Ischemia/reperfusion of mesenteric vessels is a useful model for acute vascular insufficiency and the early stages of multiorgan failure, conditions associated with high morbidity and mortality. Epidermal growth factor (EGF) is a potent mitogen that shows potential for use in intestinal injury. We therefore examined its influence on this model. Male Sprague-Dawley rats received human recombinant EGF (2 mg/kg i.p., n = 14) or saline (n = 16); 25 minutes before arterial clamping of the superior mesenteric artery (ischemic period) for 60 minutes followed by a final 60-minute reperfusion period. Additional rats were not operated on (controls, n = 7) or had sham operation (laparotomy only, n = 10). Ischemia/reperfusion caused macroscopic damage affecting 56%, 51 to 67% (median, interquartile range), of small intestinal length and intraluminal bleeding. Malondialdehyde levels (free radical marker) increased eightfold compared to nonoperated animals (2400, 2200 to 2700 micro mol/mg protein versus 290, 250 to 350 micro mol/mg protein, P < 0.01) and myeloperoxidase levels (marker for inflammatory infiltrate) increased 15-fold (3150, 2670 to 4180 U/g tissue versus 240, 190 to 250 U/g tissue, P < 0.01). Pretreatment with EGF reduced macroscopic injury to 11%, 0 to 15%; prevented intraluminal bleeding; and reduced malondialdehyde and myeloperoxidase levels by approximately 60% and 90% (all P < 0.01 versus non-EGF-treated). Mesenteric ischemia/reperfusion also damaged the lungs and kidneys and increased serum tumor necrosis factor-alpha levels (circulating cytokine activity marker). EGF pretreatment also reduced these changes. These studies provide preliminary evidence that EGF is a novel therapy for the early treatment or prevention of intestinal damage and multiorgan failure resulting from mesenteric hypoperfusion.

The rhEGF topical delivery systems have been hindered by a number of shortcomings which have led to the search of new development strategies. In this study we report the evaluation of cumulative profiles of 10, 5 and 1 microg/ml solutions of (125)I-rhEGF, in a rat full-thickness skin wound model, as well as the drug-induced modulation in the expression of the EGF receptor after lesion. The tissue-associated radioactivity, expressed as the percentage of the dose administered per grams of tissue (%D/g), peaks at 2 h after administration of all doses. (125)I-rhEGF degraded species were detected chromatographically, but no diffusion of the peptide to the surrounding skin was documented. Despite the dose, the EGF receptor expression was increased within 2 h after wounding, followed by a slow decline up to 12 h below baseline. Twelve hours after punch, differences were evident between all treated groups and control. These results demonstrate that (125)I-rhEGF saline solutions are rapidly cleared from application sites, probably by protease-driven cleavage and receptor-mediated endocytosis. Finally, we must be aware that the results herein discussed should be taken into account during the drug delivery system design in order to guarantee the necessary steady-state rhEGF levels upon wound healing process.

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Growth factors have proved to be an effective therapeutic strategy. However, some controversies have arisen concerning their efficacy in topical wound treatments. Stabilization of epidermal growth factors at the wound site and long-lasting receptor occupancy are important factors for wound repair. This study evaluated the cumulative profiles of two jellies containing 10 or 20 microg of 125I-rhEGF per gram of jelly, in a rat full-thickness skin lesion model. The prolonged time-courses at the wound sites for both strengths compared with saline solutions previously evaluated using a similar skin lesion model are reported. It seems that these two topical formulations that provide more sustained amounts of 125I-rhEGF over the period of sampling, would probably achieve the required wound healing response in terms of cell proliferation, collagen deposition and protein synthesis. Further studies need to be developed in order to elucidate whether such an in vivo disposition pattern is consistent with an earlier and stronger promotion of wound healing events.