Readressing the role of Toll-like receptor-4 alleles in inflammatory bowel disease: colitis, smoking, and seroreactivity.

BACKGROUND: Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. AIMS: To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. METHODS: TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. RESULTS: UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). CONCLUSIONS: The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles.

Calprotectin, calgranulin C, and other members of the s100 protein family in inflammatory bowel disease.

BACKGROUND: Since their discovery, S100 proteins have been associated with diverse diseases of inflammatory, degenerative, or malignant nature. Due to their participation in inflammation, they have also been studied with regard to inflammatory bowel disease (IBD). METHOD: To provide a review of available literature, a PubMed, MEDLINE, and Embase-based literature search was performed, using all available nomenclature for each member of the S100 protein family, along with the terms inflammatory bowel disease, ulcerative colitis, Crohn's disease, or indeterminate colitis. RESULT: S100A8/A9, also known as calprotectin, S100A12, or calgranulin C and in a lesser extent S100P, are involved in the pathogenesis, activity, diagnosis, and therapeutic management of IBD. The majority of available literature is focused primarily on S100A8/9, although there is growing evidence on the significance of S100A12. Most studies emphasize the potential merit of S100A8/A9 and S100A12, as markers for differential diagnosis, monitoring of activity, or disease relapse, in IBD. Limitations, regarding the diagnostic utility of these markers, seem to exist and are mainly related to the publication of conflicting results, i.e., for IBD activity, and to the fact that S100A8/A9 and S100A12 are not disease-specific. CONCLUSIONS: Although the existing data link specific S100 proteins with IBD, there are still several drawbacks in the use of these markers for diagnostic purposes. Thus, it seems that further research is mandatory in order to eliminate the impact of confounding factors but also to detect additional associations between S100 proteins and IBD or novel S100 proteins with a closer correlation with IBD.

α2-Heremans-schmid glycoprotein (fetuin A) downregulation and its utility in inflammatory bowel disease.

AIM: To investigate the impact of inflammatory bowel disease (IBD) on α2-Heremans-Schmid Glycoprotein (AHSG/fetuin A) and potential associations with disease and patient characteristics. METHODS: AHSG serum levels were determined in treatment-naïve newly-diagnosed patients, 96 with ulcerative colitis (UC), 84 with Crohn's disease (CD), 62 with diarrhea-predominant or mixed irritable bowel syndrome (IBS, D- and M- types) and 180 healthy controls (HC), by an enzyme linked immunosorbent assay (ELISA). All patients were followed for a minimum period of 3 years at the Gastroenterology Department of the University Hospital of Larissa, Greece. C-reactive protein (CRP), anti-glycan antibodies, anti-Saccharomyces cerevisiae mannan antibodies IgG, anti-mannobioside carbohydrate antibodies IgG, anti-laminariobioside carbohydrate antibodies IgG and anti-chitobioside carbohydrate antibodies IgA were also determined via immunonephelometry and ELISA, respectively. RESULTS: The mean ± SE of serum AHSG, following adjustment for confounders, was 0.32 ± 0.02 g/L in IBD, 0.32 ± 0.03 g/L in CD and 0.34 ± 0.03 g/L in UC patients, significantly lower than in IBS patients (0.7 ± 0.018 g/L) and HC (0.71 ± 0.02 g/L) (P < 0.0001, in all cases). AHSG levels were comparable between the CD and UC groups. Based on AHSG levels IBD patients could be distinguished from HC with about 90% sensitivity and specificity. Further adjusted analysis verified the inverse association between AHSG and penetrating, as well as stricturing CD (partial correlation coefficient: -0.45 and -0.33, respectively) (P < 0.05). After adjusting for confounding factors, inverse correlations between AHSG and CRP and the need for anti-TNFα therapy or surgery, were found (partial correlation coefficients: -0.31, -0.33, -0.41, respectively, P < 0.05, in all cases). Finally, IBD individuals who were seropositive, for at least one marker, had AHSG levels falling within the two lower quartiles (OR = 2.86, 95%CI: 1.5-5.44, P < 0.001) while those with at least two serological markers positive exhibited AHSG concentrations within the lowest quartile (OR = 5.03, 95%CI: 2.07-12.21, P < 0.001), after adjusting for age, sex and smoking. CONCLUSION: AHSG can be used to distinguish between IBD and IBS patients or HC while at the same time "predicting" complicated disease behavior, need for therapy escalation and surgery. Moreover, AHSG may offer new insights into the pathogenesis of IBD, since it is involved in key processes.

The role of hyperbaric oxygen in the treatment of diabetic foot ulcers.

Diabetic foot ulcers are still extremely difficult to heal. Therefore, therapeutic options to improve healing rates are continuously being explored. Hyperbaric oxygen (HBO) has been used in addition to standard treatment of the diabetic foot for more than 20 years. Evidence suggests that HBO reduces amputation rates and increases the likelihood of healing in infected diabetic foot ulcers, in association with improved tissue oxygenation, resulting in better quality of life. Nonetheless, HBO represents an expensive modality, which is only available in few centers. Moreover, adverse events necessitate a closer investigation of its safety. Finally, it is not entirely clear which patients stand to benefit from HBO and how these should be selected. In conclusion, HBO appears promising, but more experience is needed before its broad implementation in the routine care of the diabetic foot.

Epidermal growth factor in the treatment of diabetic foot ulcers: an update.

