Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics.

The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented. Lipids can also be conjugated to a drug molecule, accomplishing numerous potential benefits, one being the improved treatment effect, due to joined influence of the lipid carrier and the drug moiety. In addition, such conjugates have increased lipophilicity relative to the parent drug. This leads to improved drug pharmacokinetics and bioavailability, the ability to join endogenous lipid pathways and achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable overcoming different barriers in the body. Altogether, novel mechanisms of the lipid role in diseases are constantly discovered, and new ways to exploit these mechanisms for the optimal drug design that would advance different drug delivery/therapy aspects are continuously emerging.

Small bowel stricture is associated with abnormal motility on the cine MRI sequence in patients with Crohn's disease.

PURPOSE: A multiphasic cine sequence performed during magnetic resonance enterography (MRE) has been shown to increase diagnostic accuracy of MRE demonstrating limited movement in inflamed intestine in patients with Crohn's disease (CD). Our aim was to confirm in our study population that intestinal inflammation was associated with decreased motility and determine if factors suggestive of complicated disease such as the presence of a stricture or fistula were associated with decreased motility on the MRE cine sequence. METHODS: This was a retrospective study of 59 patients (mean age 40.8 ±â€¯16.1) with Crohn's disease who had a small bowel lesion on MRE. Two gastrointestinal radiologists independently scored MRE findings using a qualitative, subjective scoring system. Univariate and multivariable ordered logistic regression models were used to evaluate the associations between cine sequence score, radiologic image findings, and clinical data. RESULTS: On univariate analysis, radiologic findings reflecting active inflammation, the presence of a stricture, and penetrating disease were associated with decreased motility. On multivariable analysis, hyper-enhancement, the presence of a comb sign, and global evidence of active inflammation remained associated with decreased motility. Of the factors suggesting complicated disease, the presence of stricture (Odds Ratio 0.40, 95% Confidence Interval 0.17-0.95, p-value 0.038) was associated with decreased motility. CONCLUSIONS: As previously shown, well-established radiologic findings of bowel inflammation were associated with decreased small bowel motility. In this study, we have added that the radiologic finding of a fixed stricture is also associated with decreased motility.

Pre-operative total parenteral nutrition improves post-operative outcomes in a subset of Crohn's disease patients undergoing major abdominal surgery.

BACKGROUND: Despite major advances in the medical management of Crohn's disease (CD), a significant proportion of patients will require surgery within 5 years of diagnosis. Malnutrition is an independent risk factor for adverse post-operative outcomes following gastrointestinal surgery. Data on the value of pre-operative total parenteral nutrition (TPN) in CD patients are mixed and there is a paucity of data in the biologic era. We aimed to define the role of pre-operative TPN in this population. METHODS: This was a retrospective cohort study conducted at a tertiary referral center. CD patients who underwent major abdominal surgery were identified. Patients receiving pre-operative TPN were compared to controls. We compared the incidence of 30-day infectious and non-infectious post-operative complications between the two groups. RESULTS: A total of 144 CD patients who underwent major abdominal surgery between March 2007 and March 2017 were included. Fifty-five patients who received pre-operative TPN were compared to 89 controls. Twenty-one (14.6%) patients developed infectious complications (18.2% in TPN group vs 12.3% in non-TPN group, P = 0.34) and 23 (15.9%) developed non-infectious complications (14.5% in TPN group vs 16.9% in non-TPN group, P = 0.71). In a multivariate analysis, controlling for differences in baseline disease severity and malnutrition between groups, patients receiving pre-operative TPN for ≥60 days had significantly lower odds of developing non-infectious complications (odds ratio 0.07, 95% confidence interval: 0.01-0.80, P = 0.03). Weight loss of >10% in the past 6 months was a significant predictor of post-operative complications. CONCLUSIONS: In a subset of malnourished CD patients, TPN is safe and allows comparable operative outcomes to controls. Pre-operative TPN for ≥60 days reduced post-operative non-infectious complications without associated increase in infectious complications.

Real-world Pattern of Biologic Use in Patients With Inflammatory Bowel Disease: Treatment Persistence, Switching, and Importance of Concurrent Immunosuppressive Therapy.

