Anti-tumor necrosis factor α prevents bowel fibrosis assessed by messenger RNA, histology, and magnetization transfer MRI in rats with Crohn's disease.

Abstract

OBJECTIVE:

Treatment of Crohn's disease (CD) with anti-tumor necrosis factor α (TNFα) decreases intestinal inflammation, but the effect on fibrosis remains unclear. We hypothesized that treatment with rat-specific anti-TNFα will decrease the development of intestinal fibrosis in a rat model of CD. We further hypothesized that magnetization transfer magnetic resonance imaging (MT-MRI) will be sensitive in detecting these differences in collagen content.

METHODS:

Rats were injected in the distal ileum and cecum with peptidoglycan-polysaccharide (PG-PS) or human serum albumin (control) at laparotomy and then received intraperitoneal injections of rat-specific anti-TNFα or vehicle daily for 21 days after laparotomy. Rats underwent MT-MRI abdominal imaging on day 19 or 20. MT ratio was calculated in the cecal wall. Cecal tissue histologic inflammation was scored. Cecal tissue procollagen, cytokine, and growth factor messenger RNAs were measured by quantitative real-time PCR.

RESULTS:

PG-PS-injected rats treated with anti-TNFα had less histologic inflammation, and cecal tissue expressed lower levels of proinflammatory cytokine messenger RNAs than vehicle-treated PG-PS-injected rats (IL-1β: 5.59 ± 1.53 versus 10.41 ± 1.78, P = 0.02; IL-6: 23.23 ± 9.33 versus 45.89 ± 11.79, P = 0.07). PG-PS-injected rats treated with anti-TNFα developed less intestinal fibrosis than vehicle-treated PG-PS-injected rats by tissue procollagen I (2.87 ± 0.66 versus 9.28 ± 1.11; P = 0.00002), procollagen III (2.25 ± 0.35 versus 7.28 ± 0.76; P = 0.0000009), and MT-MRI (MT ratio: 17.79 ± 1.61 versus 27.95 ± 1.75; P = 0.0001). Insulin-like growth factor I (2.52 ± 0.44 versus 5.14 ± 0.60; P = 0.0007) and transforming growth factor β1 (2.34 ± 0.29 versus 3.45 ± 0.29; P = 0.006) were also decreased in anti-TNFα-treated PG-PS-injected rats.

CONCLUSIONS:

Anti-TNFα prevents the development of bowel wall inflammation and fibrosis in the PG-PS rat model of CD. MT-MRI measurably demonstrates this decrease in intestinal fibrosis.

• Authors: Jeremy Adler, Kinan Rahal, Scott D Swanson, Phyllissa Schmiedlin-Ren, Ahren C Rittershaus, Laura J Reingold, Josh S Brudi, David Shealy, Ann Cai, Barbara J McKenna, Ellen M Zimmermann
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) 2013 Mar-Apr Vol. 19 Issue 4 Pg. 683-90 ISSN: 1536-4844 [Electronic] England
• PMID: 23429466 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Peptidoglycan
• Procollagen
• RNA, Messenger
• Serum Albumin
• Tumor Necrosis Factor-alpha
• Insulin-Like Growth Factor I

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Colitis (chemically induced, pathology, prevention & control)
• Crohn Disease (chemically induced, pathology, prevention & control)
• Cytokines (genetics)
• Disease Models, Animal
• Female
• Fibrosis (chemically induced, pathology, prevention & control)
• Humans
• Inflammation (chemically induced, pathology, prevention & control)
• Insulin-Like Growth Factor I (genetics)
• Intestinal Diseases (chemically induced, pathology, prevention & control)
• Magnetic Resonance Imaging
• Magnetics
• Peptidoglycan (toxicity)
• Procollagen (genetics)
• RNA, Messenger (genetics)
• Rats
• Rats, Inbred Lew
• Real-Time Polymerase Chain Reaction
• Serum Albumin (toxicity)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)