Toll interacting protein protects bronchial epithelial cells from bleomycin-induced apoptosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by altered epithelial cell phenotypes, which are associated with myofibroblast accumulation in the lung. Atypical alveolar epithelial cells in IPF express molecular markers of airway epithelium. Polymorphisms within and around Toll interacting protein (TOLLIP) are associated with the susceptibility to IPF and mortality. However, the functional role of TOLLIP in IPF is unknown. Using lung tissues from IPF and control subjects, we showed that expression of TOLLIP gene in the lung parenchyma is globally lower in IPF compared to controls. Lung cells expressing significant levels of TOLLIP include macrophages, alveolar type II, and basal cells. TOLLIP protein expression is lower in the parenchyma of IPF lungs but is expressed in the atypical epithelial cells of the distal fibrotic regions. Using overexpression and silencing approaches, we demonstrate that TOLLIP protects cells from bleomycin-induced apoptosis using primary bronchial epithelial cells and BEAS-2B cells. The protective effects are mediated by reducing mitochondrial reactive oxygen species (ROS) levels and upregulating autophagy. Therefore, global downregulation of the TOLLIP gene in IPF lungs may predispose injured lung epithelial cells to apoptosis and to the development of IPF.

Electrical stimulation for gastroesophageal reflux disease: current state of the art.

Patients with gastroesophageal reflux disease (GERD) who are not satisfied with acid suppression therapy can benefit primarily from fundoplication, a surgical intervention. Fundoplication has been the standard surgical procedure for GERD. It is effective but is associated with adverse effects, resulting in a declining number of interventions, creating a need for alternative interventions that are effective, yet have a better adverse effect profile. One such alternative involves the application of electrical stimulation to the lower esophageal sphincter. A number of animal studies showed that such stimulation can increase resting lower esophageal sphincter pressure. An acute human study confirmed this effect, and was followed by two open-label studies, with a follow-up of up to 3 years. Results thus far show that the therapy is associated with a significant improvement in symptoms, a significant reduction in esophageal acid exposure, and a very good safety profile. This review will describe the evolution of electrical stimulation therapy for GERD, as well as the safety and efficacy of this intervention.

"Pre-cebo": an unrecognized issue in the interpretation of adequate relief during irritable bowel syndrome drug trials.

OBJECTIVES: In drug trials involving subjects with irritable bowel syndrome (IBS), the placebo effect seems to be very important. However, events even before starting the study may also impact patient expectations. In this study, we utilized consent language from prior studies of diarrhea predominant IBS (D-IBS) drug trials to determine whether the knowledge imparted during this process affects the response to different therapies. METHODS: Consecutive IBS subjects who met the Rome III criteria for IBS were enrolled. Patients were presented with a mock trial and randomized to 1 of 3 questionnaires with consent using similar language from consent forms of 3 drugs used in D-IBS: desipramine, alosetron, and rifaximin. Demographics, IBS symptoms using visual analog scale, and percent improvement needed for patients to report adequate relief of IBS from theoretically taking their assigned drug was asked. Data were expressed as mean ± SE. RESULTS: Subjects who were anticipating rifaximin had the highest expectation of improvement to determine adequate relief of 87.3 ± 10.9% compared with 73.4 ± 18.0% for desipramine (P<0.01) and 76.8 ± 20% for alosetron (P=0.049). There was no major difference in expectation of response from any medication to satisfy adequate relief on the basis of a belief that IBS is psychologic or organic in origin. In addition, sex and previous use of a drug did not influence the expectation of adequate relief. CONCLUSIONS: Benefits of drugs in D-IBS drug trials have the potential to be influenced by preconceived notions derived from familiarity of drug class and the consent process even before the study begins which we refer to as the "pre-cebo" effect. The higher pre-cebo effect for rifaximin may be an obstacle to successful treatment effect during drug trials compared with drugs such as desipramine. The pre-cebo effect may need to be taken into account when formulating consent forms for IBS study.

Gastrointestinal and psychological mediators of health-related quality of life in IBS and IBD: a structural equation modeling analysis.

OBJECTIVES: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are chronic gastrointestinal (GI) syndromes in which both GI and psychological symptoms have been shown to negatively impact health-related quality of life (HRQOL). The objective of this study was to use structural equation modeling (SEM) to characterize the interrelationships among HRQOL, GI, and psychological symptoms to improve our understanding of the illness processes in both conditions. METHODS: Study participants included 564 Rome positive IBS patients and 126 IBD patients diagnosed via endoscopic and/or tissue confirmation. All patients completed questionnaires to assess bowel symptoms, psychological symptoms (SCL-90R), and HRQOL (SF-36). SEM with its two components of confirmatory analyses and structural modeling were applied to determine the relationships between GI and psychological symptoms and HRQOL within the IBS and IBD groups. RESULTS: For both IBD and IBS, psychological distress was found to have a stronger direct effect on HRQOL (-0.51 and -0.48 for IBS and IBD, respectively) than GI symptoms (-0.25 and -0.28). The impact of GI symptoms on psychological distress was stronger in IBD compared with IBS (0.43 vs. 0.22; P<0.05). The indirect effect of GI symptoms on HRQOL operating through psychological distress was significantly higher in IBD than IBS (-0.21 vs. -0.11; P<0.05). CONCLUSIONS: Psychological distress is less dependent on GI symptom severity in IBS compared with IBD even though the degree that psychological distress impacts HRQOL is similar. The findings emphasize the importance of addressing psychological symptoms in both syndromes.