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the acute-phase response. When the acute-phase response is mild, functional capacity is suppressed; when severe, prostration and death can occur.

These changes are mediated by a flood of polypeptide molecules, the inflammatory cytokines, which are released into the circulation by lymphocytes, monocytes, macrophages, and endothelial cells and are produced locally in tissues by resident macrophages and several other types of parenchymal cells. Among the most important of the cytokines released during inflammatory stress are interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ), and several cytokines with intrinsic anti-inflammatory activity, including IL-1 receptor antagonist (IL-1ra), transforming growth factor-β, and soluble TNF receptor (Dinarello, 1994; Dinarello and Wolff, 1993). Cytokines are highly synergistic, and highly potent (Figure 18-1).

Are cytokine responses helpful to survival? That is certainly the case in experimental sepsis in animals where the cytokine effects can be neutralized early in infection. In humans, preliminary studies of extremely sick septic patients showed improved survival after blockade of IL-1 (with IL-1ra) (Fisher et al., 1994b), but in a larger study with patients of varying severity of sepsis, there was no benefit overall (Fisher et al., 1994a). However, subgroup analysis of the larger study suggests that IL-1ra may have been of benefit in a subgroup of the most severely sick individuals (Fisher et al., 1994a). The possible usefulness of the TNF component of response has been reviewed (van der Poll and Lowry, 1995).

Many neuroendocrine functions are profoundly altered during states of inflammatory disease (Reichlin, 1993, 1994, 1995; Sternberg, 1992; Wilder, 1995) (Table 18-1). Some have positive homeostatic value, while others may contribute to the deleterious impact of inflammation. This chapter focuses on changes in the pituitary and in pituitary target hormones; abnormalities in the pancreas, bone, and brain (all of which occur in sepsis or after exposure to inflammatory cytokines) are not considered further. Many of the endocrine responses observed in inflammation are due in part to the associated decrease in nutrient consumption. These are pointed out in sections below.

Hypothalamic-Pituitary-Adrenal Activation

The classical pituitary-adrenal response to stress can be induced by infection or by the injection of bacterial toxin (Kimball et al., 1968; Michie et al., 1990) (Figures 18-1, 18-2). Lipopolysaccharides (LPS) (and other toxins) act on pituitary-adrenal function by stimulating cytokine release. IL-1, IL-2, IL-6, and TNF-α are all capable of activating corticotropin-releasing hormone (CRH) secretion (Kakuscska et al., 1993; Sapolsky et al., 1987). Systemic LPS is also capable of activating central IL-1 neuronal pathways (Breder et al., 1988; Lechan et al., 1990). Toxin-induced cytokine release stimulates secretion of the hypothalamic neuropeptides, CRH, and vasopressin (VP), which synergize at



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