BACKGROUND AND AIMS: Medication persistence, defined as the time from drug initiation to discontinuation of therapy, has been suggested as a proxy for real-world therapeutic benefit and safety. This study seeks to compare the persistence of biologic drugs among patients with inflammatory bowel disease (IBD). METHODS: Patients with newly diagnosed IBD were included in a retrospective study using Truven MarketScan database. Treatment persistence and switching was compared among biologic medications including infliximab, adalimumab, certolizumab, golimumab, and vedolizumab. Predictors for discontinuation and switching were evaluated using time-dependent proportional hazard regression. RESULTS: In total, 5612 patients with Crohn's disease (CD) and 3533 patients with ulcerative colitis (UC) were included in this analysis. Less than half of the patients continued using their initial biologic treatment after 1 year (48.48% in CD cohort; 44.78% in UC cohort). In the first year, adalimumab had the highest persistence and lowest switching rates for both CD (median survival time: 1.04 years) and UC (median survival time: 0.84 years). In subsequent years, infliximab users were more likely to persist in the use of biologic. Combination therapy with immunomodulators significantly decreased the risk of discontinuation, especially when immunomodulator therapy was started more than 30 days before the biologic (hazard ratio [HR], 0.22; CI, 0.16, 0.32). The major predictors for noncompliance included infection and hospitalization. CONCLUSION: Overall, the persistence profiles of biologics suggest a high rate of dissatisfaction or adverse disease outcomes resulting in discontinuation and switching to a different agent. Early initiation of immunomodulators will substantially increase the persistence of biologic treatment.

Lipidic prodrug approach for improved oral drug delivery and therapy.

In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid-drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half-life, selective distribution profile (eg brain penetration), reduced hepatic first-pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s). The different lipid-drug conjugates (triglyceride-, fatty acids, phospholipid-, and steroid-based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed. Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.

Prospects and Challenges of Phospholipid-Based Prodrugs.

Nowadays, the prodrug approach is used already at the early stages of drug development. Lipidic prodrug approach is a growing field for improving a number of drug properties/delivery/therapy aspects, and can offer solutions for various unmet needs. This approach includes drug moiety bound to the lipid carrier, which can be triglyceride, fatty acids, steroid, or phospholipid (PL). The focus of this article is PL-based prodrugs, which includes a PL carrier covalently bound to the active drug moiety. An overview of relevant physiological lipid processing pathways and absorption barriers is provided, followed by drug delivery/therapeutic application of PL-drug conjugates, as well as computational modeling techniques, and a modern bioinformatics tool that can aid in the optimization of PL conjugates. PL-based prodrugs have increased lipophilicity comparing to the parent drug, and can therefore significantly improve the pharmacokinetic profile and overall bioavailability of the parent drug, join the endogenous lipid processing pathways and therefore accomplish drug targeting, e.g., by lymphatic transport, drug release at specific target site(s), or passing the blood-brain barrier. Moreover, an exciting gateway for treating inflammatory diseases and cancer is presented, by utilizing the PL sn-2 position in the prodrug design, aiming for PLA2-mediated activation. Overall, a PL-based prodrug approach shows great potential in improving different drug delivery/therapy aspects, and is expected to grow.

Effects of Preoperative Use of Biologic Agents on Operative Outcomes in Crohn's Disease Patients.

Although the effects of biologic agents on postoperative outcomes in Crohn's disease patients have been extensively studied, the effects on intraoperative outcomes, including blood loss, operative time, and length of small bowel resection, remain to be determined. This was a retrospective cohort study at a single tertiary referral center. Crohn's disease (CD) patients who underwent major abdominal surgery were identified. Patients receiving preoperative biologic agents were compared with controls. We compare operative outcomes between groups. A total of 144 patients who underwent major abdominal surgery at the University of Florida between March 2007 and March 2017 were included. One hundred and ten patients (76%) who received preoperative biologic therapy were compared with 34 controls. On univariate analysis, preoperative biologic use was associated with a significantly shorter length of small bowel resection (21.2 cm in biologic group vs 34.5 cm, P = 0.01). There were no significant differences in intraoperative blood loss (100 vs 87.5 mL, P = 0.40) or total operative time (142 vs 154 minutes, P = 0.39) between groups. On multivariate analysis controlling for variables reflecting severity of disease and malnutrition, biologic use remained significantly associated with shorter length of bowel resection (incident rate ratio 0.58, P = 0.04). Preoperative biologic use is associated with a significantly shorter length of bowel resection in CD patients undergoing major abdominal surgery. No negative effects were noted on operative blood loss or total operative time. Our findings allow improved preoperative planning for surgeons and informed decision-making for CD patients undergoing major abdominal surgery.

