Protein calorie malnutrition (PCM) is a significant world-wide health problem. Primary PCM is prevalent in underdeveloped countries, and secondary PCM can occur in up to 50% of hospitalized patients despite the provision or protein and calories. Impairment of host defenses is associated with neoplasia, advanced age, injury, blood transfusions, administration or immunosuppressive agents and PCM. Importantly, impaired immune function leads to increased susceptibility to infection. Infection and its sequelae also are worldwide health problems which afflict more severely those same populations that suffer from PCM. In hospitalized patients immunocompromised by PCM and other factors, normally controllable infections may escalate to overwhelming sepsis and death. In the USA alone, 500,000 cases of sepsis occur annually with a 35% mortality rate accounting for 175,000 deaths. The overall all Of this proposal is to determine the mechanisms by which PCM mediates immune dysfunction. Because macrophages are pivotal leukocytes that play key roles in both natural and adaptive immune responses, these studies will investigate PCM-induced detects in macrophage functions in two murine models of PCM. Experimental mice will be fed a protein-free diet for seven days or a 2.5% protein (casein) diet for 21 days; control mice either will be ad libitum- or pair-fed a 24% protein diet. Mechanisms of cellular dysfunction will be studied in resident ,peritoneal macrophages by: 1) characterizing defects in bacterial lipopolysaccharide- or interferon-gamma-stimulated afferent signaling pathways by measuring selected, relevant intracellular second messengers, 2) characterizing defects in efferent signaling pathways by assessing cytokine (TNF, IL-1, IL-6) gene transcription, cytokine mRNA levels and turnover, and cytokine secretion, 3) evaluating the role of glucocorticoids and prostanoids as mediators of immunosuppression, 4) studying the immunoenhancing role of supplementary, dietary glutamine, and 5) examining the therapeutic potential of reversing PCM-induced immune dysfunction by in vitro and in vivo administration of granulocyte/macrophage colony-stimulating factor and/or interferon gamma. Results of these studies should provide a biological basis for reversing PCM-induced macrophage dysfunction and reduce the incidence of morbidity and mortality resulting from the increased susceptibility to infection associated with PCM.
