Enteral vs IV Feeding: Effect on Mucosal Immunity

在美国，每年医院获得性肺炎的费用高达20亿美元，任何减少这种脓毒性并发症的廉价治疗都可能极大地影响医疗保健费用。在创伤患者中，与静脉（IV-TPN）喂养相比，肠内喂养显著减少了60- 70%的肺炎并发症。我们的实验和临床工作表明，当肠内喂养没有刺激肠道或没有提供肠内喂养的替代品时，粘膜免疫就会出现以前未被认识到的缺陷。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）分泌的IgA。小肠内佩耶氏斑免疫致敏的主要解剖部位。粘附分子通过Peyer's补丁引导未致敏的免疫细胞，这些淋巴细胞被致敏并改变其自身的表面整合素。然后它们被引导到肠道和肠外部位，如呼吸道，在那里它们产生对抗这些抗原的IgA。这种抗体与细菌结合，阻止细菌附着和感染。本研究的重点是营养途径和类型如何影响特异性粘附分子、修饰MAdCAM-1、未修饰MAdCAM-1和ICAM-1的表达，这些分子在引导未致敏的免疫细胞进入Peyer's补丁中发挥重要作用。该提案验证了这些粘附分子及其配体在幼稚T细胞和B细胞上的相互作用对于维持肠道和肠外部位的粘膜免疫至关重要的假设。该提议旨在验证这样一种假设，即抑制这些相互作用会重现体内粘膜防御的缺陷，这种缺陷是在不提供肠内喂养时引起的。该研究还关注了先前的观察结果，即特异性免疫细胞燃料谷氨酰胺和肠神经系统神经肽bombesin可以作为肠内喂养的替代品，并通过上调iv - tpn喂养动物的MAdCAM-1和ICAM- 1表达对MALT产生有益影响。这些实验旨在通过体内实验证实IgA是肺炎特异性免疫和呼吸道防御的关键因素。这些实验使用由杂交瘤细胞系产生的单克隆抗体，该单克隆抗体对铜绿假单胞菌临床分离株中高比例的多糖抗原有特异性。

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.