinal cord, and downregulated Kv1.1 mRNA in thoracic DRG without affecting the expression of Kv1.4, Nav1.8, TrpA1, TrpV1, or P2X3 in FD-like rats. Inhibition of glucocorticoid receptors during neonatal insult or the inhibition of adrenergic receptors, NGF or BDNF in FD-like rats suppressed GHS. The intrathecal administration of small interfering RNAs against Kv1.1 increased GHS in naïve rats. Inflammatory insult to the colons of rat pups leads to GHS in adult life. GHS is caused by altered expression of genes encoding neurotrophins and ion channels, and altered activity of the sympathetic nervous system.
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