Background and aims: Histamine is known as a regulator of gastrointestinal functions, such as gastric acid production, intestinal motility, and mucosal ion secretion. Most of this knowledge has been obtained from anim...Background and aims: Histamine is known as a regulator of gastrointestinal functions, such as gastric acid production, intestinal motility, and mucosal ion secretion. Most of this knowledge has been obtained from animal studies. In contrast, in humans, expression and distribution of histamine receptors (HR) within the human gastrointestinal tract are unclear. Methods: We analysed HR expression in human gastrointestinal tissue specimens by quantitative reverse transcription-polymerase chain reaction and immunostaining. Results: We found that H1R, H2R, and H4R mRNA were expressed throughout the gastrointestinal tract, while H3R mRNA was absent. No significant differences in the distribution of HR were found between different anatomical sites (duodenum, ileum, colon, sigma, and rectum). Immunostaining of neurones and nerve fibres revealed that H3R was absent in the human enteric nervous system; however, H1R and H2R were found on ganglion cells of the myenteric plexus. Epithelial cells also expressed H1R, H2R and, to some extent, H4R. Intestinal fibroblasts exclusively expressed H1R while the muscular layers of human intestine stained positive for both H1R and H2R. Immune cells expressed mRNA and protein for H1R, H2R, and low levels of H4R. Analysis of endoscopic biopsies from patients with food allergy and irritable bowel syndrome revealed significantly elevated H1R and H2R mRNA levels compared with controls. Conclusions: We have demonstrated that H1R, H2R and, to some extent, H4R, are expressed in the human gastrointestinal tract, while H3R is absent, and we found that HR expression was altered in patients with gastrointestinal diseases.展开更多
Histamine—the main product of mast cells plays critical role in the pathogenetic pathways of both allergic rhinitis and asthma. The novel concept of the unique airway diseases its only supported by the similarities w...Histamine—the main product of mast cells plays critical role in the pathogenetic pathways of both allergic rhinitis and asthma. The novel concept of the unique airway diseases its only supported by the similarities within pathogenetic process. Antagonists of H1 and H2 receptors are quite effective in allergic rhinitis, but not effective enough in asthma. In an era of corticosteroids, leucotriene antagonists and Anti-IgE treatment, there is still a challenge to search for more effective, more acurate and more safe treatment option. Antagonists (inversive agonists) of histamine receptors H4 seems to be one of the promising targets in the allergic rhinitis and asthma treatment. The first H4 antagonist entered to clinics and the results from a proof-of-concept Phase II clinical study is expected to be disclosed soon. This review article summarizes current knowledge on H4R that have been collected in various studies sharing evidences about efficacy of H4R as a reasonable target for diseases with histamine involved pathogenetic pathways.展开更多
Objective:To delineate the comparative immunomodulatory roles of H1R-H4R in antibody generation profile in rabbit model.Methods:The cohort comprised of eight groups containing 18(9 male and 9 female) rabbits in each g...Objective:To delineate the comparative immunomodulatory roles of H1R-H4R in antibody generation profile in rabbit model.Methods:The cohort comprised of eight groups containing 18(9 male and 9 female) rabbits in each group.GroupⅠremained non-immunized and received only vehicle(sterile distilled water,1 mL/kg×b.i.d.) intramuscularly.GroupⅡreceived vehicle (1 mL/kg×b.i.d.) while GroupsⅢ-Ⅶ(drugs-treated) received subcutaneous histamine (100μg/kg×b.i.d.),and intramuscular H1R-antagonist(pheniramine,10 mg/kg×b.i.d.), H2R-antagonist(ranitidine,10 mg/kg×b.i.d.),H3R-antagonist(iodophenpropit,1μg/kg×b.i.d.) and H4R-antagonist(JNJ 7777120,10μg/kg×b.i.d.),and GroupⅧDMSO(1 mL/kg×b.i.d.),respectively for 10 days(starting from day 1).They were subsequendy immunized with intravenous injection of sheep red blood cells(SRBC) at day 3.The estimation of serum Igs,IgM and IgG were done by ELISA,and observed at day 0(pre-immunization),and 7,14,21,28 and 58(post-immunization).Results:It was shown that histamine and HRs-antagonists could influence a detectable antibody response to SRBC as early as day 7-post-immunization(post-Ⅰ), which lasted until day 58 post-Ⅰ.The results were found statistically significant(P【0.05,). Conclusions:This study suggests that histamine receptors play important roles in modulation of antibody generation in which H1R,H2R and H4R have immunosuppressive roles and conversely, H3R playes an immune enhancing role.The findings of this study may have clinical significance and provide the baseline information for future study.展开更多
文摘Background and aims: Histamine is known as a regulator of gastrointestinal functions, such as gastric acid production, intestinal motility, and mucosal ion secretion. Most of this knowledge has been obtained from animal studies. In contrast, in humans, expression and distribution of histamine receptors (HR) within the human gastrointestinal tract are unclear. Methods: We analysed HR expression in human gastrointestinal tissue specimens by quantitative reverse transcription-polymerase chain reaction and immunostaining. Results: We found that H1R, H2R, and H4R mRNA were expressed throughout the gastrointestinal tract, while H3R mRNA was absent. No significant differences in the distribution of HR were found between different anatomical sites (duodenum, ileum, colon, sigma, and rectum). Immunostaining of neurones and nerve fibres revealed that H3R was absent in the human enteric nervous system; however, H1R and H2R were found on ganglion cells of the myenteric plexus. Epithelial cells also expressed H1R, H2R and, to some extent, H4R. Intestinal fibroblasts exclusively expressed H1R while the muscular layers of human intestine stained positive for both H1R and H2R. Immune cells expressed mRNA and protein for H1R, H2R, and low levels of H4R. Analysis of endoscopic biopsies from patients with food allergy and irritable bowel syndrome revealed significantly elevated H1R and H2R mRNA levels compared with controls. Conclusions: We have demonstrated that H1R, H2R and, to some extent, H4R, are expressed in the human gastrointestinal tract, while H3R is absent, and we found that HR expression was altered in patients with gastrointestinal diseases.
文摘Histamine—the main product of mast cells plays critical role in the pathogenetic pathways of both allergic rhinitis and asthma. The novel concept of the unique airway diseases its only supported by the similarities within pathogenetic process. Antagonists of H1 and H2 receptors are quite effective in allergic rhinitis, but not effective enough in asthma. In an era of corticosteroids, leucotriene antagonists and Anti-IgE treatment, there is still a challenge to search for more effective, more acurate and more safe treatment option. Antagonists (inversive agonists) of histamine receptors H4 seems to be one of the promising targets in the allergic rhinitis and asthma treatment. The first H4 antagonist entered to clinics and the results from a proof-of-concept Phase II clinical study is expected to be disclosed soon. This review article summarizes current knowledge on H4R that have been collected in various studies sharing evidences about efficacy of H4R as a reasonable target for diseases with histamine involved pathogenetic pathways.
