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Anti–Tumor Necrosis Factor α Prevents Bowel Fibrosis Assessed by Messenger RNA, Histology, and Magnetization Transfer MRI in Rats With Crohn's Disease

Adler, Jeremy MD, MSc*; Rahal, Kinan MD; Swanson, Scott D. PhD; Schmiedlin-Ren, Phyllissa MD; Rittershaus, Ahren C. MD§; Reingold, Laura J.; Brudi, Josh S. BS; Shealy, David PhD; Cai, Ann MS, MD; McKenna, Barbara J. MD§; Zimmermann, Ellen M. MD

doi: 10.1097/MIB.0b013e3182802c32
Original Basic Science Articles

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.

Article first published online 20 February 2013

*Division of Gastroenterology, Department of Pediatrics and Communicable Diseases

Division of Gastroenterology, Department of Internal Medicine

Department of Radiology

§Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan

Immunology Discovery Research, Janssen Research & Development, Radnor, Pennsylvania. K. Rahal is now with the Division of Gastroenterology, Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.

Reprints: Jeremy Adler, MSc, MD, University of Michigan, Department of Pediatrics and Communicable Diseases, Division of Pediatric Gastroenterology, Room A520 MSRB-I/SPC 5658, 1150 W. Medical Center Drive, Ann Arbor, MI 48109 (e-mail: jeradler@umich.edu).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Supported by grants from the National Institutes of Health (1RO1DK073992 to E.M.Z. and 5K12HD02882017 to J.A.). Janssen Research & Development provided material support in the form of rat-specific CNTO1081 drug. They also performed the blood drug level assay for CNTO1081 on animals. They provided no financial support.

Drs. Shealy and Cai are employees of Janssen Research & Development.

J. Adler and K. Rahal contributed equally to the studies.

The authors have no conflicts of interest to disclose.

Received July 03, 2012

Accepted July 17, 2012

© Crohn's & Colitis Foundation of America, Inc.
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