This Month in Gastroenterology

Abstract

Propofol is becoming an increasingly popular choice for delivery of sedation during endoscopic procedures and is preferred by some endoscopists over traditional sedation with narcotics and benzodiazepines. Propofol is typically administered by anesthesia specialists rather than by endoscopists, resulting in significantly higher total cost for endoscopic procedures. This higher total cost is an issue in the current environment in which reimbursement for endoscopic procedures is declining. Some have advocated the training of nurses to administer propofol in an attempt to lower total costs, but the American Society of Anesthesiologists and the American Academy of Nurse Practitioners have issued a statement against the use of propofol by non-anesthesiologists. The controversy surrounding propofol administration for endoscopic procedures is fueled by concerns about the safety of this practice by non-anesthesiologists. Rex et al report the safety experience of registered nurse-administered propofol sedation (NAPS) in 3 endoscopy units, which implemented NAPS training programs. Indiana University Hospital, University Hospital of Basel in Switzerland, and an ambulatory surgery center in Medford, Oregon, developed NAPS training programs in their respective endoscopy units. In each of these programs, registered nurses administered propofol during endoscopic procedures under the supervision of the endoscopist. The number of adverse respiratory events and the safety profiles of each individual nurse and endoscopist involved in the administration of propofol was recorded. There were 36,743 NAPS cases performed at the 3 centers. There were no cases resulting in death or endotracheal intubation. The rate of assisted ventilation was not significantly different between centers and ranged from 1 per 500 cases to 1 per 1000 cases. The safety profiles were not significantly different amongst individual nurses and endoscopists. These authors conclude that propofol can be administered safely by trained nurses and endoscopists, which may help reduce the cost of propofol-administered sedation. Transforming growth factor-β1 (TGF-β1) is a negative regulator of immune cell functions, particularly in the intestine where decreased expression is associated with the development and progression of intestinal inflammation. Its activation of type I TGF-β receptor (TGFβRI) results in the stimulation of Smad3, a process that is inhibited by Smad7 which physically interacts with TGFβRI, preventing the phosphorylation of Smad3. Smad7 also causes the ubiquitination and proteosomal degradation of the type I receptor via Smurf 1 and 2. Specific inhibition of Smad7 in lamina propria mononuclear cells (LPMC) and in explant IBD tissues restores Smad3 phosphorylation and the ability of TGF-β1 to inhibit inflammatory signaling pathways. Thus, the intracellular levels of Smad7 are very important in regulating mucosal TGF-β1 responses and in the pathogenesis of mucosal inflammation. This study by Monteleone et al was undertaken to determine how Smad7 expression is regulated in normal and inflamed human intestine. Smad7 mRNA and protein expression were assessed in whole intestinal mucosal and lamina propria mononuclear cell (LPMC) samples by real-time PCR and Western blotting, respectively. Smad7 ubiquitination and acetylation, and interaction of Smad7 with the intrinsic histone acetyltransferase, p300, were examined by immunoprecipitation and Western blotting. The effect of p300 silencing on Smad7 expression was also determined in Crohn’s disease (CD) LPMC (Figure 1, Figure 2).Figure 2Immunohistochemical analysis of the expression of p300. In all IBD samples (representative image of CD shown in A), p300 protein was clearly seen in cells in the lamina propria, with strong nuclear staining. In control samples, a very weak staining was seen (C). Control IgG gave no staining on both CD (B) and control (D) samples; (immunoperoxidase, original magnification 400×).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The investigators report that Smad7 is not transcriptionally regulated in human intestine, but is ubiquitinated and rapidly degraded in normal intestinal cells. In contrast, its expression is increased in IBD through p300-mediated posttranscriptional acetylation and stabilization that prevents Smad7 ubiquitination and proteosomal degradation. Silencing of p300 mRNA results in decreased expression of Smad7. These data provide additional insights into the mechanisms of chronic inflammation and highlight the importance of posttranslational protein modification in the pathogenesis of inflammatory bowel diseases. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with inflammatory bowel disease. Presently, there are no effective medical therapies for PSC. There have been several trials evaluating the effectiveness of ursodeoxycholic acid (UDCA) for the treatment of PSC, but the results of these trials have been inconsistent. Previously reported trials have used varying doses of UDCA and have observed patients for different lengths of time. Olsson et al report the results of their multicenter, randomized, controlled study evaluating the efficacy of high-dose ursodeoxycholic acid for PSC in patients followed for 5 years. Olsson et al enrolled 219 patients with PSC and randomized them to receive either UDCA (17–23 mg/kg) or placebo after stratifying them according to whether or not they were symptomatic. The primary endpoint was death or liver transplantation. The frequency of patients who died or had a liver transplantation was not significantly different between groups (7.2% in the UDCA group vs 10.9% in the placebo group). Kaplan–Meier analysis demonstrated no significant difference in survival without liver transplantation between the groups, although there was a trend toward better survival in the treatment group (Figure 3). There were no significant differences in liver laboratory tests between the treatment and placebo groups, although there was a trend of lower alkaline phosphatase, ALT, and bilirubin levels in the UDCA groups (Figure 4). There were no significant differences in the quality of life or frequency of PSC-associated symptoms between the 2 groups. Three patients in the UDCA group and 4 patients in the placebo group developed cholangiocarcinoma. The findings of this multicenter trial support previous evidence that UDCA given at high doses is not an effective treatment of PSC.Figure 4Changes from start in serum ALP, ALT, and bilirubin. Mean with SD.