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.

沙门氏菌和其他肠侵入微生物引起的肠道感染是艾滋病和其他免疫抑制疾病患者发病和死亡的一个主要因素。 人体肠粘膜表面积大，与外界环境直接接触，必须与肠道共生菌群共存，但排除腔内病原体。 此外，小肠中的派尔氏集结（PP）通过将管腔抗原穿过粘膜屏障传递至粘膜下抗原呈递细胞，在粘膜免疫中发挥关键作用，但PP也可能作为肠侵袭性微生物感染的入口，从而产生肠炎和败血症。 在之前的资助期间，我们获得的证据表明，猪回肠粘膜下层中的一种新型抑制性阿片受体在肠神经回路中表达，炎症介质通过该神经回路诱发上皮阴离子分泌。 在这些实验过程中，我们取得了令人兴奋的新发现：猪空肠PP和非PP上皮细胞内高致死性猪霍乱沙门氏菌的摄取可能受到宿主肠神经系统的调节。本申请旨在通过提出以下假设来继续这一新的研究路线：(1) PP 和非 PP 肠上皮细胞的细菌摄取因肠道神经活动和关键肠道神经抑制分子（包括阿片类药物和大麻素）的变化而改变； (2) 沙门氏菌摄取的神经调节对于这种微生物并不具有特异性。 这些假设将通过检查药物和其他治疗方法对猪霍乱沙门氏菌内化到猪分离的空肠 PP 和非 PP 粘膜中的影响进行检验，具体目标如下：(1) 表征投射、化学编码和受体猪空肠段中支配 PP 的肠神经元的特征； (2) 从功能上鉴定调节沙门氏菌内化为 PP 的肠道神经递质类别； (3) 明确去甲肾上腺素、阿片类药物和大麻素在改变 PP 和非 PP 粘膜摄取沙门氏菌方面的作用； (4) 检查去甲肾上腺素和其他神经抑制药物对 PP 和非 PP 肠粘膜中细菌特异性和非特异性粘膜摄取过程的作用。拟议实验的结果应增强我们对滥用药物对艾滋病相关肠道感染的有害影响的了解，并可能确定新的药物治疗方法，能够增强旨在预防人类免疫缺陷病毒和其他肠道病原体感染的口服疫苗的功效。