Inflammation & Allergy-Drug Targets (v.12, #3)

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

Modulation of GSTP1-1 Oligomerization by Electrophilic Inflammatory Mediators and Reactive Drugs by Francisco Sanchez-Gomez, Carlos Dorado, Pedro Ayuso, Jose Agundez, Maria Pajares, Dolores Perez-Sala (162-171).
Glutathione S transferase P1-1 plays a key role in the metabolism of inflammatory mediators and drugs, thusmodulating the inflammatory response. Active GSTP1-1 is a homodimer with cysteine residues close to the active site thatcan undergo oligomerization in response to stress, a process that affects enzyme activity and interactions with signalingand redox-active proteins.</p><p>Cyclopentenone prostaglandins (cyPG) are endogenous reactive lipid mediators that participate in the regulation ofinflammation and may covalently modify proteins through Michael addition. cyPG with dienone structure, which can bindto vicinal cysteines, induce an irreversible oligomerization of GSTP1-1. Here we have characterized the oligomeric stateof GSTP1-1 in Jurkat cells treated with 15-deoxy-Δ12,14-PGJ<sub>2</sub> (15d-PGJ<sub>2</sub>). 15d-PGJ<sub>2</sub> induces both reversible andirreversible GSTP1-1 oligomerization as shown by blue-native 2D electrophoresis. Interestingly, GSTP1-1 dimers werethe main species detected by analytical gel filtration chromatography in control cells, whereas only oligomers, compatiblewith a tetrameric association state, were found in 15d-PGJ<sub>2</sub>-treated cells.</p><p>cyPG-induced GSTP1-1 oligomerization also occurred in cell-free systems. Therefore, we employed this model to assessthe effects of endogenous reactive species and drugs. Inflammatory mediators, such as 15d-PGJ<sub>2</sub> and Δ12-PGJ<sub>2</sub>, and drugslike chlorambucil, phenylarsine oxide or dibromobimane elicited whereas ethacrynic acid hampered GSTP1-1oligomerization or intra-molecular cross-linking in cell-free systems, yielding GSTP1-1 species specific for eachcompound.</p><p>These observations situate GSTP1-1 at the cross-roads of inflammation and drug action behaving as a target for bothinflammatory mediators and reactive drugs, which induce or reciprocally modulate GSTP1-1 oligomerization orconformation.

Gastrin-Releasing Peptide as a Molecular Target for Inflammatory Diseases: An Update by Fabricia Petronilho, Lucineia Danielski, Rafael Roesler, Gilberto Schwartsmann, Felipe Dal-Pizzol (172-177).
Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors and is involvedin 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 suggestedthe relationship of GRP and inflammatory diseases. RC-3095, a selective GRPR antagonist, was found to have antiinflammatoryproperties in models of arthritis, gastritis, uveitis and sepsis. Furthermore, GRP mediates air pollutioninducedairway hyperreactivity and airway inflammation in mice. In conclusion, GRP and its receptor are relevant to theinflammatory response, being a potential therapeutic target several diseases are related to inflammation.

Prevention of Allergic Rhinitis by Aldose Reductase Inhibition in a Murine Model by Umesh Yadav, Rakesh Mishra, Leopoldo Aguilera-Aguirre, Sanjiv Sur, Istvan Bolodgh, Kota Ramana, Satish Srivatsava (178-186).
Background: Allergic rhinitis, one of the most common atopic diseases, is known to be elicited by Th2cytokine-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 inmediating pathological symptoms associated with allergic rhinitis in mice.</p><p>Methods: The wild-type (WT) mice treated without or with AR inhibitor and AR knock out (AR<sup>-/-</sup>) mice were sensitizedby two intraperitoneal injections of ragweed pollen extract (RWE) with adjuvant alum on days 0 and 4 followed bychallenge on day 11 and/or 18 and 25. The allergic rhinitis symptoms were assessed by monitoring the nasal scratch, mastcell degranulation and release of tryptase in nasal lavage, infiltration of inflammatory cells, production of inflammatorycytokines and nasal epithelium remodeling.</p><p>Results: Sensitization and challenge of mice with RWE produced robust and reproducible pathological symptoms ofallergic rhinitis as compared to control mice. AR inhibitor, fidarestat administered mice showed markedly reduced earlyphase response to allergen exposure such as nasal scratches, mast cells degranulation and release of tryptase in the nasalpassage as well as late phase response such as inflammatory cell infiltration and release of Th2 type cytokines and nasalepithelial remodeling. Further, prevention of these events in AR<sup>-/-</sup> mice suggests the role of AR in the mediation ofallergic rhinitis.</p><p>Conclusion: These results indicate an important role of AR in the mediation of RWE-induced allergic rhinitis in mice andprevention by AR inhibitor, fidarestat offers a novel therapeutic approach to ameliorate allergic rhinitis.