Management of diabetic foot ulcers remains a rather challenging task. Epidermal growth factor (EGF) plays a central role in wound healing. It acts on epithelial cells and fibroblasts promoting restoration of damaged epithelium. However, its bioavailability is impaired in chronic diabetic foot ulcers. Current evidence suggests that application of human recombinant EGF in addition to standard treatment is able to achieve both partial and complete healing and to prevent foot amputations. Its efficacy has been tested at various concentrations and by various administration routes (topical application and intralesional injection). Intralesional injection has better availability on the deep wound layers, but pain at the injection site is a common complaint. Generally, adverse events have been minor to mild. Finally, numerous issues need to be further clarified before widespread use of EGF becomes possible in everyday practice. Such issues include optimal dosage and administration route, characteristics of the ulcers most likely to heal (severity and ischemic/neuropathic or both), and cost-effectiveness.

The role of nerve growth factor in the prophylaxis and treatment of diabetic foot ulcers.

Diabetic foot ulcers are still particularly difficult to heal. Therefore, preventing and therapeutic adjuncts are increasingly being explored. Nerve growth factor (NGF) is a promising agent exhibiting beneficial actions on both diabetic peripheral neuropathy, one of the main causes of foot ulcers, and on ulcer healing. Indeed, preclinical research in animal models of diabetes has revealed the trophic effect of NGF on small C-fibres, while phase 2 human trials have provided evidence for a favourable effect on sensory neuropathy. However, the results of a phase 3 trial were moderate and, therefore, not enough to encourage widespread use of NGF in the treatment of diabetic neuropathy. Available literature on the role of NGF on diabetic wound healing is sparse but encouraging. Exogenous supplementation of NGF or the use of alternative techniques to increase its endogenous expression could emerge as a protective and therapeutic modality for diabetic foot ulcers in addition to standard treatment and other growth factors. The present review provides an outlook on the role of NGF in the prophylaxis and treatment of diabetic foot ulcers.

The implication of adiponectin and resistin in gastrointestinal diseases.

Adiponectin and resistin, members of the adipokine family, are multi-task hormones involved in several disorders, including those of the alimentary tract. In the present review, eligible studies focusing on the role of adiponectin and resistin in gastrointestinal diseases are manifested together and classified according to anatomic criteria. In addition, similarities and common patterns have been recognized, ultimately revealing an inverse association: the down-regulation of adiponectin and up-regulation of resistin - both in vitro and in vivo - in gastrointestinal disorders, irrespective of their diverse nature - inflammatory, autoimmune or malignant - or anatomic position - esophageal, gastric, of the small intestine, colonic. Finally, a potential role for both adipokines in alimentary tract-related carcinogenesis has been identified, possibly representing a missing link between obesity and cancer.

Unraveling the link between leptin, ghrelin and different types of colitis.

Leptin and ghrelin are hormones with a tight inverse functional connection. Their inverse association is observed not only in the modulation of metabolism but also in the interaction with the immune system. A large number of studies have been launched regarding their association with various disorders, including different types of colitis. The majority of the available literature, however, focuses on inflammatory bowel disease. The role of leptin and ghrelin appears to be aggravating in most of these studies. Concerning intestinal infections, their levels seem to depend on the presence of certain species of micro-biota. As for models of ischemic and miscellaneous colitis, both hormones seem to act protectively, although evidence deriving from human studies is needed before any safe conclusions can be made. Conclusively, it seems that available data, from in vitro, animal and human studies, suggest of a multifarious role for leptin and ghrelin, in the face of different triggers, which in turn cause diverse types of colitis. Bearing this in mind, gaps and loose ends are detected in the associated literature to encourage further research through which the association of leptin and ghrelin with intestinal inflammation could be clarified and expanded so that other types of colitis could also be included.

Angiogenin, angiopoietin-1, angiopoietin-2, and endostatin serum levels in inflammatory bowel disease.

BACKGROUND: Angiogenesis is a complex process, involving a great number of mediators. It is implicated in the pathogenesis of numerous diseases, holding a critical role in inflammatory bowel disease (IBD). The objective of this study was to assess serum levels of angiogenin, angiopoietin-1, angiopoietin-2, and endostatin in IBD patients. METHODS: Measurement of all angiogenesis mediators was performed with a commercially available enzyme-linked immunosorbent assay. Fifty-two patients with ulcerative colitis (UC), 59 with Crohn's disease (CD), and 55 healthy controls (HC) were included in the study. The values were analyzed with regard to disease and patients characteristics. RESULTS: Angiogenin levels were significantly higher in IBD patients compared to HC (P < 0.001) and in UC and CD smoker patients compared to nonsmokers (P = 0.0121 and P = 0.005, respectively). Angiogenin levels were lower in UC patients receiving 5-aminosalicylate (5-ASA) alone, compared to those receiving combined therapy (P = 0.0478). Angiopoietin-1 levels were significantly lower in IBD patients compared to HC (P < 0.0001) and increased in smokers compared to nonsmoker UC patients (P = 0.0085). IBD patients demonstrated increased angiopoietin-2 levels compared to HC (P = 0.0131), while CD patients with disease restricted to the colon had significantly lower levels compared to other disease locations (P < 0.0001). Higher endostatin levels were recorded in UC patients with extensive colitis. CONCLUSIONS: Elevated serum angiogenin and angiopoietin-2 levels and lower serum angiopoietin-1 levels were shown in IBD patients, as well as a different pattern of angiogenic factor alterations related to location, treatment, smoking habits and gender.