Inflammation & allergy drug targets最新文献

Vitamin D is well known for its classic role in the maintenance of bone mineral density. However, vitamin D also has an important "non-classic" influence on the body's immune system by modulating the innate and adaptive immune system, influencing the production of important endogenous antimicrobial peptides such as cathelicidin, and regulating the inflammatory cascade. Multiple epidemiological studies in adults and children have demonstrated that vitamin D deficiency is associated with increased risk and greater severity of infection, particularly of the respiratory tract. Although the exact mechanisms by which vitamin D may improve immune responses to infection continue to be evaluated, vitamin D supplementation trials of prevention and adjunct therapy for infection are underway. Given its influence on the immune system and inflammatory cascade, vitamin D may have an important future role in the prevention and treatment of infection.

Interleukin-6 has been shown to be increased in various pathological conditions involving the lungs, both experimentally induced in animals, or spontaneously occurring in humans. Experimental data demonstrating a significant role of interleukin-6 in commonly occurring respiratory system inflammatory diseases are reviewed. These diseases, i.e. asthma and chronic obstructive pulmonary disease, are characterised by respiratory system mechanical derangement, most of all because increased elastance and airway resistance. Recent findings showing a causative role of interleukin-6 in determining an airway resistance increment are reviewed. By applying the end-inflation occlusion method to study respiratory system mechanical properties before and after interleukin-6 administration, it was shown that this cytokine induced significant increments in both the resistive pressure dissipation due to frictional forces opposing the airflow in the airway (ohmic resistance), and in the additional resistive pressure dissipation due to the visco-elastic properties of the system, i.e. stress relaxation (visco-elastic resistance). A dose-dependent effect was also demonstrated. No effects were instead detected on respiratory system elastance. Even solely administrated in healthy mammals, interleukin-6 exhibits a significant effect on respiratory system resistances, leading to increased inspiratory muscle mechanical work of breathing. Thus, IL-6 may play an active role in the pathogenesis of respiratory system diseases. The possible involved mechanisms are discussed.

Diabetes is known to be regulated by cytokines secreted from Th1 cells, while allergic rhinitis (AR) is mainly regulated by Th2 cytokines. In recent past we have reported the development of diabetes in response to parthinium induced AR to rats. These results were contradictory to Th1/Th2 paradigm which suggests that Th1 and Th2 cells reciprocally counteract each other. Subsequently in silico interactome analysis further revealed that Th2 cytokines may signal to increase the level of Th1 along with the proteins involved in the development of diabetes. In present study we tried to understand the diabetogenic changes on the background of ovalbumin induced allergic rhinitis (OVA). Three groups of seven rats were considered; group I control (Ctrl); group II OVA and group III OVA+L-cetrizine (OVA+ D). The study continued for 48 days and the experiment was terminated on day 49, while L-cetrizine was administered for last 07 days (42-48 days). Group II showed increased levels of Th1 (IL-2) and Th2 cytokines, induction of allergic rhinitis and changes in the proteins involved in diabetes. In group III, most of the changes were reverted back towards normalcy. Induction of allergic rhinitis triggers Th2 cytokines that result increase IL-2 (Th1) and alterations in the metabolic parameters led to the condition of prediabetes.

Although oral iron preparations are widely prescribed to prevent and to treat iron deficiency anemia in pregnancy, comparative data on their effects to the mother, fetus and placenta are limited. In this study, the effects of oral iron polymaltose complex (IPC), ferrous fumarate (FF) and ferrous sulfate (FS) were compared in anemic pregnant rats, their fetuses and placentas. Hematological variables and oxidative stress markers in the liver, heart and kidneys of the dams and fetuses as well as the markers for oxidative stress, inflammation and hypoxia in placentas were assessed. Pregnancy outcome was measured by number of fetuses, and by neonate and placental weight. All therapies were comparably effective in correcting anemia. FS and FF, but not IPC, resulted in liver damage in dams and oxidative stress in dams, fetuses and placentas. FS group presented the highest catalase and GPx levels in dams, fetuses and placentas. IPC, but not FF or FS, restored normal TNF-α and IL6 expression levels in placentas whereas FS-treated animals presented the highest cytokine levels, suggesting a local inflammatory reaction. Anemia-induced high levels of HIF-1α were partially lowered by IPC and FF but further elevated by FS. Most of the negative effects associated with IDA were resolved by IPC treatment. Especially FS treatment was found to elicit hepatic damage in the dams, oxidative stress in the dams, fetuses and placenta as well as inflammation and high levels of HIF-1α in the placenta. Pregnancy outcome of FFand FS-treated animals was worse than that of IPC-treated animals.