A Mysterious Case of Gastroparesis: Could the Secret be Found in a Drink? by Mariabeatrice Principi, Ranaldo Nunzio, Giuseppe Ingravallo, Giuseppe Riezzo, Elisabetta Damiani, Antonio Ferrannini, Roberta Rossi, Leonardo Resta, Enzo Ierardi, Alfredo Leo (187-189).
Background: Gastroparesis is a disorder characterized by delayed gastric emptying of a meal in the absence of amechanical gastric outlet obstruction. Idiopathic gastroparesis is at least as common as diabetic gastroparesis in most caseseries, and the true prevalence of gastroparesis is unknown.</p><p>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 gastricendoscopy/histology, and finally by allergy tests. The disorder was found to be due to a rare cause, namely an allergicpredisposition. In fact, our patient, who demonstrated an allergy to gold salts, had drunk a glass of a liqueur containinggold flakes and developed an eosinophilic aggregation in the gastric mucosa observed at gastric endoscopy/histology. Thesymptoms disappeared after steroid administration.</p><p>Conclusion: Our experience suggests that gastric histology and close enquiry into any history of allergy may be usefuldiagnostic tools in cases of idiopathic gastroparesis.

Although oral iron preparations are widely prescribed to prevent and to treat iron deficiency anemia inpregnancy, comparative data on their effects to the mother, fetus and placenta are limited. In this study, the effects of oraliron 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 thedams 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 werecomparably effective in correcting anemia. FS and FF, but not IPC, resulted in liver damage in dams and oxidative stressin 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 animalspresented the highest cytokine levels, suggesting a local inflammatory reaction. Anemia-induced high levels of HIF-1αwere partially lowered by IPC and FF but further elevated by FS. Most of the negative effects associated with IDA wereresolved by IPC treatment. Especially FS treatment was found to elicit hepatic damage in the dams, oxidative stress in thedams, fetuses and placenta as well as inflammation and high levels of HIF-1α in the placenta. Pregnancy outcome of FFandFS-treated animals was worse than that of IPC-treated animals.

Diabetes is known to be regulated by cytokines secreted from Th1 cells, while allergic rhinitis (AR) is mainlyregulated by Th2 cytokines. In recent past we have reported the development of diabetes in response to parthiniuminduced AR to rats. These results were contradictory to Th1/Th2 paradigm which suggests that Th1 and Th2 cellsreciprocally counteract each other. Subsequently in silico interactome analysis further revealed that Th2 cytokines maysignal to increase the level of Th1 along with the proteins involved in the development of diabetes. In present study wetried to understand the diabetogenic changes on the background of ovalbumin induced allergic rhinitis (OVA). Threegroups 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 last07 days (42-48 days). Group II showed increased levels of Th1 (IL-2) and Th2 cytokines, induction of allergic rhinitis andchanges 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 metabolicparameters led to the condition of prediabetes.

Myopericarditis, as the First Sign of Rheumatoid Arthritis Relapse, Evaluated by Cardiac Magnetic Resonance by Sophie Mavrogeni, Konstantinos Bratis, Eliza Sfendouraki, Evangelia Papadopoulou, Genovefa Kolovou (206-211).
Introduction: Rheumatoid arthritis (RA) affects many organs, including the heart. Cardiac magnetic resonance(CMR) can assess heart pathophysiology in RA.</p><p>Aim: To evaluate, using CMR, RA patients under remission with recent onset of cardiac symptoms.</p><p>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 of20 RA under remission without cardiac symptoms (RAC) and 18 with systemic lupus erythematosus (SLE) with clinicallyovert myocarditis.</p><p>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 andSLE 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 toRAC (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 in2/5. In 3/5 with CMR positive for myocarditis, coronary arteries were normal, but endomyocardial biopsy revealedinflammation with normal PCR. An RA relapse was observed after 7-40 days in 10/13 RAH with myopericarditis. Theone year follow up showed that a) RAH with myocarditis had more disease relapses and b) CHF was developed in 4 RAHwith myocarditis.</p><p>Conclusions: Myopericarditis with atypical presentation, diagnosed by CMR in RA under remission, may precede thedevelopment of RA relapse. In 1 year follow up, RA patients with history of myocarditis have a higher frequency ofdisease relapse and may develop CHF.

Background: Atopic dermatitis (AD) is a chronic allergic inflammatory disease characterised by lateeczematous lesions and allergenic sensitisation that occur. Skin prick testing has been used for the causative investigationof individual allergens. However, there exists no proper tool to evaluate polysensitisation status. In this study, skinsensitisation indices were suggested, and the clinical significance of polysensitisation was evaluated.</p><p>Methods: A total of 188 AD patients were involved in this study. Blood tests including blood eosinophil % and serumtotal IgE were conducted. Skin prick tests for 50 important allergens were performed. The skin sensitisation index (SSI)was compared with the blood eosinophil % and the serum total IgE.</p><p>Results: The degree of sensitisation may be related to the serum total IgE rather than the number of allergens to which apatient is sensitised. The skin sensitisation profile was associated with IgE-related laboratory results but not with clinicalactivity or blood eosinophil %.</p><p>Conclusions: For the evaluation of polysensitisation, skin sensitisation profiles may be needed and the skin sensitisationprofile was useful for the description of polysensitisation. Polysensitisation seems to be one mechanism for the elevationof serum total IgE. Further studies may be needed to ascertain the clinical significance of skin polysensitisation and theapplication of the skin sensitisation profile in clinical use.