Inexpensive therapies which reduce septic complications of critically ill patients could greatly impact the $5-10 billion spent annually in the U.S. on these complications. Enteral feeding significantly reduces the complication of pneumonia compared with intravenous (IV-TPN) feeding through unknown defense mechanisms. Data from our laboratory demonstrates that IV-TPN or an elemental diet (ED) impairs mucosal immunity through atrophy of the gut-associated lymphoid tissue (GALT) in the mouse and reduction of IgA, the major effector arm of mucosal immunity. IgA-dependent antiviral defenses in the respiratory tract are maintained with any form of enteral feeding but deteriorate with IV feeding. This proposal focuses on the effect of route and type of nutrient administration, of gut-specific nutrients (arginine and glutamine), and various neuropeptides on IgA-mediated defenses in the GI and the respiratory tract. Following dietary manipulation with GALT-depleting (IV or ED) or GALT-maintaining diets (chow or complex enteral diet), immunized mice will be challenged in models of viral (PR8) or bacterial (Ps. aeruginosa and St. pneumoniae) pneumonia models. Immune animals with normal GALT systems avoid fatal pneumonitis while nonimmune or immunoincompetent die. Their hypothesis is that a diet-induced atrophy of the GALT impairs the ability of the respiratory tract to withstand a severe infectious challenge through depressed extraintestinal mucosal defenses after dietary, neuropeptide or specialty nutrient manipulation. GALT cells will be analyzed for changes in cytokine production or message of IgA stimulating (IL-4, IL-5, IL-6, and TGF-beta) and IgA-inhibiting (IFN and TNF-beta) cytokines.
The specific aims are to: investigate factors influencing mucosal defenses; define permutations in defenses after nutrient and neuropeptide manipulations; and to challenge these manipulated defenses with clinically applicable in vivo infectious agents. The main hypothesis is that dietary manipulations which impair the GALT also impairs normal mucosal defenses and that dietary, neuropeptide, or specialty nutrient manipulations which normalize GALT also normalize IgA-mediated mucosal defense and the GALT cytokine milieu.
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