Gene modulation in acetic acid-induced oral ulcerative mucositis

To reveal the molecular mechanisms underlying oral ulcerative mucositis-induced pain, we investigated putative pain-associated mediators, pain-related behaviors and gene modulation in a rat oral mucositis model. On day 1 after acetic acid treatment, the mucosal area showed slight redness and swelling but no evidence of ulceration or pain induction. On day 2, oral ulcers were obvious, as was the induction of spontaneous and mechanical pain. In the treated mucosal area, bacterial loading and prostaglandin E2 increased beginning on day 2; no significant changes were observed on day 1. DNA microarray analysis of trigeminal ganglion tissue collected on day 2 identified 32 significantly regulated genes (>1.5-fold change in expression). The up-regulation of the top 3 genes, Hamp (hepcidin antimicrobial peptide), Reg3b (regenerating islet-derived 3ß) and Serpina3n (serine peptidase inhibitor A3N), was validated through quantitative RT-PCR. Systemic antibiotic pre-treatment did not increase the mRNA levels. Therefore, we conclude that the oral ulcerative mucositis-induced pain is caused by infectious inflammation of the ulcerative area and stimulates anti-bacterial and anti-peptidase gene expressions in sensory neurons.为阐明口腔溃疡性黏膜炎（oral ulcerative mucositis）引发疼痛的分子机制，本研究在大鼠口腔黏膜炎模型（rat oral mucositis model）中探究了潜在疼痛相关介质、疼痛相关行为及基因调控情况。 乙酸造模处理后第1天，黏膜区域仅表现为轻度红肿，未出现溃疡形成及疼痛诱导迹象。 至第2天，口腔溃疡症状显著，自发性疼痛与机械性疼痛亦同步出现。 在处理后的黏膜区域，细菌负荷与前列腺素E2（prostaglandin E2）水平自第2天起升高，第1天未观察到显著变化。 对第2天采集的三叉神经节（trigeminal ganglion）组织开展基因芯片（DNA microarray）分析，共鉴定出32个表达量变化倍数超过1.5倍的显著差异调控基因。 通过实时定量逆转录聚合酶链反应（quantitative RT-PCR）验证了排名前三的上调基因：Hamp（铁调素抗菌肽，hepcidin antimicrobial peptide）、Reg3b（胰岛再生源蛋白3β，regenerating islet-derived 3ß）及Serpina3n（丝氨酸蛋白酶抑制剂A3N，serine peptidase inhibitor A3N）。 全身抗生素预处理并未提升上述基因的mRNA表达水平。 综上，本研究认为口腔溃疡性黏膜炎诱导的疼痛由溃疡区域的感染性炎症介导，并可刺激感觉神经元内抗菌及抗蛋白酶基因的表达。