Maria Wiśniewska-Jarosińska

Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn's disease patients.

AIM To investigate the correlation between the appearance of skin lesions and concentration of interleukin (IL)-17A, IL-23 and interferon-γ (IFN-γ) in Crohns disease (CD) patients during anti-tumor necrosis factor-α (TNF-α) therapy METHODS A prospective study included 30 adult patients with CD of Caucasian origin (19 men and 11 women; mean age ± SD 32.0 ± 8.6 years) during biological therapy with anti-TNF-α antibodies from January 2012 to March 2013. Eighteen patients were treated with infliximab, seven with adalimumab and five with certolizumab. Inclusion criteria were exacerbation of the underlying disease, Crohns Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies. Patients with a history of psoriasis, atopic dermatitis and other autoimmune skin lesions were excluded from the study. The control group consisted of 12 healthy subjects. A diagnostic survey was carried out, blood tests and careful skin examination were performed, and the serum levels of IL-17, IL-23 and IFN-γ were measured using an enzyme-linked immunosorbent assays technique. Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by anti-TNF-α therapy. RESULTS Skin manifestations occurred in 18 of CD patients during the anti-TNF-α therapy (60%), in the average time of 10.16 ± 3.42 mo following the beginning of the 52-wk treatment cycle. Skin lesions observed in CD patients during biological therapy included psoriasiform lesions (44.4%), and eczema forms lesions (22.2%). In CD patients with drug induced skin lesions significantly higher levels of hemoglobin (13.3 ± 1.5 g/dL vs 10.8 ± 1.9 g/dL, P = 0.018) and hematocrit (39.9% ± 4.5% vs 34.3% ± 5.4%, P = 0.01), as well as a significantly lower level of platelets (268 ± 62 × 10(3)/μL vs 408 ± 239 × 10(3)/μL, P = 0.046) was observed compared with CD patients without skin manifestations. The concentrations of IL-17A and IL-23 in CD patients with skin lesions developed under anti-TNF-α therapy were significantly higher compared to those in patients without lesions (IL-17A: 39.01 ± 7.03 pg/mL vs 25.71 ± 4.90 pg/mL, P = 0.00004; IL-23: 408.78 ± 94.13 pg/mL vs 312.15 ± 76.24 pg/mL, P = 0.00556). CONCLUSION Skin lesions in CD patients during biological therapy may result from significantly increased concentrations of IL-17A and IL-23, which are strongly associated with TNF-α/Th1 immune pathways.

Trandolapril restores circadian blood pressure variation in normoalbuminuric normotensive Type 1 disabetic patients

A large proportion, from 30% to 50%, of diabetic patients frequently manifests loss of the normal diurnal variation of blood pressure, i.e. their blood pressure does not show at least 10% fall at night (non-dippers). It has been demonstrated that non-dippers are at increased risk of end-organ damage, in particular, renal and cardiovascular complications. As no reliable means of reversing impaired blood pressure variation has been established so far, we aimed at assessing the effect of a long-acting angiotensin-converting enzyme (ACE) inhibitor trandolapril on the disturbed circadian blood pressure rhythm in diabetics without hypertension or nephropathy. A total of 18 type 1 diabetes patients (8 male, 10 female), aged 33.5+/-4.8, with duration of diabetes 5.8+/-2.8 years and HbA(1c) 6.6+/-0.4% (range 5.8--7.1%) were enrolled into the study. Ten well-matched type 1 diabetes patients served as an untreated control group. Twenty-four-hour ambulatory blood pressure measurements (ABPM) were performed thrice in each subject: before trandolapril, 2 mg once daily in the morning, was started; after the first dose of the drug; and after 2 weeks of the treatment. Mean (+/-S.D.) values of systolic, diastolic blood pressure, night fall in systolic, and diastolic blood pressure in the treatment group were (1) at baseline: 124.0+/-5.8 mm Hg, 89.3+/-4.2 mm Hg, 3.0+/-2.2%, 5.1+/-3.8%; (2) after the first dose: 116.1+/-7.6 mm Hg (P<.01 vs. baseline), 82.6+/-6.7 mm Hg (P<.01 vs. baseline), 4.2+/-2.6%, 4.7+/-2.5%; and (3) after 14-day treatment: 116.6+/-8.1 mm Hg (P<.01 vs. baseline), 76.9+/-9.6 mm Hg (P<.01 vs. baseline), 17.6+/-6.9% (P<.01 vs. baseline and after 24-h values), 19.4+/-8.0% (P<.01 vs. baseline and after 24-h values), respectively. ABPM results for the untreated controls were similar in all three measurements. In conclusion, within 14 days of trandolapril treatment, circadian blood pressure variation was successfully restored in normoalbuminuric normotensive insulin-dependent diabetic patients.