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Inflammatory bowel disease (IBD) appears to be caused by predisposing genes that are sufficiently penetrant to elicit clinical disease dependent on a complex interaction of such genes with the enteric environment. The gene encoding interleukin (IL)-10 (Il10, Chr. 1) is one of a number of mouse genes whose disruption can induce colitis. It is a key cytokine secreted by adaptive and innate immune cells that is required for maintaining immune homeostasis in the gut. In mice with gene-targeted deletion of the Il10 gene, the development of disease is dependent both upon the inbred strain background on which the mutation is placed, as well as in the microbial environment in which the mutant mice are maintained. A robust colitis response is particularly well seen with IL-10–deficient C3H/HeJBir (C3Bir) inbred mice, a substrain that was originally selected from C3H/HeJ (C3H) progenitors showing a high frequency of juvenile colitis after weaning. C3Bir are also highly susceptible to IBD in the cecum and colon induced by a variety of means, including dextran sodium sulfate in drinking water and trinitrobenzene sulfonic acid via enema. This may be related to its especially hyperresponsive immune system to enteric flora, manifested by unusually high humoral and CD4+ T cell responses to enteric antigens. In contrast, C57BL/6J (B6) mice are very resistant to these mucosal stresses, as well as to induction of amebic colitis. The major genetic modifier for colitis was subsequently mapped on Chromosome 3 and designated Cytokine deficiency induced colitis susceptibility-1 (Cdcs1). To confirm its role as a diseased modifier, reciprocal Cdcs1 congenic stocks on both IL-10–deficient backgrounds were developed. C3Bir congenic for the B6-derived Cdcs1 allele and reciprocal B6 congenic for the C3Bir allele were then analyzed for colitis development. Parental strains were compared by electrophoretic mobility shift assay to assess the candidacy of Nfkb1 (NF-κB p50) in the Cdcs1 interval. The study by Beckwith et al reports that Cdcs1 is within a minimum 7 megabase interval containing Nfkb1 and that C3Bir colitis was significantly diminished by the B6 genome in this interval. On the other hand, colitis in B6 was significantly exacerbated by reciprocal C3Bir genome. C3Bir macrophages constitutively expressed higher nuclear NF-κB p50. Functional assays showed that C3Bir exhibited reduced innate responsiveness both in vivo and in vitro to bacterial ligands, but increased CD4 T-cell responses compared with B6. This differential responsiveness was controlled by the respective allele at Cdcs1. Thus, the colitogenic Cdcs1 allele impairs innate immunity to bacterial products and in turn skews the adaptive immune response toward compensatory hyper-responsiveness and chronic intestinal inflammation (Figure 5). Trained Registered Nurses/Endoscopy Teams Can Administer Propofol Safely for EndoscopyGastroenterologyVol. 129Issue 5PreviewBackground & Aims: Propofol has advantages as a sedative for endoscopic procedures. Its administration by anesthesia specialists is associated with high cost. Administration by nonanesthesiologists is controversial because of concerns about safety, particularly respiratory depression. Methods: Three endoscopy units developed programs to train registered nurses supervised only by endoscopists in the administration of propofol for endoscopic procedures. The rate of adverse respiratory events was tracked from the inception of the programs. Full-Text PDF Post-transcriptional Regulation of Smad7 in the Gut of Patients With Inflammatory Bowel DiseaseGastroenterologyVol. 129Issue 5PreviewBackground & Aims: Transforming growth factor (TGF)-β1 is one of the most powerful endogenous negative regulators of inflammation. In patients with inflammatory bowel disease, despite abundant local TGF-β1, there is a failure of TGF-β–mediated negative regulation of nuclear factor κB activation and proinflammatory cytokine production because of increased intracellular expression of the endogenous inhibitor of TGF-β1 signaling, Smad7. In this study, we examined the molecular mechanism underlying the induction of Smad7 in the human gut. Full-Text PDF Cdcs1, a Major Colitogenic Locus in Mice, Regulates Innate and Adaptive Immune Response to Enteric Bacterial AntigensGastroenterologyVol. 129Issue 5PreviewBackground & Aims: The absence of interleukin 10, a key cytokine in gut homeostasis, causes severe colitis in C3H/HeJBir but not C57BL/6J mice. The major modifier for colitis was mapped on chromosome 3 and designated cytokine deficiency–induced colitis susceptibility 1 (Cdcs1). We developed reciprocal Cdcs1 congenic stocks on both interleukin 10–deficient backgrounds to identify the susceptibility gene and its function. Methods: C3H/HeJBir congenic for the C57BL/6J-derived Cdcs1 allele and reciprocal C57BL/6J congenic for the C3H/HeJBir allele were analyzed for colitis development. Full-Text PDF