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. 2001 Jan;48(1):34–40. doi: 10.1136/gut.48.1.34

Epidermal growth factor reduces multiorgan failure induced by thioacetamide

M Caballero 1, J Berlanga 1, D Ramirez 1, P Lopez-Saura 1, R Gozalez 1, D Floyd 1, T Marchbank 1, R Playford 1
PMCID: PMC1728178  PMID: 11115820

Abstract

BACKGROUND—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).
METHODS—Mice (20 per group) were fasted overnight and received a single intraperitoneal dose of human recombinant EGF at 10 or 30 µg/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.
RESULTS—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 µg/kg; p<0.01). All groups showed similar changes in liver histology (centrilobular necrosis) and alanine transaminase levels (10-fold increase).
CONCLUSIONS—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.


Keywords: gastrointestinal damage; nephrotoxicity; liver injury

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Figure 1  .

Figure 1  

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Thioacetamide (TAA) induced small intestinal injury. (A) Twenty four hours after administration of TAA (40 mg/kg) to mice, the normal villus structure of the jejunum and ileum is lost and marked necrosis is seen within the remaining mucosa. (B) Administration of epidermal growth factor (EGF, 30 µg/kg), 30 minutes prior to TAA, markedly preserved small intestinal architecture. Similar preservation was seen when a dose of 10 µg/kg of EGF was used (not shown). Tissues were stained with haematoxylin and eosin. Original magnification ×10. Bar=100 µm.

Figure 2  .

Figure 2  

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Thioacetamide (TAA) induced hepatic injury. TAA treated animals showed marked hepatic injury, mainly centrilobular necrosis with occasional haemorrhagic foci. The histological appearance was similar in all treatment groups. Tissues were stained with haematoxylin and eosin. Original magnification ×20. Bar=50 µm.

Figure 3  .

Figure 3  

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Thioacetamide (TAA) induced renal injury. Tissues were stained with haematoxylin and eosin. The renal tissue of TAA treated animals showed extensive collapse of the glomerular tufts.. Original magnification ×10. (B) Higher power photomicrograph of the same tissue demonstrating that only minor degenerative acute changes in the epithelial cells of the tubular system were seen. Original magnification ×20. Bar=50 µm. (C) Pretreatment with EGF reduced the renal changes caused by TAA. Original magnification ×20. Bar=50 µm.

Figure 4  .

Figure 4  

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Effect of epidermal growth factor (EGF) given 30 minutes after thioacetamide (TAA) on multiple organ systems. EGF reduced luminal bleeding (A), and the reduction in wet weight (B), DNA (C), and protein content (D) of the gut caused by TAA. The rise in plasma creatinine caused by TAA was also reduced by administration of EGF (E) although it did not influence the rise in serum alanine aminotransferase (ALAT) (F). *p<0.05, **p<0.01 compared with animals given TAA alone.

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