Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), represents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal macrophages play an important role in the mucosal immune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major contributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cytokine therapies have been developed and tested for the treatment of IBD patients.

Role of cytokines in inflammatory bowel disease

The Utility of Biomarkers in the Diagnosis and Therapy of Inflammatory Bowel Disease

Background Many patients with cystic fibrosis (CF) now reach adulthood, at which time the risk of cancer is increased. The aim of this study was to determine cancer risks in nontransplanted and transplanted CF patients. Methods From 1990 to 2009, we followed 41,188 patients who received care at one of the 250 CF care center programs in the United States and compared the observed number of cancers in nontransplanted and transplanted patients with that expected in the general US population. Results In 344,114 patient-years of observation of nontransplanted patients, the overall cancer risk was similar to the background risk (standardized incidence ratio [SIR] = 1.1, 95% confidence interval [CI] = 1.0 to 1.3). However, we observed an elevated risk of digestive tract cancer (SIR = 3.5, 95% CI = 2.6 to 4.7) involving the esophago-gastric junction, biliary tract, small bowel, and colon. There was also an increased risk of testicular cancer (SIR = 1.7, 95% CI = 1.02 to 2.7) and lymphoid leukemia (SIR = 2.0, 95% CI = 1.2 to 3.1) and a decreased risk of malignant melanoma (SIR = 0.4, 95% CI = 0.2 to 0.9). In 8235 patient-years of observation of transplanted patients, 26 tumors were observed compared with 9.6 expected (SIR = 2.7, 95% CI = 1.8 to 3.9). The increased risk was particularly high for digestive tract cancers (SIR = 17.3, 95% CI = 10.7 to 26.5), with most cases arising in the bowel. Conclusions The overall burden of cancer in CF patients remains low; however they have an increased risk of digestive tract cancer, particularly following transplantation. They also have increased risk of lymphoid leukemia and testicular cancer, and decreased risk of melanoma.

Cancer Risk in Cystic Fibrosis: A 20-Year Nationwide Study From the United States

Immune dysfunction in inflammatory bowel disease.

Rationale: Human lung transplantation is a therapeutic option for selected patients with advanced cardiopulmonary disease, but long-term survival is limited by chronic rejection. Persistent acute rejection and gastric aspiration have been implicated as risk factors but there is little or no evidence to date that they are associated.Objectives: We have tested the hypothesis that pepsin, a marker of gastric aspiration, is present in lung transplant recipients, and that high levels are associated with biopsy-diagnosed acute rejection and/or bronchiolitis obliterans syndrome.Methods: Levels of bronchoalveolar lavage (BAL) pepsin were measured by ELISA in 36 lung transplant recipients, 4 normal volunteers, and 17 subjects with unexplained chronic cough.Measurements and Main Results: Our primary finding was that, compared with control subjects, BAL pepsin levels were elevated in stable lung transplant recipients, subjects with acute rejection, and subjects with bronchiolitis obliterans syndrome. Our secondary f...

https://www.atsjournals.org/doi/pdf/10.1164/rccm.200610-1485OC

Pepsin, a biomarker of gastric aspiration in lung allografts: A putative association with rejection

TGF-beta is a cytokine with varied properties and pleiotropic activity. It is released in an inactive form. To exhibit its biological activity, it requires binding to extracellular matrix proteins and, after that, proteolytic elimination of LAP (Latent Associated Protein) and LTBP (Latent TGF-beta Binding Protein). The process involves, among others, tissue transglutaminase, thrombin and plasmin. By stimulation of specific receptors, it influences transcription of some genes and translation of formed mRNA. Locally, it demonstrates proinflammatory properties whereas systemically, it has primarily a potent immunosuppressive effect. TGF-beta, by affecting proliferation, differentiation and migration of cells, as well as stimulation of extracellular matrix protein production, plays an important role in tissue regeneration and remodeling, but also in fibrosis. TGF-beta is also indispensable to maintain immune homeostasis of the organism. Reduced TGF-beta activity is considered to be responsible for development of autoimmune disorders in the course of several pathologic conditions. This cytokine plays an important role in the pathogenesis of chronic inflammatory processes taking place, among others, in inflammatory bowel diseases (IBD) and chronic hepatitis B and C. The paper presents a review of literature concerning diagnostic and prognostic value of TGF-beta level determinations in blood and tissue bioptates of patients with chronic non-specific enteritis and chronic hepatitis B and C.

TGF-beta (transforming growth factor-beta) in chronic inflammatory conditions - a new diagnostic and prognostic marker?

Background Gastroesophageal reflux (GER) may aggravate chronic bronchopulmonary diseases. The study evaluated GER frequency and characteristics in children with Cystic Fibrosis (CF) as well as its consequences and pharmacological treatment. Material/methods 40 CF children aged 1.3 to 20 years were examined. The study methodology involved: medical files analysis, anamnesis, physical examination, growth status estimation, esophageal pH-metry and upper gastrointestinal tract endoscopy with histological examination of esophageal biopsies. Results Based on pH-metry results, the diagnosis of GER was established in 22 children (55%). Mild GER (Index Reflux - IR 5-10%) was found in 12 children (54.5%), moderate GER (IR 10-20%) in 7 (31.8%) and severe GER (IR>20%) in 3 (13.6%). Ten patients with moderate or severe GER underwent endoscopy, which revealed GER-related esophagitis in 8 cases. There was no statistical difference of GER frequency and degree according to: age, sex, growth status, presence of type DF508 mutation in CFTR genome and typical GERD symptoms. According to the ESPGAN proposition, cisapride or cisapride with ranitidine medication was instituted. Treatment analysis was performed in 19 cases after successful follow-up examinations carried out three months later, indicating a significant decrease in reflux index, the longest episode duration and the number of episodes longer than 5 minutes. Improvement of endoscopic picture was noticed after treatment. Conclusions High frequency of gastroesophageal reflux and its consequences among children with cystic fibrosis, as well as the possibility of well-tolerated and efficient treatment of GER, indicate that diagnostics of GER among children with CF should be obligatory.

Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis.

Objective. Inflammatory bowel disease (IBD) in children creates diagnostic and clinical challenges. Clinical data, endoscopic appearance and the histopathological assessment of biopsies are essential for diagnosis. However, new methods are required for non-invasive follow-up. Recently, we demonstrated that the dimeric isoform of pyruvate kinase (PK) detected in stool might serve as a potential non-invasive screening tool in inflamed pouch mucosa. The aim of this study was to investigate whether this test could be used to detect intestinal inflammation in pediatric IBD patients. Material and methods. Fecal PK immunoreactivity was assessed in 75 patients with proven ulcerative colitis (UC) and 32 with Crohn's disease (CD). Pediatric Crohn Disease Activity Index (PCDAI) and Truelove-Witts scores were determined in CD and UC patients, respectively. Thirty-five healthy subjects (HS) served as a control group. Results. Increased PK levels were documented in 94.1% and 100% active CD patients with a cut-off level...

Fecal pyruvate kinase: a potential new marker for intestinal inflammation in children with inflammatory bowel disease.

The pathomechanism of Helicobacter pylori action upon gastric mucosa and its role in the pathogenesis of gastritis have not been fully elucidated. The aim of this study was to evaluate the most prevalent lymphocyte subpopulations of the gastric mucosa in gastritis in children, as well as to evaluate the expression of Fas and Fas ligand receptors (FasL), periapoptotic markers of gastric mucosa lymphocytes before and after H. pylori eradication. Forty nine patients aged 6 to 17 years, investigated due to chronic abdominal pain, were studied. The obtained tissue samples were analysed by immunohistochemistry. Different lymphocyte subsets were quantified on the basis of surface antigen expression (CD3, CD4, CD8, CD20), secreted cytokines (IL-4, IL-6, IFNgamma) and Fas and FasL proteins in the gastric mucosa. B and T helper lymphocytes were found to play a major role in the inflammatory infiltration in the gastric mucosa in children during H. pylori infection. Their expression was found to decrease after eradication. The enhanced expression of Fas receptor on lymphocytes before treatment and a decrease of this expression after eradication of H. pylori were shown. It was demonstrated that there is a correlation between CD4 and Fas receptor expression that may induce apoptosis of the helper lymphocytes in infected children.

/pdf/helicobacter-pylori-increases-expression-of-proapoptotic-5az134om9n.pdf

Helicobacter pylori increases expression of proapoptotic markers Fas and FasL on CD4 lymphocytes in children.

Poznaniem składu mikroflory jelitowej i jej metabolizmu zajmuje się wielu badaczy na świecie. Coraz powszechniejsze jest przekonanie, że bakterie występujące w świetle jelita mają udział w etiopatogenezie chorób zapalnych i nowotworowych przewodu pokarmowego. Cel pracy: Ocena bakteryjnych procesów fermentacyjnych dominujących u dzieci obserwowanych z powodu podejrzenia zespołu jelita drażliwego – ZJD (IBS – irritable bowel syndrome), nieswoistych zapaleń jelit – NZJ (IBD – inflammatory bowel disease) i zaparć stolca. Materiał i metody: Badaniom poddano 40 dzieci hospitalizowanych z podanych wyżej powodów. Za pomocą wodorowego testu oddechowego – WTO (HBT – hydrogen breath test) sprawdzano, czy w wydychanym z płuc powietrzu znajduje się wodór i metan. Określano dominujący proces utylizacji wolnego wodoru oraz czas pasażu jelitowego. Wyniki: Stwierdzono, że wydłużenie czasu pasażu jelitowego sprzyja rozwojowi bakterii syntetyzujących metan, co obserwowano u większości dzieci z IBS i zaparciem stolca. Metanogeneza jelitowa narasta wraz z wiekiem i nie zależy od płci. U dzieci z nieswoistym zapaleniem jelit i postacią biegunkową zespołu jelita drażliwego początkowo wzrastało stężenie wodoru, a następnie się normalizowało, przy prawie całkowitym braku metanogenezy. Jednak u tych pacjentów po WTO nasilały się objawy kliniczne choroby, co można wiązać z rozwojem bakterii redukujących siarczany (SRB – sulfphate-reducing bacteria), które mają największe powinowactwo do wodoru. Siarkowodór, będący końcowym produktem ich metabolizmu, odpowiada za wystąpienie biegunki i prawdopodobnie wpływa na przebieg kliniczny nieswoistych zapaleń jelit. Wyniki przemawiają za koniecznością dalszych badań nad mikroflorą jelitową, czemu może służyć nieinwazyjny, wodorowy test oddechowy. Abstract

https://www.termedia.pl/Journal/-41/pdf-7973-1?filename=Ocena bakteryjnych.pdf

Jacek Brodzicki

Papers

TGF-beta (transforming growth factor-beta) in chronic inflammatory conditions - a new diagnostic and prognostic marker?

Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis.

Fecal pyruvate kinase: a potential new marker for intestinal inflammation in children with inflammatory bowel disease.

Helicobacter pylori increases expression of proapoptotic markers Fas and FasL on CD4 lymphocytes in children.

Review paper An assessment of large bowel bacterial fermentation processes in children bowel diseases