Introduction: Rheumatoid arthritis (RA) affects many organs, including the heart. Cardiac magnetic resonance (CMR) can assess heart pathophysiology in RA.

Aim: To evaluate, using CMR, RA patients under remission with recent onset of cardiac symptoms.

Patients and methods: Twenty RA under remission (15F/5M), aged 60±5 yrs, with recent onset of cardiac symptoms (RAH), were prospectively evaluated by CMR. The CMR included left ventricular ejection fraction (LVEF), T2-weighted (T2-W), early (EGE) and late gadolinium enhanced (LGE) images evaluation. Their results were compared with those of 20 RA under remission without cardiac symptoms (RAC) and 18 with systemic lupus erythematosus (SLE) with clinically overt myocarditis.

Results: Cardiac enzymes were abnormal in 5/20 RAH. CMR revealed inferior wall myocardial infarction in 2/20 (1M, 1F) and myocarditis in 13/20 (8M/5F) RAH. The T2 ratio of myocardium to skeletal muscle was increased in RAH and SLE compared to RAC (2.5 ± 0.05 and 3.4±0.7 vs 1.8 ± 0.5, p<0.001). EGE was increased in RAH and SLE compared to RAC (15 ± 3 and 12±4.7 vs 2.7±0.8, p<0.001). Epicardial LGEs were identified in 10/13 and pericarditis in 6/13 RAH. Coronary angiography, performed in 5 RAH with increased cardiac enzymes, proved a right coronary artery obstruction in 2/5. In 3/5 with CMR positive for myocarditis, coronary arteries were normal, but endomyocardial biopsy revealed inflammation with normal PCR. An RA relapse was observed after 7-40 days in 10/13 RAH with myopericarditis. The one year follow up showed that a) RAH with myocarditis had more disease relapses and b) CHF was developed in 4 RAH with myocarditis.

Conclusions: Myopericarditis with atypical presentation, diagnosed by CMR in RA under remission, may precede the development of RA relapse. In 1 year follow up, RA patients with history of myocarditis have a higher frequency of disease relapse and may develop CHF.

Background: Gastroparesis is a disorder characterized by delayed gastric emptying of a meal in the absence of a mechanical gastric outlet obstruction. Idiopathic gastroparesis is at least as common as diabetic gastroparesis in most case series, and the true prevalence of gastroparesis is unknown.

Results: We report here an interesting case of idiopathic gastroparesis characterized by sudden onset in a female patient. The diagnosis was confirmed by ultrasonographic study of gastric emptying and electrogastrography, by gastric endoscopy/histology, and finally by allergy tests. The disorder was found to be due to a rare cause, namely an allergic predisposition. In fact, our patient, who demonstrated an allergy to gold salts, had drunk a glass of a liqueur containing gold flakes and developed an eosinophilic aggregation in the gastric mucosa observed at gastric endoscopy/histology. The symptoms disappeared after steroid administration.

Conclusion: Our experience suggests that gastric histology and close enquiry into any history of allergy may be useful diagnostic tools in cases of idiopathic gastroparesis.

Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors and is involved in signal transmission in both the central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. In recent years, studies have suggested the relationship of GRP and inflammatory diseases. RC-3095, a selective GRPR antagonist, was found to have antiinflammatory properties in models of arthritis, gastritis, uveitis and sepsis. Furthermore, GRP mediates air pollutioninduced airway hyperreactivity and airway inflammation in mice. In conclusion, GRP and its receptor are relevant to the inflammatory response, being a potential therapeutic target several diseases are related to inflammation.

