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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 ± 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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

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.

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., (Copyright © 2018 AGA Institute, RSNA, and Society of Abdominal Radiology. Published by Elsevier Inc. All rights reserved.)

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 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-1β, IL-6, TNF-α, IGF-I, TGF-β1, 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., (Copyright © 2016 the American Physiological Society.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.

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.

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.

Purpose of Review: Imaging the gut provides information on Crohn's disease activity, identifies complications and provides insight into patient symptoms. Imaging can help direct therapy and can predict important patient outcomes. In a rapidly changing, technology-driven field, new imaging applications add novel insights that we are only beginning to appreciate. The purpose of this review is to highlight recent advances in imaging as they are applied to the assessment of patients with Crohn's disease., Recent Findings: In the past year, key literature describing cross-sectional imaging techniques, including computed tomography (CT) based imaging, specifically CT enterography (CTE) and magnetic resonance enterography (MRE), transcutaneous ultrasound, and PET-based imaging, has emerged in the field of inflammatory bowel disease. MRI sequences that have been recently applied to Crohn's disease assessment, including diffusion-weighted imaging (DWI) and magnetization transfer imaging (MTI), add important new insights. These new data highlight the current status of available imaging modalities and provide a glimpse into the future of our practice., Summary: CTE and MRE are our new standard imaging modalities for small bowel Crohn's disease. PET scanning is promising but currently only used routinely in centers with a strong research presence in this area. Ultrasound is emerging as a useful, potentially less costly, radiation-free technique. New MRI sequences offer future promise for effectively monitoring the natural history of Crohn's disease.

Background: It has become commonplace to categorize small intestinal Crohn's disease (CD) as "active" vs. "inactive" or "inflammatory" vs. "fibrotic" based on computed tomography enterography (CTE) findings. Data on histologic correlates of CTE findings are lacking. We aimed to compare CTE findings with histology from surgically resected specimens. We tested the hypothesis that CTE findings can distinguish tissue inflammation from fibrosis., Methods: Patients who underwent CTE within 3 months before intestinal resection for CD were retrospectively studied. Radiologists blinded to history and histology scored findings on CTE. Pathologists blinded to history and imaging scored resected histology. We compared histology with CTE findings and radiologists assessment of whether the stricture was likely "active" or "inactive.", Results: In all, 22 patients met inclusion criteria. Inflammatory CTE findings correlated with histologic inflammation (rho = 0.52). Strictures believed to be "active" on CTE were more inflamed at histology (P = 0.0002). Strictures lacking inflammatory findings on CTE or considered "inactive" were not associated with greater histologic fibrosis or significant histologic inflammation. Upstream dilation was associated with greater tissue fibrosis in univariate (P = 0.014) but not in multivariate analysis (P = 0.53). Overall, histologic fibrosis correlated best with histologic inflammation (rho = 0.52). Strictures on CTE with the most active disease activity also had the most fibrosis on histology., Conclusions: CTE findings of mesenteric hypervascularity, mucosal hyperenhancement, and mesenteric fat stranding predict tissue inflammation. However, small bowel stricture without CTE findings of inflammation does not predict the presence of tissue fibrosis. Therefore, caution should be used when using CTE criteria to predict the presence of scar tissue., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background: Resveratrol has antiinflammatory and antifibrotic effects. Resveratrol decreases proliferation and collagen synthesis by intestinal smooth muscle cells. We hypothesized that resveratrol would decrease inflammation and fibrosis in an animal model of Crohn's disease., Methods: Peptidoglycan-polysaccharide (PG-PS) or human serum albumin (HSA) was injected into the bowel wall of Lewis rats at laparotomy. Resveratrol or vehicle was administered daily by gavage 1-27 days postinjection. On day 28, gross abdominal and histologic findings were scored. Cecal collagen content was measured by colorimetric analysis of digital images of trichrome-stained sections. Cecal levels of procollagen, cytokine, and growth factor mRNAs were determined., Results: PG-PS-injected rats (vehicle-treated) developed more fibrosis than HSA-injected rats by all measurements: gross abdominal score (P < 0.001), cecal collagen content (P = 0.04), and procollagen I and III mRNAs (P ≤ 0.0007). PG-PS-injected rats treated with 40 mg/kg resveratrol showed a trend toward decreased gross abdominal score, inflammatory cytokine mRNAs, and procollagen mRNAs. PG-PS-injected rats treated with 100 mg/kg resveratrol had lower inflammatory cytokine mRNAs (IL-1β [3.50 ± 1.08 vs. 10.79 ± 1.88, P = 0.005], IL-6 [17.11 ± 9.22 vs. 45.64 ± 8.83, P = 0.03], tumor necrosis factor alpha (TNF-α) [0.80 ± 0.14 vs. 1.89 ± 0.22, P = 0.002]), transforming growth factor beta 1 (TGF-β1) mRNA (2.24 ± 0.37 vs. 4.06 ± 0.58, P = 0.01), and histologic fibrosis score (6.4 ± 1.1 vs. 9.8 ± 1.0; P = 0.035) than those treated with vehicle. There were trends toward decreased gross abdominal score and decreased cecal collagen content. Procollagen I, procollagen III, and IGF-I mRNAs also trended downward., Conclusions: Resveratrol decreases inflammatory cytokines and TGF-β1 in the PG-PS model of Crohn's disease and demonstrates a promising trend in decreasing tissue fibrosis. These findings may have therapeutic applications in inflammatory bowel disease., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Purpose: To determine the utility of magnetization transfer (MT) in the identification and quantification of intestinal fibrosis in a rat model of Crohn disease., Materials and Methods: The university committee on the use and care of animals approved this study (UCUCA 08592). Lewis rats injected subserosally with peptidoglycan-polysaccharide (PG-PS) develop bowel inflammation 1 day after laparotomy (early phase) and fibrosis starting 14 days after laparotomy (late phase). The authors performed 2.0-T magnetic resonance (MR) imaging in 25 rats injected with PG-PS and 13 injected with human serum albumin (HSA) (control animals). Imaging was performed before laparotomy and on a weekly basis thereafter for up to 28 days. The MT ratio in the bowel wall was calculated. Resected cecal tissue was scored for inflammation and fibrosis. Tissue fibrosis was determined with colorimetric analysis of trichrome-stained specimens. Collagen content was measured with Western blot analysis. Statistical analyses were performed with the Student t test for continuous bivariate comparisons, the Pearson correlation for continuous variables, and the Spearman correlation for ordinal variables., Results: All rats developed early inflammation, which subsided over time. Rats injected with PG-PS developed increased fibrosis in the late phase, whereas control rats did not. The mean MT ratio of rats injected with PG-PS with late-phase fibrosis was higher than that in rats with early phase inflammation (P = .017). In addition, the MT ratio of rats injected with PG-PS with late-phase fibrosis was higher than that of control animals that did not develop fibrosis in the late phase (P = .0001). The MT ratio of control animals remained unchanged over time as inflammation subsided. The MT ratio in rats injected with PG-PS showed correlation with tissue fibrosis (ρ = 0.63). The MT ratio showed correlation with tissue collagen (R = 0.74). The positive and negative predictive values of the MT ratio in the prediction of fibrosis were 92% (12 of 13 rats) and 83% (five of six rats), respectively., Conclusion: These results indicate that MT is sensitive to bowel wall fibrosis as occurs in Crohn strictures., (© RSNA, 2011.)

