Inflammation & Allergy-Drug Targets (v.10, #3)

Nasal Polyposis: From Pathogenesis to Treatment, An Update by Manuele Casale, Marco Pappacena, Massimiliano Potena, Emanuela Vesperini, Giacomo Ciglia, Ranko Mladina, Caterina Dianzani, Anna Marta Degener, Fabrizio Salvinelli (158-163).
Nasal polyps (NP) are common benign degeneration of nasal sinus mucosa with a prevalence around 4% in theadult population. The causes are still uncertain but there is a strong association with allergy, infection, asthma and aspirinsensitivity. Histologically, the presence of a large quantity of extracellular fluid, mast cell degranulation and eosinophiliahas been demonstrated. Typically the patients show nasal obstruction, anosmia and rhinorrhoea. Nasal endoscopicexamination and CT imaging allow evaluation of the disease extention. A combined medical and surgical treatment is recommended for symptoms control in preventing symptomatic NPrecurrence. We will review the current knowledge in the pathogenesis and treatment of this complex disease entity.

There may be some difficulties to differentiate Behcet’s disease (BD), recurrent aphthosis (RA), and herpeticaphthous ulceration, from other mimicking oral disorders. Despite of unexpected sensitivity and responsiveness, the skinpathergy test regarding a non-specific hypersensitivity has long been thought as one of auxiliary diagnostic benefits forBD. To determine the potential usefulness and disease specificity of the prick reaction with saliva, a skin prick test with neatand filter-sterilized saliva was performed on the forearm skin of 26 individuals; 10 patients with BD (8 incomplete typewithout uveitis, 1 complete type, and 1 neurological type), 5 with RA, 3 with herpetic oral aphthosis, 2 with erythemanodosum alone, and 6 healthy controls. We assessed the skin reaction at 48 hours after pricking, and the pricked skinlesions were biopsied and analyzed immunohistologically. Nine of 10 BD patients (90 %) exhibited an indurative erythema at the skin site pricked with self-saliva, whereas 3 of 5RA patients (60%) were relatively weak reaction. Pricking with filter-sterilized saliva failed to recapitulate any of positiveskin reactions, albeit a faint erythematous dot appeared in a few BD patients, implicating the involvement of causativemicroorganism(s) in oral bacterial flora. Culture of saliva from 3 randomly chosen BD patients revealed numerousstreptococcal colonies on Mitis-Salivarius agar. Histology of the pricked skin sites showed perivasucular inflammatoryinfiltrates, composed of CD4+ T cells and CD68+ monocyte/macrophage lineage, a feature consistent with a delayed typehypersensitive reaction. Our results suggested that skin prick test using self-saliva (a new diagnostic pathergy) can be a simple and valuable invivo diagnostic approach for differentiating BD and RA from other mimicking mucocutaneous diseases. The positive skinprick may be triggered by resident intra-oral microflora, particularly streptococci, and may in part address the underlyingimmunopathology in BD.

Double-Stranded RNA Induces MMP-9 Gene Expression in HaCaT Keratinocytes by Tumor Necrosis Factor-.. by Andreas Voss, Kirsten Gescher, Andreas Hensel, Wolfgang Nacken, Claus Kerkhoff (171-179).
Viral double-stranded RNA (dsRNA) and its synthetic analog poly(I:C) are recognized via multiple pathwaysand induce the expression of genes related to inflammation. In the present study, we demonstrate that poly(I:C)specifically induced the expression of matrix metalloproteinase-9 (MMP-9) in HaCaT keratinocytes. Studies usingspecific pharmacological inhibitors revealed the involvement of NF-..B, p38 MAPK, and PI-3K signal transductionpathways in poly(I:C)-induced MMP-9 gene expression. MMP-9 gene induction was sensitive toward treatment with themacrolide antibiotic bafilomycin A1, a vacuolar H+-ATPase inhibitor, and with the lysosomotropic agent chloroquine.However, cycloheximide treatment only partially blocked poly(I:C)-induced MMP-9 gene expression. Although HaCaTkeratinocytes produce a number of cytokines and chemokines in response to poly(I:C), stimulation experiments revealedthat exclusively TNF-.. strongly promoted MMP-9 gene expression. During the antiviral response MMP-9 expression maybe of importance for the tissue injury phase.

Biology of the Interleukin-9 Pathway and its Therapeutic Potential for the Treatment of Asthma by Chad K. Oh, Donald Raible, Gregory P. Geba, Nestor A. Molfino (180-186).
Asthma is a complex disease characterized by variable airflow limitation, hyperresponsiveness, and airwaysinflammation. Despite valuable therapeutic advances to control asthma symptoms in the last decade, a quantifiableproportion of patients with moderate to severe asthma continue to experience inadequate disease control, highlighting animportant unmet need. In animal models of asthma, interleukin (IL)-9 regulates the development of airway inflammation,mucus production, airway hyperresponsiveness, and airway fibrosis largely by increasing mast cell numbers and activityin the airways. Mast cells are involved in the pathogenesis of eosinophilic and noneosinophilic asthma. Thus, targeting theIL-9 pathway may provide a new therapeutic modality for asthma. The purpose of this review is to summarize theIL-9-mast cell axis in the pathogenesis of asthma and discuss clinical studies with a humanized anti-IL-9 monoclonalantibody, MEDI-528, in subjects with asthma.

