The long term objectives of this application are to improve host defense in critically ill surgical patients as a means for preventing or attenuating the deleterious consequences of infection during intravenous feeding (TPN). TPN is immunosuppressive and predisposes to hospital acquired infection by unclear mechanisms. Infection in TPN-fed patients results in an altered neuroendocrine and catabolic response which may contribute to multiple organ failure and increased mortality during surgical critical illness. The roles that the macrophage (Mphi) sympathetic and hypothalamic- pituitary-adrenal axis play in mediating these pathophysiologic events during TPN are incompletely understood. Studies are proposed to investigate the hypothesis that TPN activates the sympathoadrenal, sympathetic nervous and hypothalamic pituitary -adrenal axis play in mediating these pathophysiologic events during TPN are incompletely understood. Studies are proposed to investigate the hypothesis that TPN activates the sympathoadrenal, sympathetic nervous and hypothalamic pituitary adrenal axis and impairs Mphi function. Mphis will be isolated from the mesenteric lymph nodes, peritoneal cavity, lung, and spleen and their function studied. Mphi functions to be studied include: 1) ability to kill bacteria, 2) production of superoxide anion; and 3) basal and lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor (TNF), Prostaglandin E2 (PGE2), and procoagulant activity (PCA). Immunohistochemistry will be used to count the number of Mphis in the gut wall. Quantitative northern assays of Mphi TNF and PCA mRNA will be performed on unsolicited mphis from the peritoneal cavity, lung, spleen and mesenteric lymph nodes and used as an indirect marker of Mphi activation and exposure to LPS. Mphi fatty acid composition will be measured and correlated with specific functions and alterations in cytokine responses to LPS. Mesenteric lymph nodes will be cultured for bacteria. Sympathoadrenal and sympathetic nervous activity will be assessed by measuring urinary catecholamine excretion and tissue norepinephrine content and turnover respectively. Activation of the hypothalamic-pituitary- adrenal axis will be indirectly assessed by measuring serum corticosterone. Mphi functions and bacterial translocation to mesenteric lymph nodes will be correlated with plasma corticosterone, urinary catecholamine excretion, tissue norepinephrine content and tissue norepinephrine turnover. Studies will investigate several mechanisms of TPN-induced stress a d macrophage dysfunction and include: oral antibiotic gut decontamination, intravenous polymixin B, partial duodenal nutrition, ingestion of a non digestible non-nutritious meal, chewing on a metal spoon, and anatomic sympathectomy. It is hypothesized that all of these interventions will improve Mphi function decrease bacterial translocation to MLN, and attenuate sympathetic, sympathoadrenal, and hypothalamic-pituitary adrenal activation during TPN. Fundamental knowledge of the physiologic effects of TPN on Mphi function and the neuroendocrine system are potentially useful in the development of therapies for the prevention of sepsis and multiple organ failure in TPN-fed critically ill surgical patients.
| Babcock, Tricia A; Helton, W Scott; Hong, David et al. (2002) Omega-3 fatty acid lipid emulsion reduces LPS-stimulated macrophage TNF-alpha production. Surg Infect (Larchmt) 3:145-9 |
| Johnson, K M; Garcia, R M; Heitkemper, M et al. (1995) Polymyxin B prevents increased sympathetic activity and alveolar macrophage tumor necrosis factor release in parenterally fed rats. Arch Surg 130:1294-9;discussion 1299-300 |
