Inflammation & Allergy-Drug Targets (Discontinued) - Volume 9, Issue 2, 2010

Studies of the molecular mechanisms associated with allergic diseases have lead to a better understanding of the complex processes that underlie their pathogenesis. These mechanisms involve Th2- and Th1-type cells and also some recently described cytokines, such as IL-25 and IL-33. Regulatory mechanisms of allergic inflammation have also been identified. For instance, IL-10, a cytokine produced by many cell types, promotes a decrease in IgE production, and inhibits the release of histamine and other inflammatory mediators by mast cells. Recently, a variety of regulatory cells have been discovered, which, either by direct contact or through the production of IL-10 and/or TGF-β, can inhibit the allergic inflammatory response. IL-10 is produced in high levels by cells of helminth-infected individuals. There is some evidence that such infections protect against the development of allergic diseases. In asthmatic individuals living in endemic areas of schistosomiasis, it has been shown in in vitro studies that there is a modulation of the Th2 response, both by mechanisms involving IL-10, which is produced mainly by monocytes and CD4+CD25+ T regulatory cells, and also by the expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in CD4+ T cells. Studies using parasite antigens to induce the modulation of allergic inflammatory response are being conducted by several groups of researchers and represent new perspectives for the treatment of allergic diseases.

An innate immune response to bacterial and viral components is thought to be involved in the pathogenesis of cholangiopathies in case of primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess the Toll-like receptor (TLR) family which recognizes pathogen-associated molecular patterns (PAMPs) and plays a pivotal role in the innate immune response. In PBC, disordered regulations of TLRs and a negative regulator of intracellular signaling, peroxisome proliferator-activated receptor-γ (PPARγ), with Th1-predominant cytokine milieu are involved in the pathogenesis of cholangitis such as chronic non-suppurative destructive cholangitis (CNSDC). Moreover, CD4-positive Th17 cells characterized by the secretion of IL-17, are implicated in the chronic inflammation of bile ducts in PBC and the induction of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses could directly induce the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and apoptosis in biliary epithelial cells as a result of the biliary innate immune response via dsRNA-recognizing receptors such as TLR3 and retinoic acid inducible gene I (RIG-I). Moreover, as a mechanism behind the sclerosing cholangiopathy in biliary atresia, epithelial-mesenchymal transition (EMT) has been proposed and the biliary innate immune response to dsRNA viruses is demonstrated to induce biliary epithelial cells to undergo EMT. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems.

In this paper we shortly discuss epidemiological data on the relationship between asthma and atopy according to recent personal and literature epidemiological publications. The coexistence in several subjects of asthma (and of other “atopic” diseases) and IgE hyperproduction generated the dogma that these two biological conditions are mainly genetic in origin and are linked by a strong casual relationship. In the last decades atopy increased at 5-10% annual rate and at present atopy prevalence, although variable in different countries, reaches somewhere the prevalence of more than 60%. Similarly, asthma prevalence increased in the last decades, especially so in western and English speaking countries, reaching in certain countries prevalence values higher than 40%. For these reasons, although certainly dependent on a genetic predisposition, atopy and asthma can nowadays be considered to be largely determined by environmental factors. Moreover, the analysis of epidemiological data derived from studies conducted worldwide, showed that the prevalence of the two conditions were clearly not correlated so that in certain countries with a 50-60% prevalence of atopy asthma prevalence is lower than 2-6%, while in other countries asthma prevalence is double than atopy prevalence. Further, in countries with high atopy, the prevalence this conditions is high both in asthmatics and in normal subjects and in the places where asthma prevalence reaches high levels this condition is high both in atopic and non atopic people. In conclusion, epidemiological data show that environmental factors affecting asthma prevalence are different from those affecting atopy prevalence and that subjects bearing one of the two conditions don't show any preferential tendency to develop the other one. From aetiological and pathogenetic point of view asthma and atopy appear to be independent conditions. We therefore believe that the association between asthma and atopy demonstrated in almost all the “population studies” (atopy prevalence has always been found 20-30% higher in asthmatics than in non asthmatic subjects) doesn't prove the existence of a “causal” relationship between the two conditions: this could be a kind of association without causative meaning as is the association between blond hair and blue eyes which in no way can be considered a prove that one of the two conditions is the cause of the other.

Acute pancreatitis starts as a local inflammation of the pancreatic tissue but often leads to the systemic inflammatory response syndrome and death by multiple organ failure. Pro-inflammatory cytokines, particularly TNF-α and Il-1β, play a pivotal role together with oxidative stress and glutathione depletion in the inflammatory response in this disease. Most inflammatory mediators act through mitogen activated protein kinases and nuclear factor κB. Nevertheless, elucidation of the precise mechanisms involved in activation and attenuation phases of the inflammatory cascade is still underway. Redox signaling mediated by inactivation of protein phosphatases and histone acetylation triggered by histone acetyltransferases, particularly CBP/p300, decisively contribute to the activation phase of the inflammatory cascade. Reversible oxidation of thiols in serine threonine protein phosphatase PP2A and in protein tyrosin phosphatases SHP1, SHP2 and CD45 leads to their inactivation generally by formation of intramolecular disulfides. Consequently, oxidative stress promotes the activation of MAP kinases through the inactivation of protein phosphatases, which act as sensors of the cellular redox state. On the other hand, histone deacetylases together with serine threonine protein phosphatases PP1 and PP2A and dual specificity phosphatases down-regulate the expression of pro-inflammatory genes in the attenuation phase. Treatment with phosphodiesterase inhibitors, such as pentoxifylline, in the very early stage of the disease prevents the loss of pancreatic PP2A activity abrogating the recruitment of histone acetyltransfereases to the promoters of proinflammatory genes and their up-regulation. Inhibitors of histone deacetylases are also proposed as potential therapy in acute pancreatitis, and their therapeutic window discussed.