Purpose of Review: To highlight the advances in MRI of the small intestine in patients with Crohn's disease. MRI of the gut has become more feasible with improved spatial resolution and speed of the MR sequences allowing parallel evaluation for both disease activity and extra-enteric complications., Recent Findings: Recent literature highlights excellent diagnostic accuracy of MR enterography (MRE) that is comparable to computed tomography enterography (CTE). Compared to CTE the image quality is not quite as good, and there is slightly more interobserver variability in interpretation. Despite these performance characteristics, the overall diagnostic yield of MRE is comparable to CTE. The lack of radiation exposure related to MRE is a significant strength, especially in Crohn's population that by virtue of their younger age, body habitus and potential need for repeated imaging, is at highest risk of potential cancer from radiation exposure due to diagnostic imaging. MRE should not be viewed as a 'safer' version of a CTE. The physics of MRI allows the application of unique sequences that add novel insights not possible with other imaging modalities., Summary: MRE is a highly effective technique for assessing Crohn's disease. We are only starting to explore new MRI sequences and the future of this technology is extremely exciting.

CT enterography is an important tool in the noninvasive diagnosis and follow-up of pediatric Crohn disease. This imaging modality is particularly useful for assessing extent of disease (including both intestinal and extraintestinal manifestations), response to medical therapy, and disease-related complications. The purpose of this article is to provide a contemporary review of CT enterography technique as well as the spectrum of intestinal and extraintestinal findings in pediatric Crohn disease.

Background: Adjustment to college is critical for academic success. Poor college adjustment correlates with poor academic performance, low graduation rates, and poor success later in life. Limited data are available on the effects of inflammatory bowel disease (IBD) on college adjustment. We hypothesize that disease activity negatively impacts on QOL, and adversely affects college adjustment., Methods: Undergraduate students (6 Crohn's disease [CD], 12 ulcerative colitis [UC], 19 healthy controls) completed a standardized college adjustment survey (SACQ) and QOL instrument (SF-12). Where appropriate, disease specific activity and QOL indices were obtained (HBI, SCCAI, SIBDQ)., Results: There was an inverse correlation between disease activity and college adjustment in CD and UC (R = -0.6554, p = 0.0032). IBD students had lower physical QOL (SF-12) than controls (p = 0.0009). Emotional domain of college adjustment correlated best with SIBDQ (R = 0.8228, p < 0.0001), and correlated better in CD (R = 0.8619) than UC (R = 0.7946). Mental QOL (SF-12) was worse in CD than UC (p = 0.0211), but neither differed from controls (p = 0.4, p = 0.6)., Conclusions: Students with active Crohn's and colitis adjust less well to college life. Physical and emotional factors likely contribute. More aggressive medical therapy and better emotional support before and during college may result in happier and healthier college students, leading to higher graduation rates and future success. Interventions resulting in better disease control and support systems may improve college performance and provide long-term benefits to young adults with IBD.

