IL-4 regulates neutrophilic pulmonary inflammation in a mouse model of bronchial asthma.

Neutrophilic pulmonary inflammation in asthmatics substantially exacerbates the severity of the disease leading to resistance to conventional corticosteroid therapy. Many studies established the involvement of Th1- and Th17-cells and cytokines produced by them (IFNg, IL-17A, IL-17F etc.) in neutrophilic pulmonary inflammation. Recent studies revealed that IL-4 - a Th2-cytokine regulates neutrophil effector functions and migration. It was showed that IL-4 substantially reduces neutrophilic inflammation of the skin in a mouse model of cutaneous bacterial infection and blood neutrophilia in a mouse model systemic bacterial infection. However, there are no data available regarding the influence of IL-4 on non-infectious pulmonary inflammation. In the current study we investigated the effects of IL-4 in a previously developed mouse model of neutrophilic bronchial asthma. We showed that systemic administration of IL-4 significantly restricts neutrophilic inflammation of the respiratory tract probably through the suppression of Th1-/Th17-immune responses and downregulation of CXCR2. Additionally, pulmonary neutrophilic inflammation could be alleviated by IL-4-dependant polarization of N2 neutrophils and M2 macrophages, expressing anti-inflammatory TGFß. Considering these, IL-4 might be used for reduction of exaggerated pulmonary neutrophilic inflammation and overcoming corticosteroid insensitivity of asthma patients.

[Pleiomorphism of the cytokine profile in nasal polyp tissue depending on the phenotype of chronic rhinosinusitis with nasal polyps]. / Pleiomorfizm tsitokinovogo profilya v tkani polipov v zavisimosti ot fenotipa polipoznogo rinosinusita.

Clinical phenotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) are characterized with different inflammation patterns of mRNA expression of cytokines and depend on presence of allergic rhinitis (AR), atopic bronchial asthma (aBA) or nonatopic bronchial asthma (nBA). OBJECTIVE: To compare inflammation response in patients with different phenotypes of CRSwNP according to level secretion of the key cytokines in nasal polyp tissue. MATERIAL AND METHODS: 292 patients with CRSwNP were divided into four phenotypes: group 1 - CRSwNP without respiratory allergy (RA) and without BA; group 2a - CRSwNP+ AR with aBA; group 2b - CRSwNP+AR without aBA; group 3 - CRSwNP+nBA. Control group (n=36) included patients with hypertrophic rhinitis without atopy or BA. Using multiplex assay we defined the level of IL-1ß, IL-4, IL-5, IL-6, IL-13, IFN-γ, TGF-ß1, TGF-ß2, TGF-ß3 in nasal polyp tissue. RESULTS: The evaluation of cytokines levels in nasal polyps in different CRSwNP phenotypes showed a pleiotropy of different cytokine secretion depending on different comorbid pathology. In control group we estimated the lowest levels of all detected cytokines in comparison with other CRS groups. High levels of local proteins IL-5 and IL-13 and low levels of all isoform of TGF-ß characterized CRSwNP without RA and BA. The combination of CRSwNP with AR showed high levels of proinflammatory cytokines IL-6 and IL-1ß, and high levels of TGF-ß1 and TGF-ß2. The combination of CRSwNP with aBA estimated low levels of proinflammatory cytokines IL-1ß, IFN-γ; in case of CRS+nBA we determined the highest levels of TGF-ß1, TGF-ß2 and TGF-ß3 in nasal polyp tissue. CONCLUSIONS: Each CRSwNP phenotype is characterized by different mechanism of local inflammation. This underlies the necessity to diagnose BA and respiratory allergy among these patients. The evaluation of local cytokine profile in different CRSwNP phenotypes can help to determine the target anticytokine therapy for patients who has low efficacy of basic corticosteroid therapy.

Modern View of Neutrophilic Asthma Molecular Mechanisms and Therapy.

For a long time asthma was commonly considered as a homogeneous disease. However, recent studies provide increasing evidence of its heterogeneity and existence of different phenotypes of the disease. Currently, classification of asthma into several phenotypes is based on clinical and physiological features, anamnesis, and response to therapy. This review describes five most frequently identified asthma phenotypes. Neutrophilic asthma (NA) deserves special attention, since neutrophilic inflammation of the lungs is closely associated with severity of the disease and with the resistance to conventional corticosteroid therapy. This review focuses on molecular mechanisms of neutrophilic asthma pathogenesis and on the role of Th1- and Th17-cells in the development of this type of asthma. In addition, this review presents current knowledge of neutrophil biology. It has been established that human neutrophils are represented by at least three subpopulations with different biological functions. Therefore, total elimination of neutrophils from the lungs can result in negative consequences. Based on the new knowledge of NA pathogenesis and biology of neutrophils, the review summarizes current approaches for treatment of neutrophilic asthma and suggests new promising ways to treat this type of asthma that could be developed in future.

The Role of Interleukin-37 in the Pathogenesis of Allergic Diseases.