Perioperative Care of Patients with Inflammatory Bowel Disease: Focus on Nutritional Support.

Patients with inflammatory bowel disease (IBD) commonly require surgery despite the availability of an increasingly large repertoire of powerful immunosuppressive medications for the treatment of IBD. Optimizing patients' care preoperatively is crucial to obtaining good surgical outcomes. This review discusses preoperative assessment and management principles including assessing disease location and activity with cross-sectional or endoscopic imaging, addressing modifiable risk factors (i.e., stopping smoking, weaning steroids, and correcting anemia), and properly managing medications. The major focus of our literature review is the evaluation for malnutrition, a common finding that affects up to 70% of patients with IBD and a well-known, independent risk factor for adverse postoperative outcomes. Our review confirms that whenever feasible, oral or enteral nutrition (EN) is the preferred method of nutritional support; parenteral nutrition (PN) should be reserved for nutritionally deficient IBD patients unable to tolerate EN. In selected patients, recent data demonstrated that the use of preoperative PN resulted in improved nutritional status, fewer postoperative complications, and reduced disease severity. Our review highlights the need for well-designed, prospective trials investigating perioperative nutritional support in patients with IBD. Future studies should perform modern nutritional assessment, standardize for diet, and include patients with UC since this subset of patients is underrepresented in existing studies. In addition, relevant outcome of interest specific to Crohn's disease (CD) patients such as length of small bowel resected, number of anastomoses, and need for an ostomy should be included as these patients may require repeated small bowel resections.

Consensus Recommendations for Evaluation, Interpretation, and Utilization of Computed Tomography and Magnetic Resonance Enterography in Patients With Small Bowel Crohn's Disease.

Computed tomography and magnetic resonance enterography have become routine small bowel imaging tests to evaluate patients with established or suspected Crohn's disease, but the interpretation and use of these imaging modalities can vary widely. A shared understanding of imaging findings, nomenclature, and utilization will improve the utility of these imaging techniques to guide treatment options, as well as assess for treatment response and complications. Representatives from the Society of Abdominal Radiology Crohn's Disease-Focused Panel, the Society of Pediatric Radiology, the American Gastroenterological Association, and other experts, systematically evaluated evidence for imaging findings associated with small bowel Crohn's disease enteric inflammation and established recommendations for the evaluation, interpretation, and use of computed tomography and magnetic resonance enterography in small bowel Crohn's disease. This work makes recommendations for imaging findings that indicate small bowel Crohn's disease, how inflammatory small bowel Crohn's disease and its complications should be described, elucidates potential extra-enteric findings that may be seen at imaging, and recommends that cross-sectional enterography should be performed at diagnosis of Crohn's disease and considered for small bowel Crohn's disease monitoring paradigms. A useful morphologic construct describing how imaging findings evolve with disease progression and response is described, and standard impressions for radiologic reports that convey meaningful information to gastroenterologists and surgeons are presented.

Consensus Recommendations for Evaluation, Interpretation, and Utilization of Computed Tomography and Magnetic Resonance Enterography in Patients With Small Bowel Crohn's Disease.

Computed tomography and magnetic resonance enterography have become routine small bowel imaging tests to evaluate patients with established or suspected Crohn's disease, but the interpretation and use of these imaging modalities can vary widely. A shared understanding of imaging findings, nomenclature, and utilization will improve the utility of these imaging techniques to guide treatment options, as well as assess for treatment response and complications. Representatives from the Society of Abdominal Radiology Crohn's Disease-Focused Panel, the Society of Pediatric Radiology, the American Gastroenterological Association, and other experts, systematically evaluated evidence for imaging findings associated with small bowel Crohn's disease enteric inflammation and established recommendations for the evaluation, interpretation, and use of computed tomography and magnetic resonance enterography in small bowel Crohn's disease. This work makes recommendations for imaging findings that indicate small bowel Crohn's disease, how inflammatory small bowel Crohn's disease and its complications should be described, elucidates potential extra-enteric findings that may be seen at imaging, and recommends that cross-sectional enterography should be performed at diagnosis of Crohn's disease and considered for small bowel Crohn's disease monitoring paradigms. A useful morphologic construct describing how imaging findings evolve with disease progression and response is described, and standard impressions for radiologic reports that convey meaningful information to gastroenterologists and surgeons are presented. ©2018, RSNA, AGA Institute, and Society of Abdominal Radiology This article is being published jointly in Radiology and Gastroenterology.