Background: Allergic rhinitis, one of the most common atopic diseases, is known to be elicited by Th2 cytokine-mediated inflammatory response. We have shown earlier that a polyol pathway enzyme aldose reductase (AR) regulates airway inflammation; however its role in allergic rhinitis is not known. We have investigated the role of AR in mediating pathological symptoms associated with allergic rhinitis in mice.

Methods: The wild-type (WT) mice treated without or with AR inhibitor and AR knock out (AR(-/-)) mice were sensitized by two intraperitoneal injections of ragweed pollen extract (RWE) with adjuvant alum on days 0 and 4 followed by challenge on day 11 and/or 18 and 25. The allergic rhinitis symptoms were assessed by monitoring the nasal scratch, mast cell degranulation and release of tryptase in nasal lavage, infiltration of inflammatory cells, production of inflammatory cytokines and nasal epithelium remodeling.

Results: Sensitization and challenge of mice with RWE produced robust and reproducible pathological symptoms of allergic rhinitis as compared to control mice. AR inhibitor, fidarestat administered mice showed markedly reduced early phase response to allergen exposure such as nasal scratches, mast cells degranulation and release of tryptase in the nasal passage as well as late phase response such as inflammatory cell infiltration and release of Th2 type cytokines and nasal epithelial remodeling. Further, prevention of these events in AR(-/-)) mice suggests the role of AR in the mediation of allergic rhinitis.

Conclusion: These results indicate an important role of AR in the mediation of RWE-induced allergic rhinitis in mice and prevention by AR inhibitor, fidarestat offers a novel therapeutic approach to ameliorate allergic rhinitis.

Diabetes is one of the risk factors to human health, which progressively leads to renal complications known as diabetic nephropathy. Many previous studies illustrated biochemical and morphological abnormalities in various animal models of diabetic nephropathy, which may be attributed to altered action of adenosine, an endogenous purine nucleoside released from various tissues and organs. Adenosine is a potent autocrine anti-inflammatory and immunosuppressive molecule that is released from cells into the extracellular space at sites of inflammation and tissue injury. This review will give a general overview of the adenosine receptors and focuses on their role in diabetes nephropathy. The insight into the signaling pathway through adenosine receptors could be helpful in developing novel therapeutic tools to regulate the pathophysiological conditions that arise progressively in diabetes.

Glutathione S transferase P1-1 plays a key role in the metabolism of inflammatory mediators and drugs, thus modulating the inflammatory response. Active GSTP1-1 is a homodimer with cysteine residues close to the active site that can undergo oligomerization in response to stress, a process that affects enzyme activity and interactions with signaling and redox-active proteins. Cyclopentenone prostaglandins (cyPG) are endogenous reactive lipid mediators that participate in the regulation of inflammation and may covalently modify proteins through Michael addition. cyPG with dienone structure, which can bind to vicinal cysteines, induce an irreversible oligomerization of GSTP1-1. Here we have characterized the oligomeric state of GSTP1-1 in Jurkat cells treated with 15-deoxy-Δ12,14-PGJ₂ (15d-PGJ₂). 15d-PGJ₂ induces both reversible and irreversible GSTP1-1 oligomerization as shown by blue-native 2D electrophoresis. Interestingly, GSTP1-1 dimers were the main species detected by analytical gel filtration chromatography in control cells, whereas only oligomers, compatible with a tetrameric association state, were found in 15d-PGJ₂-treated cells. cyPG-induced GSTP1-1 oligomerization also occurred in cell-free systems. Therefore, we employed this model to assess the effects of endogenous reactive species and drugs. Inflammatory mediators, such as 15d-PGJ₂ and Δ12-PGJ₂, and drugs like chlorambucil, phenylarsine oxide or dibromobimane elicited whereas ethacrynic acid hampered GSTP1-1 oligomerization or intra-molecular cross-linking in cell-free systems, yielding GSTP1-1 species specific for each compound. These observations situate GSTP1-1 at the cross-roads of inflammation and drug action behaving as a target for both inflammatory mediators and reactive drugs, which induce or reciprocally modulate GSTP1-1 oligomerization or conformation.