Cheng Ling, Cao Weibiao, Behar Jose, Fiocchi Claudio, Biancani Piero, Harnett Karen M
Division of Gastroenterology, Rhode Island Hospital and Brown University, Providence, RI 02903, USA.
J Pharmacol Exp Ther. 2006 Oct;319(1):117-26. doi: 10.1124/jpet.106.106104. Epub 2006 Jun 28.
In a human in vitro model of esophagitis, we investigated the genesis of esophagitis-associated dysmotility by examining HCl-induced production of inflammatory mediators in the mucosa and investigating their effect on esophageal circular muscle. Muscularis propria was removed from organ donors' esophagi, leaving the mucosal tube intact. The tube was tied at both ends, forming a sac, and filled with HCl at pH 4. After 3 h of incubation, the supernatant surrounding the sac was analyzed or applied to circular muscle strips. HCl alone did not affect circular muscle contraction in response to electrical field stimulation (EFS), but supernatant of HCl-treated mucosa abolished contraction. The inhibition was reversed by the platelet-activating factor (PAF) antagonist CV3988 [(+/-)-3-(N-octadecylcarbamoyl)-2-methoxy) propyl-(2-thiazolioethyl) phosphate], whereas the PAF analog 2-O-methyl platelet-activating factor C-16 (PAF-16) inhibited EFS-induced contraction and acetylcholine (ACh) release in circular muscle strips. The hydrogen peroxide scavenger catalase reversed the inhibition in contraction, to the same extent as CV3988. We therefore measured PAF and hydrogen peroxide (H(2)O(2)) in mucosa, mucosa supernatant, and circular muscle. HCl increased PAF and interleukin (IL)-1beta (but not IL-6, prostaglandin E(2), or H(2)O(2)) in mucosa, and only PAF was released into the supernatant, presumably to affect circular muscle. In circular muscle, exogenous PAF induced sequential formation of IL-6, H(2)O(2), IL-1beta, and PAF. Release of PAF by the mucosa inhibits ACh release from circular muscle layer neurons and initiates sequential formation of inflammatory mediators in muscle, resulting in production of PAF by the muscle itself, possibly initiating in a self-sustaining cycle.
在一种人类食管炎体外模型中，我们通过检测盐酸诱导的黏膜中炎症介质的产生，并研究其对食管环行肌的影响，来探究食管炎相关性运动障碍的发生机制。从器官捐献者的食管中分离出固有肌层，保留黏膜管完整。将黏膜管两端结扎形成囊袋，并注入pH值为4的盐酸。孵育3小时后，分析囊袋周围的上清液或应用于环行肌条。单独的盐酸不影响电场刺激（EFS）引起的环行肌收缩，但经盐酸处理的黏膜上清液可消除收缩。血小板活化因子（PAF）拮抗剂CV3988 [（±）-3-（N-十八烷基氨甲酰基）-2-甲氧基）丙基-（2-噻唑啉乙基）磷酸盐]可逆转这种抑制作用，而PAF类似物2-O-甲基血小板活化因子C-16（PAF-16）则抑制环行肌条中EFS诱导的收缩和乙酰胆碱（ACh）释放。过氧化氢清除剂过氧化氢酶可将收缩抑制作用逆转至与CV3988相同的程度。因此，我们检测了黏膜、黏膜上清液和环行肌中的PAF和过氧化氢（H₂O₂）。盐酸可增加黏膜中PAF和白细胞介素（IL）-1β（但不增加IL-6、前列腺素E₂或H₂O₂），且只有PAF释放到上清液中，可能作用于环行肌。在环行肌中，外源性PAF可诱导IL-6、H₂O₂、IL-1β和PAF的顺序形成。黏膜释放的PAF抑制环行肌层神经元释放ACh，并启动肌肉中炎症介质的顺序形成，导致肌肉自身产生PAF，可能启动一个自我维持的循环。