Evaluation of enterochromaffin cells and melatonin secretion exponents in ulcerative colitis.

AIM To study an assessment of the number of enterochromaffin cells and expression of hydroxyindole-O-methyltransferase in colonic mucosa and urine excretion of 6-sulfatoxymelatonin in patients with ulcerative colitis. METHODS The study included 30 healthy subjects (group I-C), 30 patients with ulcerative proctitis [group II-ulcerative proctitis (UP)] and 30 patients with ulcerative colitis [group III-ulcerative colitis (UC)] in acute phases of these diseases. The number of enterochromaffin cells (EC) was estimated in rectal and colonic mucosa. Bioptates were assembled from many different parts of the large intestine. Immunorective cells collected from various parts of the colon were counted according to the Eurovision DAKO (Dako A/S, Copenhagen, Denmark) System in the range of 10 fields in each bioptate at × 200 magnification. The level of mRNA expression of hydroxyindole-O-methyltransferase (HIOMT) in colonic mucosa was estimated with RT-PCR. Urine 6-sulfatoxymelatonin (6-HMS) excretion was determined immunoenzymatically using an IBL (IBL International GmbH, Hamburg, Germany) kit (RE 54031). RESULTS The number of EC cells in healthy subjects (C) was 132.40 ± 31.26. In patients of group II (UP) and group III (UC) the number of these cells was higher--225.40 ± 37.35 (P < 0.001) and--225.24 ± 40.50 (P < 0.001) respectively. Similar differences were related to HIOMT expression, which was 1.04 ± 0.36 in group C, 1.56 ± 0.56 (P < 0.01) in group UP and 2.00 ± 0.35 (P < 0.001) in group UC. Twenty-four hour 6-HMS urinary excretion was as follows: C--6.32 ± 4.95 μg/24 h, UP - 26.30 ± 7.29 μg/24 h (P < 0.01), UC--2.30 ± 12.56 μg/24 h (P < 0.001). A correlation between number of EC cells and 6-HMS excretion was noted in all groups: r = 0.766 in patients with UP, r = 0.703 with UC and r = 0.8551 in the control group; the correlation between the results is statistically significant. CONCLUSION In the acute phases of both UP and UC, proliferation of EC cells and high expression of HIOMT and urine excretion of 6-HMS is noted. These changes may represent a beneficial response in the anti-inflammatory and defense mechanism.

Evaluation of selected parameters of the inflammatory response to endoscopic retrograde cholangiopancreatography.

Introduction Endoscopic retrograde cholangiopancreatography (ERCP) is a well-established method in diagnosis and management of biliary and pancreatic diseases. The procedure carries the risk of serious complications; the most common is pancreatitis. The severity of ERCP-related pancreatitis largely depends on the inflammatory response to the procedure. Aims The aim of our study was to evaluate the inflammatory response after diagnostic and therapeutic ERCP based on monitoring of plasma concentration of the following substances: amylase, lipase, white blood cells, interleukin 6 (IL-6), C-reactive protein (CRP), hydrogen peroxide, malonylodialdehyde (MDA), and conjugated dienes (CD). Methodology The study was performed on 40 patients who were divided into two groups according to the procedure performed: Group1–28 patients after ERCP with endoscopic sphincterotomy (ES) and Group 2–12 patients after diagnostic ERCP. The parameters were measured before ERCP and 2, 24, and 48 hours after the procedure. Results After diagnostic and therapeutic ERCP, the increase in plasma concentration of amylase, lipase, IL-6, and CRP were observed. Acute pancreatitis developed in three of the patients from group 1. The increase in lipase and CRP concentration was significantly higher after therapeutic ERCP with ES than after the diagnostic procedure. Asymptomatic hyperamylasemia and hyperlipasemia occurred more often after therapeutic than diagnostic ERCP. A positive correlation between the increase of IL-6 and CRP concentration was found. After uncomplicated diagnostic or therapeutic ERCP, no increase of reactive oxygen species and lipid peroxidation products was observed. Conclusion Diagnostic ERCP stimulates a systemic inflammatory response, the intensity of which is magnified after ES. After uncomplicated ERCP, the balance between oxidative and anti-oxidative mechanisms is retained.