Effective communication of cross-sectional imaging findings in Crohn's disease: comparing conventional EMR reporting to a published scoring system.

PURPOSE: The purpose of the article is to compare information regarding small bowel lesions in Crohn's disease (CD) patients communicated by a published scoring system and radiology reports from electronic medical record (EMR) of cross-sectional abdominal imaging. METHODS: Two gastrointestinal radiologists (reference readers) blinded to EMR reports scored cross-sectional imaging exams using a published scoring system. Investigators compared EMR and radiologist scores based on the mentioned findings and severity documentation of each variable. Statistical analysis involved means and difference in proportions and logistic regression modeling. RESULTS: Seventy-three CD patients, with average age 40.6 years (± SD 14.4), having 80 small bowel lesions on imaging were included. EMR reports reliably mentioned within the consensus score included thickness (79%, p = 0.000), enhancement (70%, p = 0.000), active inflammation (86%, p = 0.000), perienteric fluid (82%, p = 0.000), and presence of stricture (62%, p = 0.002). Minimal lumen diameter (19%, p = 0.000), comb sign (19%, p = 0.000), lesion length (57%, p = 0.06), and fistula (50%, p = 1.0) were reported less often. There was a strong association between the EMR and scoring scale in noting severity of active inflammation (88%, p = 0.000), perienteric fluid (76%, p = 0.000), and internal fistula (71%, p = 0.000). The proportion matching severity values of comb sign and minimal lumen were 24% and 21%, respectively (p = 0.000). Severity matches for stricture were less likely among the non-GI radiologists (odds ratio = 0.33, SE = 0.168, p = 0.029). The odds of reporting stricture and fistula severity were 3.6 and 5.7, respectively, on MRE. CONCLUSIONS: Findings and severity of inflammation were communicated consistently. Stricture severity including minimal luminal diameter, was less reliably reported, though its prognostic significance impacts management.

A Fixed Stricture on Routine Cross-sectional Imaging Predicts Disease-Related Complications and Adverse Outcomes in Patients with Crohn's Disease.

BACKGROUND: Patients with Crohn's disease (CD) typically undergo multiple cross-sectional imaging exams including computed tomography and magnetic resonance enterography during the course of their disease. The aim was to identify imaging findings that predict future disease-related poor outcomes. METHODS: This was a retrospective, case control study at a single tertiary center. Cases were CD patients diagnosed with complications (bowel obstruction, perforation, internal fistula, or abscess); controls were CD patients without complications. Two radiologists blinded to clinical outcomes, independently scored cross-sectional imaging examinations obtained before the complication. RESULTS: One hundred eight patients (67 F; 41 M) with CD (51 cases; 57 controls) were included. For the cases, 21 had internal fistulae, 15 had bowel obstructions, 13 had abdominal abscesses, and 2 developed bowel perforations. Patients with complications were more likely to have a fixed small bowel stricture on cross-sectional imaging (P = 0.01). A patient with a stricture and upstream dilatation was 3.4 times more likely to develop a complication in the next 2 years. When present in the setting of hypervascularity and/or evidence of active inflammation, the risk increased further to 15-fold. Cases were more likely to be active smokers (29% versus 12%, P = 0.033). Cases had more evidence of inflammation based on higher Harvey Bradshaw Index values and inflammatory biomarkers and lower hemoglobin values. CONCLUSIONS: Information from radiologic studies, especially the presence of fixed strictures, can predict future CD complications. These findings, along with smoking and ongoing inflammation, should alert the clinician to the possibility of future complications.

Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease.

Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% (P = 0.003), d7 = 57% (P = 0.18), d14 = no change (P = 0.99); histologic inflammation: d1 = 57% (P = 0.006), d7 = 50% (P = 0.019), d14 = no change (P = 0.99)]. This was also reflected in changes in IL-1ß, IL-6, TNF-α, IGF-I, TGF-ß1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.

MR imaging of the small bowel in Crohn disease.

