Mucosal Defense Mechanisms in Substance Abuse

药物滥用中的粘膜防御机制

• 批准号: 6634223
• 负责人: DAVID R BROWN
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-29 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634223
• 关键词: Peyer's patches; Salmonella infections; adrenergic receptor; antigen presenting cell; cannabinoids; endogenous opioid; gastrointestinal epithelium; host organism interaction; intestinal mucosa; jejunum; mucosal immunity; neuropharmacology; neuroregulation; neurotransmitter metabolism; norepinephrine; opioid receptor; receptor expression; swine

Enteric infections by Salmonella and other enteroinvasive microorganisms are a major contributing factor to morbidity and mortality in individuals with AIDS and other immunosuppressed conditions. The large surface area of the human intestinal mucosa is in direct contact with the external environment, and must coexist with commensal enteric microflora but exclude luminal pathogens. In addition, Peyer's patches (PP) in the small intestine play a key role in mucosal immunity by delivering luminal antigens across the mucosal barrier to submucosal antigen-presenting cells, but PP may also serve as entryways for infection by enteroinvasive microorganisms which can produce enteritis and septicemia. In the previous funding period, we obtained evidence that a novel inhibitory opioid receptor in the porcine ileal submucosa is expressed in an enteric neural circuit through which inflammatory mediators evoke epithelial anion secretion. In the course of these experiments, we made the exciting new discovery that the intracellular uptake of the highly lethal Salmonella serovar choleraesuis into PP and non-PP epithelia of porcine jejunum may be modulated by the enteric nervous system of the host. This application seeks to continue this novel line of investigation by addressing the hypotheses that (1) bacterial uptake into PP and non-PP intestinal epithelia is altered by changes in enteric neural activity and key enteric neuroinhibitory molecules, including opioids and cannabinoids; and (2) that neuroregulation of Salmonella uptake is not specific for this microorganism. These hypotheses will be tested by examining the effects of drugs and other treatments on the internalization of S. choleraesuis into isolated jejunal PP and non-PP mucosa from pigs through the following Specific Aims: (1) to characterize the projections, chemical coding and receptor signatures of enteric neurons innervating PP in porcine jejunal segments; (2) to functionally identify classes of enteric neurotransmitters modulating Salmonella internalization into PP; (3) to define the actions of norepinephrine, opioids and cannabinoids in altering PP and non-PP mucosal uptake of Salmonella; and (4) to examine the actions of norepinephrine and other neuroinhibitory drugs on bacteria-specific and non-specific mucosal uptake processes in PP and non-PP intestinal mucosae. The results of the proposed experiments should enhance our understanding of the deleterious effects of abused drugs in AIDS- related enteric infections and may identify new pharmacological treatments capable of enhancing the efficacy of oral vaccines designed to prevent infections by the human immunodeficiency virus and other enteropathogens.

沙门氏菌和其他肠道侵入性微生物的肠道感染是艾滋病和其他免疫抑制疾病患者发病率和死亡率的主要因素。 人体肠粘膜的大表面积与外部环境直接接触，必须与肠道微生物菌群共存，但排除管腔病原体。 此外，小肠中的派伊尔集合淋巴结（PP）通过将管腔抗原穿过粘膜屏障递送至粘膜下抗原呈递细胞而在粘膜免疫中起关键作用，但PP也可作为肠侵入性微生物感染的入口，所述肠侵入性微生物可产生肠炎和败血症。 在上一个资助期，我们获得的证据表明，一种新的抑制性阿片受体在猪回肠粘膜下层表达的肠神经回路，通过炎症介质引起上皮阴离子分泌。 在这些实验的过程中，我们取得了令人兴奋的新发现，高度致命的猪霍乱沙门氏菌血清型的细胞内摄取到猪空肠的PP和非PP上皮细胞可能是由宿主的肠神经系统调节。本申请试图通过解决以下假设来继续这一新的研究路线：（1）通过肠神经活性和关键肠神经抑制分子（包括阿片类和大麻素）的变化来改变细菌对PP和非PP肠上皮的摄取;以及（2）沙门氏菌摄取的神经调节对该微生物不是特异性的。 这些假设将通过检查药物和其他治疗对S。本研究的目的是：（1）研究猪空肠段中支配PP的肠神经元的投射、化学编码和受体特征;（2）功能性鉴定调节沙门氏菌内化为PP的肠神经递质的种类;（3）确定去甲肾上腺素、阿片类和大麻素在改变沙门氏菌的PP和非PP粘膜摄取中的作用;和（4）检查去甲肾上腺素和其他神经抑制药物对PP和非PP中细菌特异性和非特异性粘膜摄取过程的作用。PP肠粘膜。拟议实验的结果应加强我们对滥用药物在艾滋病相关肠道感染中的有害影响的理解，并可能确定新的药理学治疗方法，这些方法能够增强口服疫苗的效力，这些疫苗旨在预防人类免疫缺陷病毒和其他肠道病原体的感染。