epidermal-growth-factor and Multiple-Organ-Failure

Novel therapies for the treatment of MOF (multiple organ failure) are required. In the present study, we examined the effect of synthetic GHRP-6 (growth hormone-releasing peptide-6) on cell migration and proliferation using rat intestinal epithelial (IEC-6) and human colonic cancer (HT29) cells as in vitro models of injury. In addition, we examined its efficacy when given alone and in combination with the potent protective factor EGF (epidermal growth factor) in an in vivo model of MOF (using two hepatic vessel ischaemia/reperfusion protocols; 45 min of ischaemia and 45 min of reperfusion or 90 min of ischaemia and 120 min of reperfusion). In vitro studies showed that GHRP-6 directly influenced gut epithelial function as its addition caused a 3-fold increase in the rate of cell migration of IEC-6 and HT29 cells (P<0.01), but did not increase proliferation ([3H]thymidine incorporation). In vivo studies showed that, compared with baseline values, ischaemia/reperfusion caused marked hepatic and intestinal damage (histological scoring), neutrophilic infiltration (myeloperoxidase assay; 5-fold increase) and lipid peroxidation (malondialdehyde assay; 4-fold increase). Pre-treatment with GHRP-6 (120 microg/kg of body weight, intraperitoneally) alone truncated these effects by 50-85% (all P<0.05) and an additional benefit was seen when GHRP-6 was used in combination with EGF (1 mg/kg of body weight, intraperitoneally). Lung and renal injuries were also reduced by these pre-treatments. In conclusion, administration of GHRP-6, given alone or in combination with EGF to enhance its effects, may provide a novel simple approach for the prevention and treatment of MOF and other injuries of the gastrointestinal tract. In view of these findings, further studies appear justified.

Topics: Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Epidermal Growth Factor; Growth Hormone-Releasing Hormone; Humans; Intestinal Mucosa; Lipid Peroxidation; Male; Multiple Organ Failure; Neutrophil Infiltration; Oligopeptides; Rats; Rats, Wistar; Recombinant Proteins; Reperfusion Injury; Tumor Cells, Cultured

Major burns are associated with multiple internal organ damages, including necrosis of the gastrointestinal mucosa. Failure of the intestinal barrier is a serious complication in burned patients. Epidermal growth factor (EGF) is a mitogenic polypeptide that stimulates wound repair and affords protection to the gastric mucosa. We examined whether a single systemic intervention with EGF prevents organ systems damages, following full-thickness scalds (25-30%) in rodents. Animals were randomly assigned to receive an intraperitoneal injection of EGF (30 microg/kg in mice, 10 microg/kg in rats) or saline solution, 30 min prior thermal injury in mice or after the cutaneous injury in rats. General clinical condition and mortality during 24h were recorded. Animals were autopsied and histopathological and histomorphometric studies were conducted. Mice treated with EGF exhibited a milder clinical evolution and acute lethality was significantly reduced as compared to saline counterparts (P<0.01). Histopathological and morphometric analysis showed that EGF significantly reduced intestinal necrosis and contributed to preserve jejunoileal architecture in mice (P<0.05) and rats (P<0.01). The onset of renal hemorrhagic foci was significantly reduced in EGF-treated groups (P<0.01). Lung damages appeared attenuated in EGF-treated animals. These data indicate the salutary effects of EGF by attenuating internal complications associated to thermal injuries. Further studies are warranted to fully elucidate the usefulness of this therapy.

Topics: Animals; Burns; Digestive System; Disease Models, Animal; Epidermal Growth Factor; Injections, Intraperitoneal; Male; Mice; Mice, Inbred BALB C; Multiple Organ Failure; Random Allocation; Rats; Rats, Sprague-Dawley; Time Factors; Trauma Severity Indices

Multiorgan failure is a severe life threatening state where present therapeutic approaches are suboptimal. Epidermal growth factor (EGF) is a potent stimulant of repair in in vitro and in vivo models. We therefore examined its potential beneficial effect in reducing mortality and injury induced by the noxious agent thioacetamide (TAA).. Mice (20 per group) were fasted overnight and received a single intraperitoneal dose of human recombinant EGF at 10 or 30 microg/kg or saline (control). Either 30 minutes before or after EGF, all animals also received TAA (40 mg/kg intraperitoneally). Twenty four hours later, surviving animals were killed, tissues collected, and degree of organ injury assessed.. Fifty per cent (10/20) of control animals died within the first 24 hour period. Mortality was almost completely prevented by the higher dose of EGF whether given before or after TAA (p<0.01) and was reduced by about 50% with the lower dose of EGF. In control animals, the entire length of the jejunum and ileum had necrosis with or without mucosal denudation. In contrast, necrosis affected only about 10-20% of the total length in EGF treated groups (both p<0.01 v control). Control animals showed marked glomerular tuft collapse, interstitial haemorrhage, and increased plasma creatinine levels. These effects were significantly reduced in animals given EGF (30 microg/kg; p<0.01). All groups showed similar changes in liver histology (centrilobular necrosis) and alanine transaminase levels (10-fold increase).. Although EGF did not prevent the hepatotoxicity associated with TAA, it reduced mortality, renal injury, and gastrointestinal damage. These studies provide preliminary evidence that EGF may be a novel approach for the prevention and/or treatment of multiorgan failure.

Topics: Animals; Disease Models, Animal; Epidermal Growth Factor; Intestinal Mucosa; Intestine, Small; Kidney; Liver; Male; Mice; Multiple Organ Failure; Random Allocation; Recombinant Proteins; Statistics, Nonparametric; Thioacetamide