基金University Grants Commission, New Delhi,India for providing UGC Fellowship[UGC letter DON F.19-33/2006(CU)]Department of Science & Technology,Ministry of Science & Technology, Government of India for awarding "Young Scientist Project Award"(FT/SR-L-111/2006)
文摘Objective:To delineate the comparative immunomodulatory roles of H1R-H4R in antibody generation profile in rabbit model.Methods:The cohort comprised of eight groups containing 18(9 male and 9 female) rabbits in each group.GroupⅠremained non-immunized and received only vehicle(sterile distilled water,1 mL/kg×b.i.d.) intramuscularly.GroupⅡreceived vehicle (1 mL/kg×b.i.d.) while GroupsⅢ-Ⅶ(drugs-treated) received subcutaneous histamine (100μg/kg×b.i.d.),and intramuscular H1R-antagonist(pheniramine,10 mg/kg×b.i.d.), H2R-antagonist(ranitidine,10 mg/kg×b.i.d.),H3R-antagonist(iodophenpropit,1μg/kg×b.i.d.) and H4R-antagonist(JNJ 7777120,10μg/kg×b.i.d.),and GroupⅧDMSO(1 mL/kg×b.i.d.),respectively for 10 days(starting from day 1).They were subsequendy immunized with intravenous injection of sheep red blood cells(SRBC) at day 3.The estimation of serum Igs,IgM and IgG were done by ELISA,and observed at day 0(pre-immunization),and 7,14,21,28 and 58(post-immunization).Results:It was shown that histamine and HRs-antagonists could influence a detectable antibody response to SRBC as early as day 7-post-immunization(post-Ⅰ), which lasted until day 58 post-Ⅰ.The results were found statistically significant(P【0.05,). Conclusions:This study suggests that histamine receptors play important roles in modulation of antibody generation in which H1R,H2R and H4R have immunosuppressive roles and conversely, H3R playes an immune enhancing role.The findings of this study may have clinical significance and provide the baseline information for future study.
文摘目的探讨黄连解毒汤改善1-氯-2,4-二硝基苯(DNCB)诱导特应性皮炎(AD)小鼠瘙痒症状的作用及机制。方法将36只Balb/c小鼠随机分为正常组、模型组、地塞米松组(阳性对照,2.5 mg·kg^(-1))及黄连解毒汤低、中、高剂量组(0.4、0.8、1.6 g·kg^(-1)),每组6只。剃除小鼠背部毛发后将200μL DNCB溶液涂抹于小鼠背部进行致敏(1%DNCB,连续3 d)与激发(1.5%DNCB,从第14天开始,每3 d激发1次,共进行5次)。激发与药物干预同时进行,各组按照设定剂量对小鼠进行灌胃给药,每日1次,连续14 d。参照特应性皮炎评分标准(SCORAD)计算小鼠皮损严重程度评分;记录小鼠20 min内抓挠次数。采用HE染色法观察皮损组织病理形态变化;甲苯胺蓝染色法观察皮损组织肥大细胞浸润情况;RT-q PCR法检测皮损组织中胸腺基质淋巴细胞生成素(TSLP)、白细胞介素(IL)13、组胺H4受体(HRH4)、IL-31 m RNA表达水平。结果与正常组比较,模型组小鼠的背部皮肤经DNCB激发后出现明显的红斑、苔藓化、结痂、表皮脱落等现象,皮损严重程度评分显著增高(P<0.001);表皮角化过度,棘层厚度显著增加(P<0.001),海绵水肿,真皮层内可见大量炎性细胞浸润;皮损组织肥大细胞数量显著升高(P<0.001);20 min内的抓挠次数显著增加(P<0.01);皮损组织中TSLP、IL-13、HRH4、IL-31 m RNA表达水平均明显升高(P<0.05,P<0.01)。与模型组比较,黄连解毒汤低、中、高剂量组小鼠背部的皮损情况得到明显改善,苔藓化面积明显缩小,皮损严重程度评分显著降低(P<0.001),皮损组织中肥大细胞数量及IL-13、HRH4、IL-31 m RNA表达水平均显著降低(P<0.05,P<0.01,P<0.001);黄连解毒汤中、高剂量组棘层厚度显著降低(P<0.001),真皮层内炎性细胞数量显著减少;黄连解毒汤高剂量组小鼠20 min内的抓挠次数显著减少(P<0.01),皮损组织中TSLP m RNA表达水平明显降低(P<0.05)。结论黄连解毒汤能够缓解AD小鼠瘙痒症状,其作用机制可能与修复AD小鼠皮肤屏障,减轻炎性细胞及肥大细胞浸润,下调皮肤组织中瘙痒相关因子TSLP、IL-13、IL-31、HRH4 mRNA表达有关。
