Prophylactic Use of Epidermal Growth Factor Reduces Ischemia/Reperfusion Intestinal Damage

Abstract

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.

Blockade of the EGF Receptor Induces a Deranged Chemokine Expression in Keratinocytes Leading to Enhanced Skin Inflammation

“…27,28 In different animal models, EGFR activation accelerates epithelial cell regeneration while it dampens inflammation following mechanical, chemical, or ischemic tissue damage. 29,30 However, the specific impact of EGFR activation state on immune/inflammatory reactions has received very limited attention. Chronic T cell-mediated skin diseases share the common feature of increased epidermal thickness due to epidermal hyperplasia.…”

Epidermal Growth Factor Enemas with Oral Mesalamine for Mild-to-Moderate Left-Sided Ulcerative Colitis or Proctitis

“…It is a potent stimulant of cell migration (restitution) and cell proliferation, 10,20 both of which are important in reestablishing epithelial continuity. 5 EGF also reduces injury and stimulates repair in animal models of gastric, small intestinal, and colonic injury, 9,20,[23][24][25] although the exact mechanisms of this effect remain unclear. In our patients, it is likely that EGF facilitated the reformation of the epithelial barrier, and this in turn reduced the secondary inflammatory response to luminal antigens.…”

Ghrelin attenuates intestinal ischemia/reperfusion injury in mice by activating the mTOR signaling pathway

“…Acute intestinal ischemia is a serious abdominal emergency which is commonly observed in patients affected by trauma, burns and shock, as well as in those undergoing cardiovascular surgery and organ transplantation, resulting in a mortality rate as high as 60 to 80% (1)(2)(3). Transient ischemia results in biological and chemical changes which lead to intestinal mucosal damage and barrier dysfunction (4).…”