Pretreatment with anti-VEGF therapy may exacerbate inflammation in experimental acute colitis.
OBJECTIVE
Our previous investigations of angiogenesis in inflammatory bowel disease showed that vascular endothelial growth factor (VEGF) blockade reduced colonic neovascularization and inflammation. We hypothesized that pretreatment with bevacizumab, a monoclonal anti-VEGF antibody, would attenuate the severity of angiogenesis and inflammation in a murine model of colitis.


METHODS
C57BL/6 mice were treated with intraperitoneal injections of bevacizumab (250 μg/dose) before induction of colitis with dextran sulfate sodium (DSS). The colons were examined at predetermined time points. Colonic inflammation and microvessel density were assessed microscopically.


RESULTS
All mice acutely developed melena and weight loss (18.8% ± 1.1% control vs 20.2% ± 1.1% treated, P = .37) and regained a similar weight percentage after the recovery (26.5% ± 4.0% vs 20.9% ± 4.4%, P = .37). Microvessel density acutely increased in both groups in response to DSS, with a trend toward inhibited angiogenesis in the treated group at the conclusion of the acute phase (194,100 ± 14,240 vs 149,400 ± 17,590 μm(2), P = .11). Bevacizumab-treated mice exhibited significantly increased inflammation after the acute phase (8.3 ± 0.8 vs 13.0 ± 2.0, P = .05), but were similar to control after the recovery (7.3 ± 1.5 vs 5.5 ± 1.0, P = .27).


CONCLUSIONS
Preemptive VEGF inhibition does not significantly attenuate angiogenesis and, in fact, worsens inflammation in a model of acute colitis. Preventive VEGF blockade may disrupt healing and exacerbate injury via alternative angiogenic or inflammatory pathways.
Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Artur
A
Chernoguz
Kelly
K
Crawford
Abbey
A
Vandersall
Marepalli
M
Rao
Tara
T
Willson
Lee A
LA
Denson
Jason S
JS
Frischer
D000208:Acute Disease; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D000068258:Bevacizumab; D003092:Colitis / Q000139:chemically induced* / Q000150:complications; D016264:Dextran Sulfate / Q000633:toxicity; D018450:Disease Progression; D007249:Inflammation; D008551:Melena / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control; D011292:Premedication / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D015431:Weight Loss
D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000068258:Bevacizumab; D016264:Dextran Sulfate