Although thermal injury is known to induce a profound depression in the inflammatory and immune systems, the effects on macrophage function are poorly understood. Preliminary studies in our laboratory have demonstrated thermal injury-induced suppression of two important functional characteristics of murine inflammatory peritoneal macrophages, tumor necrosis factor alpha (TNFalpha) production and tumoricidal capacity. In parallel, macrophages from injured animals produce more prostaglandin E2 (PGE2) than do macrophages from sham-treated mice. PGE2 serves as an autocrine signal limiting expression of several effector functions of macrophages, including TNFalpha production and tumoricidal capacity. Thus, it is hypothesized that the suppression of macrophage function occurring upon thermal injury is due to hyperproduction of PGE2. The studies proposed in this investigation will further characterize the effect of thermal injury on these effector functions as well as production of interleukin-1 beta and reactive oxygen intermediates, and expression of class II histocompatibility antigens. These effector functions are not usually expressed by inflammatory macrophages, but must be induced by specific signals such as bacterial lipopolysaccharide (LPS) and gamma interferon (IFNgamma). The ability of macrophages to acquire these effector functions following thermal injury will be assessed, and compared with the pattern of PGE2 production to identify alterations in the normal autocrine regulatory pathways. Any causal relationship between hyperproduction of PGE2 and suppression of macrophage function will be examined with the use of nonsteroidal anti-inflammatory drugs (NSAID), which block PGE2 synthesis. In additional, whether thermal injury induces production of transforming growth factor beta (TGFbeta) will be addressed. TGFbeta is necessary for wound healing, and also has profound inhibitory effects on the immune system in general and the macrophage in particular. Thus, the involvement of TGFbeta in the suppression of macrophage function will also studied. Finally, to identify mechanisms responsible for suppressed macrophage function, the effect of thermal injury on signal transduction and early nature of the suppression of macrophage function following thermal injury is an essential first step towards the rational design of pharmacologic intervention protocols in thermally injured patients.
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| Schwacha, M G; Somers, S D (1998) Thermal injury-induced immunosuppression in mice: the role of macrophage-derived reactive nitrogen intermediates. J Leukoc Biol 63:51-8 |
| Schwacha, M G; Somers, S D (1998) Thermal injury induces macrophage hyperactivity through pertussis toxin-sensitive and -insensitive pathways. Shock 9:249-55 |