Interleukin-25 Negatively Controls Pathogenic Responses in the Gut by Eleonora Franze, Angelamaria Rizzo, Roberta Caruso, Francesco Pallone, Giovanni Monteleone (187-191).
Although interleukin-25 (IL-25) has been traditionally considered as a cytokine involved in T helper (Th) 2cell-associated allergic diseases and host defence against helminthic parasites, recent studies have shown that IL-25 exertsnegative effects on the initiation and progression of Th1/Th17-mediated pathologies. This later function of IL-25 isparticularly evident at the gut level, where IL-25 could contribute to attenuate tissue-damaging immune responses. Thesenew and exciting pre-clinical observations suggest that therapeutic interventions aimed at enhancing IL-25 activity couldbe useful in the management of patients with chronic gut inflammation.

Immunologic Diseases and Brain Tumors by Maria Morales-Suarez-Varela, Marina Pollan, Nuria Aragones, Teresa Garcia-Martinez, Raquel Solis-Plaza, Agustin Llopis-Gonzalez (192-197).
To do a bibliographic review of the given association of atopic [AD] and immunological diseases with centralnerve system tumors [CNST] described a few years ago and to know the knowledge available. It gives an overview of thestudies describing this association, and those explaining its mechanism. A negative association of AD with CNST standsout in case-control studies, which is not observed in cohort studies. The greatest association is seen for gliomas and is lesssignificant for meningiomas. A clearer definition for the AD under study, tumour types, and the exact biochemical andclinical parameters to help diagnoses are the recommended as well as to establish an aetiologic and temporal relationshipbetween AD and CNST.

Toll-Like Receptors: Role in Inflammation and Commensal Bacteria by Abbas Ali Imani Fooladi, Seyed Fazlollah Mousavi, Sepideh Seghatoleslami, Samaneh Yazdani, Mohammad Reza Nourani (198-207).
TLR ligands are present on both commensal and pathogenic microbes. Intestinal epithelial cells (IECs) havebeen observed to be largely unresponsive to TLR ligands. This observation has partly been explained by the fact that TLRexpression on IECs is sparse. The discovery of the Toll-like receptors finally identified the innate immune receptors thatwere responsible for many of the innate immune functions that had been studied for many years. Interestingly, TLRs seemonly to be involved in the cytokine production and cellular activation in response to microbes, and do not play asignificant role in the adhesion and phagocytosis of microorganisms. One member of this group, interleukin-1β (IL-1β),together with tumour-necrosis factor (TNF), is defined as an ‘alarm cytokine’. It is secreted by macrophages and initiatesinflammation on activation of TLRs.

NF-..B in Type 1 Diabetes by Yuxing Zhao, Balasubramanian Krishnamurthy, Zia U.A. Mollah, Thomas W.H. Kay, Helen E. Thomas (208-217).
Type 1 diabetes is an autoimmune disease in which pancreatic beta cells are destroyed by autoreactive T cells. It isa common pediatric disease with increasing incidence. Islet transplantation may be a therapeutic option, however, the currentlimitations of this procedure mean that for most sufferers of type 1 diabetes there is no cure. The transcription factor NF-κBhas been widely studied for its role in development of type 1 diabetes. Recent data have shown that NF-κB is required foractivation of autoreactive T cells, and its hyperactivity in monocytes and dendritic cells results in altered cytokine secretionand antigen presentation, which ultimately contributes to the initiation of type 1 diabetes. NF-κB is also activated by anumber of proinflammatory cytokines to regulate both the survival and death of beta cells. The critical role of NF-κB in type1 diabetes renders it a promising pharmaceutical target in the intervention of this disease and further understanding of the NF-κB pathway will have an important implication on the development of novel and safe therapeutic strategies.

Regulation of Inflammation and Myocardial Fibrosis in Experimental Autoimmune Myocarditis by Kenichi Watanabe, Vijayakumar Sukumaran, Punniyakoti T. Veeraveedu, Rajarajan A. Thandavarayan, Narasimman Gurusamy, Meilei Ma, Wawaimuli Arozal, Flori R. Sari, Arun Prasath Lakshmanan, Somasundaram Arumugam, Vivian Soetikno, Varatharajan Rajavel, Kenji Suzuki (218-225).
Autoimmune responses and inflammation are involved in the pathogenesis of many cardiovascular diseases.There is compelling evidence that inflammatory mechanisms may contribute to progressive heart failure. Thus,myocardial infiltration of lymphocytes and mononuclear cells, increased expression of pro-inflammatory chemokines andcytokines and circulating autoantibodies are frequently observed in myocarditis and dilated cardiomyopathy (DCM).Experimental autoimmune myocarditis (EAM) in rodents may be elicited by immunization of cardiac myosin and EAM inrats mimics human fulminant myocarditis in the acute phase and human DCM in the chronic phase. Our animal model,EAM was demonstrated to progress into the clinicopathological state similar to DCM in the chronic phase, and was foundto be characterized by the enlargement of the heart, dilatation of ventricles, diffuse and extensive myocardial fibrosis,besides being a cellular immunity and inflammation mediated disease. Severity of myocarditis was characterized byincreased inflammation, cardiac fibrosis and decreased myocardial performance in rats with DCM. Pharmacologicalinterventions such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs)significantly attenuated the myosin-induced inflammation and cardiac fibrosis and thereby improving myocardial functionin rats with DCM. A growing body of evidence shows that ACEI and ARBs contribute to the pharmaceutical managementof patients with heart failure mediated by immune and inflammatory response. The purpose of this review is to emphasizethe role of inflammation and myocardial fibrosis in rats with DCM after EAM and study the effects of pharmacologicalinterventions such as ACEI, ARBs in the treatment of heart failure through the suppression of inflammatory cytokines andfibrosis.