Circadian rhythm abnormalities – Association with the course of inflammatory bowel disease

Crohns disease (CD) and ulcerative colitis (UC) are the main representatives of inflammatory bowel diseases (IBD), a group of chronic, immune system-mediated inflammatory diseases of the gastrointestinal (GI) tract. The pathogenesis of the intestinal lesions in IBD is not entirely identified and understood: excessive activation of the immune system may come as a result of the interaction of various environmental and infectious factors, genetic predisposition, and the mediation of abnormal intestinal flora. The main objective of the current study is to further identify the risk factors for the development of IBD. Currently, there is very little knowledge about circadian rhythm and IBD and there are only a few studies on the relationship between sleep disturbances and the course of the disease, as well as pro- and anti-inflammatory cytokine profile and general immune system functioning. Furthermore, the relationship between the expression of circadian rhythm genes and severe course of IBD is still unknown. The aim of this review is to show the current state of knowledge about the relationship between circadian rhythm disorders, sleep disturbance and inflammation in the GI tract and to analyze the possibility of employing this knowledge in diagnosis and treatment of IBD.

Association of the-801G/A Polymorphism of CXCL12 Gene with the Risk of Inflammatory Bowel Diseases Development in a Polish Population

UNLABELLED Inflammatory bowel diseases (IBDs), mainly ulcerative colitis (UC) and Crohns disease (CD), are characterized by chronic and idiopathic inflammatory conditions of gastrointestinal tract that are immunologically mediated. Stromal cell-derived factor 1 (CXCL12) has been demonstrated to be involved in the pathophysiology of IBD.The aim of the study was to investigate whether the CXCL12 -G/A polymorphism (rs1801157) is associated to IBD in a sample of Polish population. MATERIAL AND METHODS A total of 188 patients with IBD including 103 patients with CU and 72 patients with CD and 184 controls were enrolled in the study. Both groups came from the Polish population. The G/A polymorphism of CXCL12 was determined by PCR-RFLP analysis. RESULTS There was no association between G/A polymorphism at position -801 promoter region of CXCL12 gene and increased risk of IBD. The study population was not found a difference in genotype distribution between the control group and with both CD and CU patients. CONCLUSIONS These results suggest that G/A polymorphism at position -801 promoter region of CXCL12 gene relates neither to the risk of the development of inflammatory bowel disease nor to the clinical subtypes of IBD in the Polish population. Whether this polymorphism truly contributes to disease susceptibility needs to be further addressed, and should stimulate additional studies in other populations.

Helicobacter pylori infection can modulate the susceptibility of gastric mucosa cells to MNNG

The pathogenesis of stomach cells can be associated with their susceptibility to exogenous dietary irritants, like nitrosamines such as dimethylnitrosamines (DMNA), and to the effects of non-dietary factors, including Helicobacter pylori infection. We used N-methyl-N’-nitro N-nitrosoguanidyne (MNNG) as a surrogate agent that induces a spectrum of DNA damage similar to DMNA. Using the alkaline comet assay, we showed that antioxidants — vitamins C and E, quercetin, and melatonin — reduced the genotoxic effect of MNNG in H. pylori-infected and non-infected human gastric mucosa cells (GMCs). To compare the sensitivity of the stomach and the blood, the experiment was also carried out in peripheral blood. We observed a higher level of DNA damage induced by MNNG in H. pylori-infected than in noninfected GMCs. We did not note any difference in the efficacy of the repair of the damage in either type of GMC. H. pylori infection may play an important role in the pathogenesis of GMCs, as it can modulate their susceptibility to dietary mutagens/carcinogens, thus contributing to gastric cancer.

