Mantyh C R, Pappas T N, Lapp J A, Washington M K, Neville L M, Ghilardi J R, Rogers S D, Mantyh P W, Vigna S R
Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
Gastroenterology. 1996 Nov;111(5):1272-80. doi: 10.1053/gast.1996.v111.pm8898641.
BACKGROUND & AIMS: Nerves have been suggested to mediate the effects of bacterial toxins in intestinal diseases. However, the mechanisms involved are unknown. This study examined endogenous substance P (SP) activation of the substance P receptor (SPR) on enteric neurons in the rat ileum after exposure to intraluminal Clostridium difficile toxin A.
After intraluminal injection of toxin A in ileal loops, tissue was examined for pathological changes by histology and for SPR activation by immunocytochemical analysis of SP-induced SPR endocytosis.
After toxin A administration, > 70% of enteric neurons showed SPR endocytosis and became swollen with thickened dendrites. In contrast, SPRs in control rats were largely confined to the plasma membrane. Rats denervated of primary afferent fibers with neonatal capsaicin injection and animals pretreated with a nonpeptide SPR antagonist showed few endosomal SPRs, and the pathological inflammatory effects of toxin A were ablated.
Intraluminal toxin A causes the release of SP from primary afferent neurons: this endogenous SP then acts on enteric neurons in the submucosal and myenteric plexuses. SP is the primary mediator of an axon reflex mediating neurogenic inflammation in the intestine. SPR blockade may prove to be a novel therapy used to prevent intestinal inflammation.
有研究表明神经可介导细菌毒素在肠道疾病中的作用。然而，其中涉及的机制尚不清楚。本研究检测了在大鼠回肠腔内暴露于艰难梭菌毒素A后，内源性P物质（SP）对肠神经元上P物质受体（SPR）的激活作用。
在回肠肠袢内注射毒素A后，通过组织学检查组织的病理变化，并通过免疫细胞化学分析SP诱导的SPR内吞作用来检测SPR的激活情况。
给予毒素A后，超过70%的肠神经元出现SPR内吞作用，且细胞肿胀，树突增粗。相比之下，对照大鼠的SPR主要局限于质膜。新生大鼠注射辣椒素使初级传入纤维去神经支配后，以及用非肽类SPR拮抗剂预处理的动物，内体SPR很少，毒素A的病理炎症作用消失。
腔内毒素A导致初级传入神经元释放SP：这种内源性SP随后作用于黏膜下和肌间神经丛中的肠神经元。SP是介导肠道神经源性炎症的轴突反射的主要介质。SPR阻断可能被证明是一种预防肠道炎症的新疗法。
