Neutralizing Anti-Vascular Endothelial Growth Factor (VEGF) Antibody Reduces Severity of Experimental Ulcerative Colitis in Rats: Direct Evidence for the Pathogenic Role of VEGF
| Autor: | Xiaoming Deng, Andrzej S. Tarnawski, Amrita Ahluwalia, Sandor Szabo, Longchuan Chen, Ganna Tolstanova, Tetyana Khomenko, Zsuzsanna Sandor |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Vascular Endothelial Growth Factor A
medicine.medical_specialty Pathology Cell Membrane Permeability Colon medicine.medical_treatment Vascular permeability Antibodies Iodoacetamide Rats Sprague-Dawley Pathogenesis chemistry.chemical_compound Neutralization Tests Internal medicine medicine Animals RNA Messenger Colitis Pharmacology biology business.industry Microcirculation Enema medicine.disease Ulcerative colitis Rats Vascular endothelial growth factor Disease Models Animal Endocrinology chemistry biology.protein Molecular Medicine Colitis Ulcerative Female Antibody business |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 328:749-757 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.108.145128 |
| Popis: | In ulcerative colitis (UC), an increased expression of vascular endothelial growth factor (VEGF) correlates with disease activity, but a causal relationship is unknown. We tested the hypothesis that VEGF plays a mechanistic role in the pathogenesis of experimental UC and that VEGF neutralization may exert therapeutic effect. UC was induced in Sprague-Dawley rats by 6% iodoacetamide given intracolonically. Neutralizing anti-VEGF antibody (50 microg/rat), nonspecific IgG, or saline (0.1 ml/rat) was injected intramuscularly on the 3rd and 5th days after iodoacetamide enema. Rats were euthanized on the 7th day. We examined the extent of macroscopic, histologic, and clinical features of colitis and colonic vascular permeability. Colonic VEGF mRNA and protein expressions increased as early as 0.5 h after iodoacetamide enema and remained elevated in the active phase of colitis. Treatment with anti-VEGF antibody markedly improved the clinical and morphologic features of UC. Colonic lesion area was significantly reduced from 370 +/- 140 or 311 +/- 170 mm(2) in saline- or IgG-treated groups to 122 +/- 57 mm(2) in the anti-VEGF-group (p0.05). Increased colonic vascular permeability was decreased by the anti-VEGF antibody (p0.05) and the Src inhibitor PP1 [pyrazolopyrimidine, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine] (p0.01). The number of acute and chronic inflammatory cells in the lesion area was significantly reduced in anti-VEGF-treated rats. In the anti-VEGF-treated group, mucosal levels of VEGF, platelet-derived growth factor, and basic fibroblast growth factor were also reduced.1) Neutralizing anti-VEGF antibody significantly ameliorates experimental UC in rats in part by reducing excessive vascular permeability and decreasing inflammatory cells infiltration; and 2) VEGF seems to mediate increased colonic vascular permeability in experimental UC via the Src-dependent mechanism. |
| Databáze: | OpenAIRE |
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