Enteral vs IV Feeding: Effect on Mucosal Immunity

在美国，医院获得性肺炎每年花费高达20亿美元，任何减少这种脓毒性并发症的廉价疗法都可能极大地影响医疗保健成本。 与静脉（IV-TPN）喂养相比，肠内喂养可显著减少创伤患者肺炎并发症的60 - 70%。 我们的实验和临床工作涉及以前未被认识到的粘膜免疫缺陷，当肠道未被肠内喂养刺激或未提供肠内喂养的替代品时，会发生这种缺陷。 粘膜表面的主要特异性免疫防御是由粘膜相关淋巴组织（MALT）产生的分泌型IgA。 小肠内派尔集合淋巴结免疫致敏的主要解剖部位。 粘附分子引导未致敏的免疫细胞通过派尔集合淋巴结，在派尔集合淋巴结中这些淋巴细胞被致敏并改变它们自身的表面整合素。 然后，它们被引导到肠道和肠外部位，如呼吸道，在那里它们产生针对这些抗原的IgA。 抗体与细菌结合，阻止它们附着并阻止它们感染。 该建议的重点是营养的途径和类型如何影响特定粘附分子的表达，修饰的MAdCAM-1，未修饰的MAdCAM-1和ICAM-1，它们在引导未致敏的免疫细胞进入派尔集合淋巴结中是重要的。 该提案检验了以下假设，即这些粘附分子与幼稚T和B细胞上的配体之间的相互作用对于维持肠和肠外部位的粘膜免疫至关重要。 该提案旨在检验以下假设：抑制这些相互作用会重新产生体内粘膜防御缺陷，这些缺陷是在不提供肠内喂养时诱导的。 它还关注了先前的观察结果，即特定的免疫细胞燃料谷氨酰胺和肠神经系统神经肽蛙皮素可以作为肠内喂养的替代物，并通过上调MAdCAM-1和ICAM-1表达对IV-TPN喂养动物的MALT产生有益作用。 这些实验旨在通过体内实验证实IgA是特异性免疫和呼吸道防御肺炎的关键因素。 这些实验使用由杂交瘤细胞系产生的单克隆抗体，其对在高百分比的铜绿假单胞菌临床分离株上发现的多糖抗原具有特异性。

Hospital acquired pneumonia costs up to 2 billion dollars per year in the United States, and any inexpensive therapy which reduces this septic complication could greatly impact health care costs. Enteral feeding significantly reduces the complications of pneumonia compared with intravenous (IV-TPN) feedings by 60-70 percent in trauma patients. Our experimental and clinical work implicates previously unrecognized defects in mucosal immunity which develop when the intestinal tract is not stimulated with enteral feeding or when surrogates of enteral feeding are not provided. The principal specific immunologic defense at mucosal surfaces is secretory IgA produced by the mucosal-associated lymphoid tissue (MALT). The principal anatomic site for immunologic sensitization of Peyer's patches within the small intestine. Adhesion molecules direct unsensitized immunocytes through the Peyer's patches where these lymphocytes are sensitized and change their own surface integrins. They are then directed to both intestinal and extraintestinal sites, such as the respiratory tract, where they produce IgA against those antigens. The antibody binds to bacteria, preventing their attachment and their ability to infect. This proposal focuses on how route and type of nutrition affects the expression of the specific adhesion molecules, modified MAdCAM-1, unmodified MAdCAM-1, and ICAM-1 which are important in directing unsensitized immunocytes into Peyer's patches. The proposal tests the hypothesis that interaction between these adhesion molecules and their ligands on naive T and B cells are critical in maintaining mucosal immunity in both intestinal and extraintestinal sites. The proposal is designed to test the hypothesis that inhibition of these interactions recreates the defects in in vivo mucosal defenses that are induced when enteral feeding is not provided. It also focuses on previous observations that a specific immunocyte fuel, glutamine, and the enteric nervous system neuropeptide, bombesin, can act as surrogates for enteral feeding and exert beneficial effects upon the MALT in IV-TPN-fed animals by upregulating MAdCAM-1 and ICAM- 1 expression. The experiments are designed to confirm that IgA is a critical element of specific immunity and respiratory defenses against pneumonia with in vivo experiments. These experiments use a monoclonal antibody produced by a hybridoma cell line which is specific for polysaccharide antigen(s) found on a high percentage of clinical isolates of Pseudomonas aeruginosa.