Enteral vs IV Feeding: Effect on Mucosal Immunity

在美国，医院获得性肺炎每年的成本高达20亿美元，任何减少这种败血症并发症的廉价疗法都可能极大地影响医疗保健成本。在创伤患者中，肠内喂养与静脉(IV-TPN)喂养相比，可显著降低肺炎并发症60%-70%。我们的实验和临床工作涉及到以前未知的粘膜免疫缺陷，当肠道没有被肠道喂养刺激或没有提供肠道喂养替代品时，这种缺陷就会发生。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Peyer氏斑免疫致敏的主要解剖部位。黏附分子引导未致敏的免疫细胞通过Peyer‘s斑块，在那里这些淋巴细胞被致敏，并改变它们自己的表面整合素。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，防止细菌附着和感染能力。本研究的重点是营养途径和营养类型如何影响特定的黏附分子、修饰的MAdCAM-1、未修饰的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斑块中起重要作用。该提议验证了一种假设，即这些黏附分子与它们在幼稚T和B细胞上的配体之间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。该提案旨在测试一种假设，即抑制这些相互作用会重建体内粘膜防御系统的缺陷，这些缺陷是在没有提供肠道喂养的情况下诱导的。它还着重于先前的观察，即一种特定的免疫细胞燃料谷氨酰胺和肠道神经系统神经肽蛙皮素可以作为肠内喂养的替代品，并通过上调MAdCAM-1和ICAM-1的表达而对IV-TPN喂养的动物的MALT起到有益的作用。这些实验旨在通过体内实验证实IgA是抵抗肺炎的特异性免疫和呼吸防御的关键要素。这些实验使用的是杂交瘤细胞株产生的针对铜绿假单胞菌临床分离株中高比例的多糖抗原(S)的单抗。

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.