Serum Cyclophilin A Correlates with Increased Tissue MMP-9 in Patients with Ulcerative Colitis, but Not with Crohn’s Disease

BackgroundCyclophilin A (CyPA) is an immunomodulatory protein, high expression of which correlates with poor outcome of patients with inflammatory diseases. However, its role in inflammatory bowel disease (IBD) has not been studied.AimThis study analyzes the correlation between cyclophilin A, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP (TIMP)/MMP-9 complexes in the inflamed and non-inflamed colon mucosa of UC and CD patients.MethodsSerum and biopsy specimens from inflamed and non-inflamed colonic mucosa of 38 patients with IBD (19 with UC and 19 with CD) and 16 controls were included in our study. We measured serum and tissue level of CyPA, and tissue level of TNF-α, MMP-9, TIMP-1/MMP-9, and TIMP-2/MMP-9 using ELISA method.ResultsOur results indicated that serum, but not tissue CyPA is increased in UC, rather than in CD patients, compared to the control. The increase correlated with higher tissue concentration of MMP-9 and TNF-α, especially in the UC group. Moreover, we observed significantly higher level of TIMP-1/MMP-9 in UC and CD group, which overlapped with the change in MMP-9. There was no change in TIMP-2/MMP-9 in the analyzed groups.ConclusionThe current study suggests that serum CyPA may be an independent additional marker of IBD, especially of UC. Higher CyPA level may be followed by increased MMP-9 in those patients. However, further studies are necessary to verify the role of CyPA in IBD development.

G protein-coupled receptor 30 (GPR30) expression pattern in inflammatory bowel disease patients suggests its key role in the inflammatory process : a preliminary study

BACKGROUND AND AIMS G protein-coupled receptor 30 (GPR30) is a recently de-orphanized estrogen receptor that mediates the effects of estrogens on different cells. It has been postulated that in inflammatory bowel diseases (IBD) activation of GPR30 blocks the pathways dependent on pro-inflammatory cytokines. The aim of our study was to investigate GPR30 expression in patients with IBD and its potential implication in future therapies. METHODS Fifty-seven patients were enrolled in our study: 20 subjects with Crohns disease (CD), 22 with ulcerative colitis (UC) and 15 controls. In each subject, biopsies were taken from various left-colonic locations. Gene and protein expression of GPR30 was quantified using real time RT-PCR or Western blot. RESULTS GPR30 mRNA and protein expression were detected in all tested colonic tissues. No significant differences in GPR30 gene expression were observed. In non-inflamed areas, GPR30 protein was strongly increased in CD patients, but moderately in UC patients (p= 0.014 and p=0.143, respectively, vs. controls). In CD patients, a significantly lower GPR30 protein content in inflamed than in non-inflamed tissue was observed (p=0.039). The change was independent of patient gender. CONCLUSION Our observations indicate that GPR30 may play a role in the development and progression of inflammatory lesions in IBD, thus affecting disease severity, and consequently IBD treatment. Therefore, GPR30 may become an attractive target for novel anti-IBD drugs, particularly in CD.

The role of adipose tissue in the pathogenesis of Crohn’s disease

Crohns disease (CD) is a chronic, immune system-mediated inflammatory disease affecting gastrointestinal (GI) tract. The pathogenesis of the intestinal lesions is not entirely explained and understood: excessive activation of the immune system may come as a result of the interaction of environmental, genetic and infectious factors and the mediation of abnormal intestinal flora. The main objective of the current study is to further identify the role of adipose tissue in the pathogenesis of CD. Alterations in body fat distribution, accumulation of intra-abdominal white adipose tissue (WAT) and mesenteric obesity are well-known features of CD. Up to date, data concerning the role of WAT in the pathogenesis of CD is limited with only a few studies on the relationship between WAT and the course of the disease, as well as pro- and anti-inflammatory cytokine profile and general immune system functioning. In this review, we focus on the importance of physiological and pathophysiological WAT functions and secreted adipokines, which seem to have a vital role in the inflammatory and fibrotic processes in CD sufferers.