Altered esophageal histamine receptor expression in Eosinophilic Esophagitis (EoE): implications on disease pathogenesis.
Altered esophageal histamine receptor expression in Eosinophilic Esophagitis (EoE): implications on disease pathogenesis.
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DOI：
10.1371/journal.pone.0114831
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wang ML
中科院分区：
文献类型：
--
作者：
Merves J;Chandramouleeswaran PM;Benitez AJ;Muir AB;Lee AJ;Lim DM;Dods K;Mehta I;Ruchelli ED;Nakagawa H;Spergel JM;Wang ML
嗜酸性食管炎（EoE）是一种慢性变态反应性疾病，其病理机制尚不完全清楚.组胺产生细胞，包括肥大细胞和嗜碱性粒细胞已牵连在EoE。然而，目前对食管上皮中组胺和组胺受体（HR）表达和信号传导的作用知之甚少。在此，我们的特点是HR（H1 R，H2 R，H3 R，和H4 R）在人食管活检组织中的表达，并研究组胺信号在体外人食管上皮细胞中诱导细胞因子表达的作用。使用qRT-PCR和免疫荧光定位在来自非EoE对照（N = 23）、非活动性EoE（<15 eos/hpf，N = 26）和活动性EoE（>15 eos/hpf，N = 22）受试者的食管活检中定量HR表达。HR表达和组胺介导的细胞因子分泌进行了评估，在人原代和端粒酶永生化食管上皮细胞。与非活动性EoE和对照组相比，活动性EoE活检组织中H1 R、H2 R和H4 R表达增加。H2 R是表达最丰富的受体，H3 R表达在所有3个队列中可忽略不计。浸润性嗜酸性粒细胞表达H1 R、H2 R和H4 R，这导致在活性受试者中观察到的HR增加。原代细胞和永生化细胞组成型表达H1 R和H2 R，但不表达H3 R或H4 R，上皮组织胺刺激诱导GM-CSF、TNFα和IL-8分泌，但不诱导TSLP或eotaxin-3分泌。用TLR 3配体poly（I：C）引发上皮诱导H1 R和H2 R表达，并增强组胺诱导的GM-CSF、TNFα和IL-8分泌。这些作用主要被H1 R拮抗剂抑制，但不受H2 R拮抗作用的影响。组胺在体外以H1 R依赖的方式直接激活食管上皮细胞因子分泌。然而，H1 R、H2 R和H4 R在体内EoE的活动性炎症中被诱导。虽然全身性抗组胺药（抗H1 R）治疗可能不会诱导EoE的临床缓解，但我们的研究表明，需要进一步研究EoE中的组胺受体信号传导，靶向其他组胺受体可能会导致这种重要疾病的新治疗策略。
Eosinophilic Esophagitis (EoE) is a chronic allergic disorder, whose pathobiology is incompletely understood. Histamine-producing cells including mast cells and basophils have been implicated in EoE. However, very little is currently known about the role of histamine and histamine receptor (HR) expression and signaling in the esophageal epithelium. Herein, we characterized HR (H1R, H2R, H3R, and H4R) expression in human esophageal biopsies and investigate the role of histamine signaling in inducible cytokine expression in human esophageal epithelial cells in vitro. HR expression was quantified in esophageal biopsies from non-EoE control (N = 23), inactive EoE (<15 eos/hpf, N = 26) and active EoE (>15 eos/hpf, N = 22) subjects using qRT-PCR and immunofluorescent localization. HR expression and histamine-mediated cytokine secretion were evaluated in human primary and telomerase-immortalized esophageal epithelial cells. H1R, H2R, and H4R expression were increased in active EoE biopsies compared to inactive EoE and controls. H2R was the most abundantly expressed receptor, and H3R expression was negligible in all 3 cohorts. Infiltrating eosinophils expressed H1R, H2R, and H4R, which contributed to the observed increase in HR in active subjects. H1R and H2R, but not H3R or H4R, were constitutively expressed by primary and immortalized cells, and epithelial histamine stimulation induced GM-CSF, TNFα, and IL-8, but not TSLP or eotaxin-3 secretion. Epithelial priming with the TLR3 ligand poly (I:C) induced H1R and H2R expression, and enhanced histamine-induced GM-CSF, TNFα, and IL-8 secretion. These effects were primarily suppressed by H1R antagonists, but unaffected by H2R antagonism. Histamine directly activates esophageal epithelial cytokine secretion in vitro in an H1R dependent fashion. However, H1R, H2R and H4R are induced in active inflammation in EoE in vivo. While systemic antihistamine (anti-H1R) therapy may not induce clinical remission in EoE, our study suggests that further study of histamine receptor signaling in EoE is warranted and that targeting of additional histamine receptors may lead to novel treatment strategies for this important disease.
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影响因子：
24.5
作者：
Cheng E;Zhang X;Huo X;Yu C;Zhang Q;Wang DH;Spechler SJ;Souza RF
通讯作者：
Souza RF
影响因子：
14.2
作者：
Abonia, J. Pablo;Blanchard, Carine;Butz, Bridget Buckmeier;Rainey, Heather F.;Collins, Margaret H.;Stringer, Keith;Putnam, Philip E.;Rothenberg, Marc E.
通讯作者：
Rothenberg, Marc E.
影响因子：
3.6
作者：
Alonso, Natalia;Fernandez, Natalia;Shayo, Carina
通讯作者：
Shayo, Carina
DOI：
10.1152/ajplung.1995.268.1.l117
发表时间：
1995-01-01
影响因子：
4.9
作者：
ERGER, RA;CASALE, TB
通讯作者：
CASALE, TB
影响因子：
6.5
作者：
Kanda, N;Watanabe, S
通讯作者：
Watanabe, S