lithium-chloride and Burns

We reported previously that IGF-I inhibits burn-induced muscle proteolysis. Recent studies suggest that activation of the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway with downstream phosphorylation of Forkhead box O transcription factors is an important mechanism of IGF-I-induced anabolic effects in skeletal muscle. The potential roles of other mechanisms in the anabolic effects of IGF-I are less well understood. In this study we tested the roles of mammalian target of rapamycin and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation as well as MAPK- and calcineurin-dependent signaling pathways in the anticatabolic effects of IGF-I by incubating extensor digitorum longus muscles from burned rats in the presence of IGF-I and specific signaling pathway inhibitors. Surprisingly, the PI3K inhibitors LY294002 and wortmannin reduced basal protein breakdown. No additional inhibition by IGF-I was noticed in the presence of LY294002 or wortmannin. Inhibition of proteolysis by IGF-I was associated with phosphorylation (inactivation) of GSK-3beta. In addition, the GSK-3beta inhibitors, lithium chloride and thiadiazolidinone-8, reduced protein breakdown in a similar fashion as IGF-I. Lithium chloride, but not thiadiazolidinone-8, increased the levels of phosphorylated Foxo 1 in incubated muscles from burned rats. Inhibitors of mammalian target of rapamycin, MAPK, and calcineurin did not prevent the IGF-I-induced inhibition of muscle proteolysis. Our results suggest that IGF-I inhibits protein breakdown at least in part through a PI3K/Akt/GSK3beta-dependent mechanism. Additional experiments showed that similar mechanisms were responsible for the effect of IGF-I in muscle from nonburned rats. Taken together with recent reports in the literature, the present results suggest that IGF-I inhibits protein breakdown in skeletal muscle by multiple mechanisms, including PI3K/Akt-mediated inactivation of GSK-3beta and Foxo transcription factors.

Topics: Animals; Burns; DNA-Binding Proteins; Enzyme Activation; Enzyme Inhibitors; Forkhead Transcription Factors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hindlimb; Insulin-Like Growth Factor I; Lithium Chloride; Male; Muscle Proteins; Muscle, Skeletal; Nerve Tissue Proteins; Peptide Hydrolases; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Thiadiazoles; Toes

The effects of postburn serum (PBS) on the production of colony-stimulating factor (CSF) was evaluated in 13 burned patients by adding PBS to normal peripheral blood mononuclear cells (MNC) and assaying the MNC-conditioned media for CSF content. PBS inhibited CSF production by at least 50%. PBS from non-survivors significantly inhibited CSF production more than PBS from survivors. The addition of lithium chloride restored production of CSF in the presence of day 15 PBS but could not overcome the inhibitory effects of day 1 or day 8 PBS. The nature of the inhibitor(s) is uncertain, but correction of the CSF production defect by lithium chloride later in the course of thermal injury suggests that the defect may be reversible.

Topics: Adult; Burns; Chlorides; Colony-Stimulating Factors; Granulocytes; Hematopoiesis; Humans; In Vitro Techniques; Infections; Leukocytes; Lithium; Lithium Chloride; Middle Aged

We used a model of full-thickness burn injury in the mouse and quantitated cell-mediated immunity (CMI) by measuring the degree of sensitization to the contact antigen, 2,4-dinitrofluorobenzene (DNFB). Our previous studies have shown that CMI in the burned mouse is severely suppressed. Using this immunosuppression model, we were able to significantly restore CMI by treating animals following the burn injury either with one of the nonsteroidal anti-inflammatory drugs ibuprofen or indomethacin or with the cytotoxic alkylating agent cyclophosphamide. These drugs probably restore CMI by inhibiting generation of suppressor T lymphocytes in the burned host.

Topics: Animals; Burns; Chlorides; Cimetidine; Cyclophosphamide; Dinitrofluorobenzene; Drug Hypersensitivity; Female; Ibuprofen; Immune Tolerance; Immunity, Cellular; Indomethacin; Lithium; Lithium Chloride; Mice; Mice, Inbred Strains