Cytokines of the interleukin-1 (IL-1) family play an important role in the realization of the protective functions of innate immunity and are the key mediators involved in the pathogenesis of a wide range of diseases, including various manifestations of allergy. The IL-1 family includes more than 11 members. However, the functions of many of them remain to be elucidated. Recently, new members of the IL-1 family have been discovered. In 2000, several independent research groups reported the discovery of a new interleukin of this family, which was named IL-37, or IL-1F7 (according to the new nomenclature). IL-37 was assigned to the IL-1 family based on its structural similarity with other members of this family. The study of its biological properties showed that its activity changes in inflammatory diseases, such as rheumatoid arthritis, psoriasis, as well as allergic diseases (allergic rhinitis, bronchial asthma, and atopic dermatitis). However, unlike most members of the IL-1 family, IL-37 acts as a negative regulator of inflammation. Activation of IL-37 suppresses inflammation, resulting in the suppression of inflammatory cytokines and chemokines, which in turn prevents infiltration of pro-inflammatory cells, mainly eosinophils and neutrophils. The exact molecular and cellular mechanisms of the anti-inflammatory effect of IL-37 in the development of allergic diseases (AD) have not been fully studied. This review summarizes and analyzes the accumulated experimental data on the role of IL-37 in the pathogenesis of AD, such as allergic rhinitis, bronchial asthma, and atopic dermatitis.

[Gene expression levels of cytokines in different phenotypes of CRSwNP]. / Uroven' ékspressii genov tsitokinov pri raznykh fenotipakh polipoznogo rinosinusita.

INTRODUCTION: Rhinosinusitis with nasal polyps (CRSwNP) is often followed by a range of comorbid states, influence of which on the course of the main pathology process remains insufficiently studied. PURPOSE: To study the gene expression level of cytokines potentially talking part in the development of inflammation in nasal polyps with different phenotypes of CRSwNP. MATERIAL AND METHODS: All the patients with CRSwNP were divided into 4 equal groups, 36 patients in each subgroup: group 1 - CRSwNP without comorbid pathology; group 2 - CRSwNP+atopy; group 3 - CRSwNP + non-allergic bronchial asthma (BA); control group 4 - 36 patients diagnosed with hypertrophic rhinitis without atopy and without bronchial asthma. Using the real-time polymerase chain reaction (Real-Time PCR) method, the study of expression level of mRNA genes coding proteins IL-1ß, IL-4, IL-5, IL-13, IL-17F, IL-25, IFN-y, TSLP in polyp tissue was conducted. RESULTS: The statistically proved difference of expression level of cytokines depending on the CRSwNP phenotype was educed. If CRSwNP and atopy were combined, the gene expression level of all studied cytokines was statistically higher than that of CRSwNP without comorbid pathology; and the expression level of IL-17F, IL-25 and TSLP was more intense that in the group of CRSwNP + BA. There was no difference between the patients with comorbid allergy and comorbid BA regarding the gene expression of IFN-y, IL-5 and IL-13 cytokines. Among different phenotypes of CRSwNP no difference in IL-1ß expression level was detected, which evidences of persisting inflammatory process, and the IL-4 gene expression level was lower than the detection level in all the groups. CONCLUSION: With different CRSwNP phenotypes different inflammatory patterns are detected, which indicates different character of the pathology process course among these groups of patients. Higher expression level of cytokine genes, which are a marker of epithelial damage of IL-25 and TSLP, is found only among the patients with CRSwNP and atopy. It suggests that forming of CRSwNP without comorbid pathology is connected with other pathologic mechanisms, not with the damage to epithelial barrier. If CRSwNP + BA and CRSwNP + atopy were combined, the expression level of IFN-y, IL-5, IL-13 and IL-17F genes was higher than the one in the group of patients with CRSwNP without comorbid pathology. In view of obtained data, all the patients with CRSwNP shall be screened for bronchial asthma and the allergy diagnostic shall be conducted.

[Possibilities of azelastine in the treatment of chronic rhinitis]. / Vozmozhnosti azelastina v terapii khronicheskogo rinita.

There is considered modern classification of rhinitis and the accents in diagnostic and therapeutic approaches to patients with this disease are indicated, as well as the possibilities of using topical intranasal antihistamines in the treatment of allergic, vasomotor and medicamentous rhinitis.

[Granulomatosis with polyangiitis associated with the cytoplasmic antineutrophil antibodies]. / Granulematoz s poliangiitom, assotsiirovannyi s antineitrofil'nymi tsitoplazmaticheskimi antitelami.

The objective of the present work was to analyze the clinical case of granulomatosis with polyangiitis associated with the presence of cytoplasmic antineutrophil antibodies. We considered the medical records of the patient presenting with this condition. It was shown that systemic vasculitis had a polymorphic clinical picture; its diagnostics and treatment encountered serious difficulties. It is concluded that the development of progressive perforation of the nasal septum and destructive changes in the intranasal and adjacent structures after the endonasal surgical intervention implies the necessity of the detailed analysis of the clinical and laboratory observations with the subsequent counselling by a rheumatologist and oncologist for the clarification of the diagnosis and the choice of adequate therapy.