Background: CT enterography yields striking findings in the bowel wall in Crohn's disease. These images may help to evaluate whether small bowel narrowing results from active disease requiring anti-inflammatory therapy. However, the clinical relevance of these images is unknown. It is also not known if these radiologic findings correlate with objective biomarkers of inflammation., Methods: In a blinded and independent evaluation, IBD subspecialty gastroenterologists reviewed clinical data, and CT radiologists reviewed CT enterography scans of 67 consecutive patients with Crohn's disease and suspicion of either small bowel inflammation or stricture. Comparisons were made between (1) clinical and radiologic assessments of inflammation and stricture, (2) clinical assessments before and after computed tomographic enterography (CTE) reports were revealed, and (3) radiologic findings and objective biomarkers of inflammation., Results: (1) Individual CTE findings correlated poorly (Spearman's rho < 0.30) with clinical assessment; (2) clinicians did not suspect 16% of radiologic strictures, and more than half the cases of clinically suspected strictures did not have them on CTE; (3) CTE data changed clinicians' perceptions of the likelihood of steroid benefit in 41 of 67 cases; (4) specific CTE findings correlated with CRP, and a distinct set of CTE findings correlated with ESR in the subset of patients who had these biomarkers measured., Conclusions: CTE seems to add unique information to clinical assessment, both in detecting additional strictures and in changing clinicians' perceptions of the likelihood of steroids benefiting patients. The biomarker correlations suggest that CTE is measuring real biologic phenomena that correlate with inflammation, providing information distinct from that in a standard clinical assessment.

Background: Delivery of genes encoding anti-inflammatory proteins has been proposed as a strategy for the treatment of inflammatory bowel disease (IBD). The goal of this study was to assess the ability of a standard adenoviral vector to transfect epithelial cells in intestinal explants from patients with IBD compared with controls., Methods: Endoscopic colon biopsies obtained from patients with no history of IBD and endoscopically normal colon (n = 4), patients with a history of ulcerative colitis (UC; n = 5), and patients with a history of Crohn's disease (CD; n = 3) were placed in explant culture and exposed to an adenoviral vector carrying the nuclear targeted beta-galactosidase reporter gene., Results: X-Gal staining showed that the total number of transduced cells per square millimeter was greater in UC explants than in controls (mean, 11.3 versus 0.9 blue nuclei/mm, respectively; P < 0.02) and that the frequency of epithelial cell transduction was greater in UC explants than in controls (86% versus 47% of explants, respectively; P = 0.01). Transduction of mature columnar surface epithelial cells occurred exclusively in UC and CD explants and was not seen in controls. Attenuated epithelial cells at sites of tissue damage or ulceration showed increased transduction compared with mature columnar epithelial cells (62% versus 19% of occurrences, respectively; P < 0.0001)., Conclusions: We conclude that intestinal epithelial cells from IBD patients are more readily transfected by standard adenoviral vectors than are those from control patients. These results suggest that targeting genes to inflamed intestine through the luminal route may be possible.

IGF-I is a potent fibrogenic growth factor that stimulates proliferation of intestinal smooth muscle cells and increases synthesis of collagen and IGF-I-binding proteins by the cells. These processes contribute to intestinal fibrosis that develops in patients with Crohn's disease and in Lewis-strain rats with experimental Crohn's disease. The aim of this study was to determine which early docking proteins are associated with IGF-I receptor signal transduction and which transduction pathway is involved in IGF-I-mediated gene regulation in intestinal smooth muscle cells. Primary cultures of smooth muscle cells isolated from the muscularis externa of the distal colon of Lewis rats were treated with IGF-I (100 ng/ml). Immunoprecipitation studies demonstrated that IGF-I stimulation resulted in tyrosine phosphorylation of IRS-1, IRS-2, and Shc. Coimmunoprecipitation demonstrated a close association between the IGF-I receptor and these three early docking proteins. Concurrent treatment with the MAPK inhibitor PD98059 (10 microM) resulted in an inhibition of the IGF-I-mediated increase in IGFBP-5 and collagen alpha(1)(I) mRNAs, while concurrent treatment with the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin (100 nM) had no effect. In additional experiments, cells were transiently transfected with adenoviral vectors dominantly expressing inactive mutant Akt or constitutively expressing wild-type Akt. In both cases, the IGF-I-mediated increase in collagen I protein did not differ from that observed in control cultures that had been transfected with an adenoviral vector carrying the LacZ reporter gene. These results suggest that the MAPK pathway is key to IGF-I-mediated gene regulation in intestinal smooth muscle cells, whereas data do not suggest a role for the Akt-dependent pathway in our system.