Insulin-like growth factor I in combination with insulin-like growth factor binding protein 3 affects the hepatic acute phase response and hepatic morphology in thermally injured rats.

Abstract

To modulate the hepatic acute phase response after a thermal injury by the administration of insulin-like growth factor I (IGF-I) in combination with its principal binding protein 3 (IGFBP-3). The hepatic acute phase response is a cascade of events initiated to restore homeostasis after trauma; however, a prolonged response contributes to multiorgan failure, hypermetabolism, complications, and death. Although IGF-1 has been shown to improve cell recovery and play a major role in liver regeneration, its effect on the hepatic acute phase response is not known. Sprague-Dawley rats (56 males) received a 60% total body surface area third-degree scald burn and were randomly divided to receive either rhIGF-I/BP-3 (10 mg/kg/day given subcutaneously) or saline (control). Rats were killed on postburn days 1, 2, 5, and 7 and serum glucose, electrolytes, acute phase reactant proteins, tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and rat and human serum IGF-I and IGFBP-3 were measured. Hepatic protein concentrations, hepatocyte proliferation, and hepatocyte apoptosis were determined. No hypoglycemia or electrolyte imbalance could be shown in rats receiving the growth factor complex compared with saline. rhIGF-I/BP-3 increased serum protein on postburn days 2 and 7, albumin on days 5 and 7, and transferrin on days 1, 5, and 7, and decreased haptoglobin and alpha1-acid glycoprotein on postburn days 5 and 7 compared with controls. IGF-I/ BP-3 had no effect on type II acute phase proteins. Rats receiving IGF-I/BP-3 had lower serum levels of interleukin 1 beta and tumor necrosis factor alpha on the first day after burn compared with controls, whereas serum levels of interleukin 6 did not change. rhIGF-I/BP-3 significantly increased total liver protein content on postburn days 1, 2, 5, and 7 compared with controls. IGF-I/BP-3 increased hepatocyte proliferation and decreased hepatocyte apoptosis versus controls. In combination with its principal binding protein, rhIGF-I decreases the proinflammatory cytokines interleukin 1 beta and tumor necrosis factor alpha, followed by a decrease in type I acute phase proteins. IGF-I/BP-3 had no effect on interleukin 6 and type II acute phase proteins. Decreases in acute phase protein and proinflammatory cytokine synthesis were associated with increases in constitutive hepatic proteins, total liver protein content, and hepatocyte proliferation. IGF-I/BP-3 attenuates the hypermetabolic response after thermal injury and may improve the clinical outcome.