Patients with severe head injury are hypermetabolic and hypercatabolic. Postulated mechanisms for these metabolic disturbances include increased levels of catecholamines and increased levels of cortisol, glucagon and other regulatory hormones. Interleukin-1 (IL-1) is a monokine which is released from a variety of monocyte/macrophage cells within the body. IL-1 plays a major role in modulation of the immune system and in mediation of several aspects of the acute phase response. The nonimmunologic role of IL-1 is the focus of this grant. IL-1 has been shown to mediate fever, cause synthesis of acute phase reactants, induce neutrophilia, produce muscle breakdown, and cause alterations and redistribution of minerals such as zinc. We recently described marked alterations of zinc metabolism in head trauma patients, which we suggest are mediated by interleukin-1 release. Preliminary data from our laboratory revealed that 8/8 patients with severe head injury had elevated ventricular fluid IL-1 activity; whereas, no control patients undergoing myelograms had detectable cerebral spinal fluid IL-1 activity. Similarly, in 7 other severe head injury patients studied, the mean admission serum IL-1 activity index was significantly increased, and this index decreased toward normal during the course of hospitalization. We propose to measure IL-1 activity in severe head injured patients with or without extracranial trauma. We will determine whether IL-1 activity and/or the additin of multiple trauma correlates with factors such as mineral levels, indicators of muscle catabolism, and suggested mediators of the hypermetabolic/hypercatabolic state such as catecholamines and endorphins. In vitro studies will evaluate the role of various hypermetabolic/hypercatabolic mediators such as epinephrine, norepinephrine and ACTH on release of IL-1 from human monocyte and astrocyte cell lines. Studies in animals will evaluate the effect of IL-1 injection on release of hormones such as ACTH, corticosterone and catecholamines. Lastly, we will determine whether there is detectable proteolysis inducing factor (a cleavage product of IL-1) in the serum of head trauma patients that causes in vitro muscle breakdown. This series of studies will provide initial information concerning the role of interleukin-1 in head injured patients and may provide new insight in the treatments of the altered metabolic state regularly observed in these patients.
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