Inflammation & Allergy-Drug Targets (v.13, #5)

Glucocorticoids are used to treat chronic and severe forms of allergic conjunctivitis. Although they exert a rapid and powerful therapeutic activity, relevant side effects may limit their ocular use: increase of intraocular pressure, cataract formation and reduced resistance to infections. New glucocorticoids displaying the same potency of classical glucocorticoids but with fewer adverse effects are needed for the treatment of ocular disorders. Mapracorat (also known as ZK245186 or BOL-303242-X) is a novel non-steroidal selective glucocorticoid receptor agonist that is in the first phases of clinical evaluation (Phase II Clinical trials) for topical treatment of inflammatory skin and ocular disorders. Mapracorat binds selectively to human glucocorticoid receptor and displays powerful anti-inflammatory effects. In experimental models of ocular diseases, mapracorat reduces clinical symptoms, eosinophil recruitment, chemokines and pro-inflammatory cytokines production at ocular level, confirming that it acts preventing both the early and late phase of allergic response. Interestingly, mapracorat induces a lower increase of intraocular pressure in comparison to the classical glucocorticoid dexamethasone. Several clinical trials are ongoing to investigate the efficacy and safety of mapracorat for the treatment of several ocular diseases. Transrepressive mechanisms are thought to account for the majority of mapracorat's antiinflammatory effects; however, the induction of anti-inflammatory proteins likely involved in transactivation events may contribute to mapracorat-mediated anti-inflammatory properties and deserve to be further investigated in suitable in vivo and in vitro models. These observations may influence how novel “differential” ligands are discovered, identified and evaluated.

HCV-Related Central and Peripheral Nervous System Demyelinating Disorders by Sara Mariotto, Sergio Ferrari, Salvatore Monaco (299-304).
Chronic infection with hepatitis C virus (HCV) is associated with a large spectrum of extrahepatic manifestations (EHMs), mostly immunologic/rheumatologic in nature owing to B-cell proliferation and clonal expansion. Neurological complications are thought to be immune-mediated or secondary to invasion of neural tissues by HCV, as postulated in transverse myelitis and encephalopathic forms. Primarily axonal neuropathies, including sensorimotor polyneuropathy, large or small fiber sensory neuropathy, motor polyneuropathy, mononeuritis, mononeuritis multiplex, or overlapping syndrome, represent the most common neurological complications of chronic HCV infection. In addition, a number of peripheral demyelinating disorders are encountered, such as chronic inflammatory demyelinating polyneuropathy, the Lewis-Sumner syndrome, and cryoglobulin-associated polyneuropathy with demyelinating features. The spectrum of demyelinating forms also includes rare cases of iatrogenic central and peripheral nervous system disorders, occurring during treatment with pegylated interferon. Herein, we review HCV-related demyelinating conditions, and disclose the novel observation on the significantly increased frequency of chronic demyelinating neuropathy with anti-myelin-associated glycoprotein antibodies in a cohort of 59 consecutive patients recruited at our institution. We also report a second case of neuromyelitis optica with serum IgG autoantibody against the water channel aquaporin-4. The prompt recognition of these atypical and underestimated complications of HCV infection is of crucial importance in deciding which treatment option a patient should be offered.

Antineutrophil cytoplasmic antibody (ANCA)-related vasculitis is a systemic small-vessel vasculitis, including 3 clinical syndromes: granulomatosis with polyangiitis, known as Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and the Churg-Strauss syndrome (CSS). ANCA-related vasculitis usually presents with severe kidney or pulmonary disease, has a mortality of 28% at 5 years, and also contributes to increased morbidity in vasculitis patients. ; Cardiac involvement in this entity may have different forms, including coronary vessels, pericarditis, myocarditis, endocarditis, myocardial infarction and subendocardial vasculitis that can contribute to reduced life expectancy. ; Cardiovascular magnetic resonance using oedema and fibrosis imaging can early reveal, noninvasively and without radiation, heart involvement during vasculitis, undetected by other imaging techniques and guide further risk stratification and treatment of these patients.

Disulfide Stress and its Targets in Acute Pancreatitis by Mari-Luz Moreno, Javier Escobar, Isabela Finamor, Antonio Martinez-Ruiz, Juan Sastre (312-322).
Under physiological conditions, the balance between ROS production and removal properly maintains the intracellular redox-sensitive signaling as well as the appropriate status of protein thiols and disulfides. However, inflammation among other factors can modify this balance causing a rapid increase in intracellular ROS levels and hence thiol oxidation, eventually leading to oxidative stress. In the case of acute pancreatitis, both redox signaling and oxidative stress seem to contribute to the progression of the severe form of the disease. In this review we will focus on the reversible oxidation of protein cysteines during the course of acute pancreatitis. We describe disulfide stress in an acute inflammatory process, which is characterized by thiol oxidation in proteins, particularly protein cysteinylation, without significant changes in the glutathione redox status.