A total of 4668 patients from four university hospitals, all representing cases with inner ear tumours or other inner ear disorders were evaluated. No primary cancer or melanoma could be detected. These results are in compliance with publications of other institutions discussing their own results in detecting inner ear pathologies. This finding is unusual and leads to the assumption that the epithelial cells of the auditory inner ear may be protected from malignant transformations. The aim of this study is to investigate the reasons for this supposed anticarcinogenic privilege of the auditory inner ear. The auditory inner ear has some unique features in the organism by reversing the relationship between intra- and extracellular ion concentrations of potassium and sodium in the endolymph. Furthermore it has a physiologically extremely high membrane potential and an unusual transmembrane and extracellular circulation of potassium ions. How these aspects contrast with the corresponding features at the carcinoma site, will be investigated. This comparison will be further deepened by reviewing the published actions of antitumoral substances in connection with these issues. On the basis of this comparative study one might speculate that the auditory inner ear is privileged by an anticarcinogenic principle and that the specific features of membrane potential, certain potassium channels and the unique transmembrane as well as extracellular potassium movements may play a decisive role in it.

Having defined a putative anticarcinogenic principle under physiological conditions of the auditory inner ear in the previous part of this study, part 2 is the continuation to evaluate this hypothesis under pathological conditions, i.e. with regard to the inflamed auditory inner ear. Inflammation of the auditory inner ear shows three characteristic phases. It starts with an acute phase, progresses to a fibrotic one and ends with ossification as the last phase. At the end of the fibrotic phase the inflammatory cells disappear, probably due to apoptosis, the ganglion neurons die and the fibrous matrix ossifies. No proliferating cells can be found in this area any more. Thus this kind of inflammation does not result in a restoration of the former state, but always in the destruction of the hearing organ and corresponding neurons. The osteoimmune axis is involved in this characteristic type of inflammation. Important factors hereby are M-CSF, RANKL/RANK and osteoprotegerin. In the inner auditory ear they inhibit the resorption of the fibrotic matrix, induce apoptosis of inflammatory cells and calcification. This inflammatory osteoimmune axis plays an important role at the cancer site as well. The relation of each factor to the other ones is however fundamentally different from that in the inner ear. Consequently inflammatory processes induced by a tumour foster its progression and may induce bone metastasis. Instead of a dominating and enclosing osteoblastic activity like in the inner ear, matrix resolving and often osteoclastic properties are developed allowing the spread of cancer cells. These processes allows us to set out the anticarcinogenic hypothesis more precisely and define its putative mechanistic rationale for the inflamed auditory inner ear.

The trend in asthma therapy for the last two decades has been based on the suppression of inflammation and bronchodilation via adrenergic agonism or cholinergic antagonism. These strategies help to control asthmatic symptoms but do not lead to a cure. Substantial populations of patients may still have poorly managed symptoms and suffer a decline in quality of life due to the disease. Reversible airflow obstruction and nonspecific airway reactivity are the key features of asthma. Inflammatory changes do not correlate always with symptoms in asthma patients. It is our opinion that the primary defect in asthma is cell membrane excitation — bronchoconstriction and reactivity — rather than inflammation. Our research, clinical experience and the accumulated evidence from medical literature strongly suggest that controlling other excitatory mechanisms such as voltage-gate sodium channel and glutamate receptors in the central nervous system and lung tissue could lead to more effective and safer strategies for asthma prevention and treatment.

Hepatitis C virus (HCV) infection related hepatitis remains one of the most serious health problems worldwide. During investigation of hypervariable region 1 (HVR1) of HCV, a seven amino acids mimic peptide (GQTYTSG, named 7-P) was identified within the N-terminal of HVR1 that could protect porcine serum (PS)-induced hepatic injury in rats. 7-P could not only decrease the serum levels of aminotransferases (ALT, AST), alkaline phosphatase (AKP), and billirubin, but were also effective in reversing histopathological evidence of PS-induced rat chronic liver injury. The protective mechanism was investigated in detail using Affymetrix microarrays analysis. The bioinformatic data was confirmed by western blotting. Further studies revealed that IL-1β, tumor necrosis factor receptor superfamily 14 (TNFRSF14), intercellular adhesion molecule 2 (ICAM2), sterol regulatory element-binding protein 1 (SREBP 1), Prohibitin (PHB), and inhibitor of DNA binding 2 (Id2) were the key factors for 7-P-induced hepatoprotective effect. Together these data suggest that 7-P mimic from HVR1 of HCV protects hepatic injury by reducing the expression of key pro-inflammatory factors. 7-P might have potential therapeutic application for hepatitis in human beings.