MR enterography has an established role in evaluating patients with Crohn disease providing essential complementary information to clinical assessment, and as an indispensible adjunct to clinical tools such as colonoscopy. MR enterography examinations can establish the diagnosis of Crohn disease, evaluate disease activity and complications, and assess treatment response, thus providing support for clinical decision-making. Currently, MR imaging findings are highly predictive of tissue inflammation and can be used clinically to guide clinical care.

Endothelial PAS domain protein 1 activates the inflammatory response in the intestinal epithelium to promote colitis in mice.

BACKGROUND & AIMS: Hypoxic inflammation (decreased oxygen tension at sites of inflammation) is a feature of inflammatory bowel disease (IBD). The hypoxia response is mediated by the transcription factors hypoxia-inducible factor (HIF) 1α and endothelial PAS domain protein 1 (EPAS1 or HIF2α), which are induced in intestinal tissues of patients with IBD. HIF1α limits intestinal barrier dysfunction, but the role of EPAS1 has not been assessed under conditions of hypoxic inflammation or in models of IBD. METHODS: Acute colitis was induced by administration of Citrobacter rodentium or dextran sulfate sodium (DSS) to transgenic hypoxia reporter mice (oxygen-dependent degradation-luciferase), mice with conditional overexpression of Epas1 (Epas1(LSL/LSL)), mice with intestinal epithelium-specific deletion of Epas1 (Epas1(ΔIE) ), or wild-type littermates (controls). Colon tissues from these mice and from patients with ulcerative colitis or Crohn's disease were assessed by histologic and immunoblot analyses, immunohistochemistry, and quantitative polymerase chain reaction. RESULTS: Levels of hypoxia and EPAS1 were increased in colon tissues of mice after induction of colitis and patients with ulcerative colitis or Crohn's disease compared with controls. Epas1(ΔIE) mice had attenuated colonic inflammation and were protected from DSS-induced colitis. Intestine-specific overexpression of EPAS1, but not HIF-1α, led to spontaneous colitis, increased susceptibility to induction of colitis by C rodentium or DSS, and reduced survival times compared with controls. Disruption of intestinal epithelial EPAS1 attenuated the inflammatory response after administration of DSS or C rodentium, and intestine-specific overexpression of EPAS1 increased this response. We found EPAS1 to be a positive regulator of tumor necrosis factor-α production by the intestinal epithelium. Blocking tumor necrosis factor-α completely reduced hypoxia-induced intestinal inflammation. CONCLUSIONS: EPAS1 is a transcription factor that activates mediators of inflammation, such as tumor necrosis factor-α, in the intestinal epithelium and promotes development of colitis in mice.

Development of a peptidoglycan-polysaccharide murine model of Crohn's disease: effect of genetic background.

The peptidoglycan-polysaccharide (PGPS) model using inbred rats closely mimics Crohn's disease. Our aim was to identify mouse strains that develop ileocolitis in response to bowel wall injection with PGPS. Mouse strains studied included NOD2 knockout animals, RICK/RIP2 knockout animals, and genetically inbred strains that are susceptible to inflammation. Mice underwent laparotomy with intramural injection of PGPS or human serum albumin in the terminal ileum, ileal Peyer's patches, and cecum. Gross abdominal score, cecal histologic score, and levels of pro-fibrotic factor mRNAs were determined 20 to 32 days after laparotomy. PGPS-injected wild-type and knockout mice with mutations in the NOD2 pathway had higher abdominal scores than human serum albumin-injected mice. The RICK knockout animals tended to have higher mean abdominal scores than the NOD2 knockout animals, but the differences were not significant. CBA/J mice were shown to have the most robust response to PGPS, demonstrating consistently higher abdominal scores than other strains. Animals killed on day 26 had an average gross abdominal score of 6.1 ± 1.5, compared with those on day 20 (3.0 ± 0.0) or day 32 (2.8 ± 0.9). PGPS-injected CBA/J mice studied 26 days after laparotomy developed the most robust inflammation and most closely mimicked the PGPS rat model and human Crohn's disease.

Crohn's disease complicated by strictures: a systematic review.

The occurrence of strictures as a complication of Crohn's disease is a significant clinical problem. No specific antifibrotic therapies are available. This systematic review comprehensively addresses the pathogenesis, epidemiology, prediction, diagnosis and therapy of this disease complication. We also provide specific recommendations for clinical practice and summarise areas that require future investigation.

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

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-1ß: 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 ß1 (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.