The Association Between the Chronic Use of Non-Steroidal Anti- Inflammatory Drugs and Oxidative and Inflammatory Markers in the Elderly by Luisa Scheer Ely, Maria Gabriela Valle Gottlieb, Paula Engroff, Irenio Gomes, Rafael Noal Moresco, Etiane Tatsch, Guilherme Vargas Bochi, Fernanda Bueno Morrone, Geraldo Attilio De Carli (323-329).
Objectives: Investigate the association between the chronic or occasional use of nonsteroidal anti-inflammatory drugs (NSAIDs) and plasma levels of oxidative and inflammatory markers in elderly at the Family Health Strategy in Brazil. ; Methods: It was a cross-sectional study of data collected from random elderly volunteers. A questionnaire including sociodemographic, health and medicine use data was administered. The blood levels of FRAP (ferric reducing ability of plasma), AOPP (plasma advanced oxidation protein products), MDA (malondialdehyde) and insulin were measured. ; Results: The study sample comprised 758 elderly patients, of which 121 (15.96%) used NSAIDs. The mean age was 68.53 years and 68.41 for individuals who used NSAIDs occasionally and chronically, respectively. Gastric problems may be associated with the chronic or occasional use of NSAIDs (P = 0.042). Which indicates mean plasma levels of Insulin and HOMA-IR (Homeostasis Model Assessment Insulin Resistance) are increased in chronic use of NSAIDs and describes a statistical trend (P = 0.065) for the association of chronic NSAIDs use with the BMI (body mass index) of the subjects studied. ; Conclusion: This study suggests that there is no association between the chronic or occasional use of NSAIDs and oxidative and inflammatory markers. It is known that NSAIDs have innumerable adverse effects, but they can have some benefits. So, additional studies are needed to clarify whether NSAIDs are associated with these markers and whether they are related with their real consequences.

Increased Expression of Forkhead Box Protein 3 Gene of Regulatory T Cells in Patients with Active Tuberculosis by Elham Beiranvand, Saeid Abediankenari, Mohammad Sadegh Rezaei, Soghra Khani, Soroush Sardari, Behnoush Beiranvand (330-334).
Cell mediated immunity is the most important response against Mycobacterium tuberculosis (MTB). Regulatory T cells (Treg) play a vital role in suppressing the effector T cell response in tuberculosis (TB) patients. Forkhead box protein 3 (Foxp3) is an important regulator of Treg cells development and function. In this study, we showed that the expression of Foxp3 gene in Treg cells is increased in patients with active tuberculosis. ; In a case-control study, 183 TB patients and 183 controls were recruited according to ethnicity, gender and living area. Then, after isolation of peripheral blood mononuclear cells (PBMCs), FoxP3 gene expression was studied by real-time PCR. ; The expression of this gene in patients with pulmonary and extra-pulmonary tuberculosis was 2.8 fold higher than normal subjects (CI=1.29±2.37, P≤0.001). Also comparing the patients with pulmonary tuberculosis and the control group, a significant difference was observed (CI=1.81±2.96, P≤0.001). FoxP3 gene expression was 1.5 fold higher in women with pulmonary and extrapulmonary tuberculosis than in men with tuberculosis (CI=0.12±2.01, P=0.02). ; According to this study, the increased Foxp3 gene expression in patients with TB was observed and this may play as a contributing factor to suppression of Th1-type immune responses.

Clinical Queries Addressed in Patients with Systemic Autoimmune Diseases. Can Cardiovascular Magnetic Resonance Give the Final Solution? by Sophie Mavrogeni, Georgia Karabela, Elias Gialafos, George Spiliotis, George Pentazos, Maria Mylona, Stelios Panopoulos, Sotirios Plastiras, Genovefa Kolovou, Efthymios Stavropoulos, Maria Boutsikou, George Kitas, Petros P. Sfikakis (335-338).
Objectives: To evaluate the potential of cardiovascular magnetic resonance (CMR) to answer queries, addressed in systemic autoimmune diseases (SAD). ; Methods: Thirty-six patients aged 52±6 years, (range 27-71) with SAD and suspected cardiac disease underwent CMR by a 1.5 T, after routine evaluation, including clinical, ECG and echocardiographic examination. Steady-state, free precession cines, STIR T2-W and late gadolinium enhanced (LGE) images were evaluated. ; Results: Abnormal findings were detected by: clinical evaluation in 14/36, ECG in 17/36, echocardiography in 11/36 and CMR in 30/36 SAD. Clinical, ECG and echocardiographic examination could not assess cardiac disease acuity and lesions'pathophysiology. In contrary, CMR identified cardiac lesions' etiology, acuity, need for catheterization and heart disease persistence, even if SAD was quiescent. ; Conclusion: Clinical, ECG and echocardiographic abnormalities may suggest, but not always interpret cardiac involvement in SAD. CMR can help to identify both etiology and acuity of cardiac lesions and guide further diagnostic and/or therapeutic approach in these patients.

Chronic Pain: Cytokines, Lymphocytes and Chemokines by Marcia de Miguel, Durval Campos Kraychete, Roberto Jose Meyer Nascimento (339-349).
Chronic pain is a debilitating condition and, in most cases, difficult to treat. A prominent example of this is neuropathic pain. Understanding pathophysiological mechanisms of pain and, therefore, making this knowledge into an effective treatment is still a challenge to experts. Pain can now be considered as a neuro-immune disorder, since recent data indicate critical involvement of innate and adaptive immune responses following injury, and this interaction plays an important role in the onset and perpetuation of chronic pain. The aim of this article is to review the relationship between immune system and chronic pain, especially about neuropathic pain, and focusing on cytokines, chemokines and lymphocytes.