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.

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.

[Prospects For the Use of Peptides against Respiratory Syncytial Virus].

The human respiratory syncytial virus (RSV) is one of the most common viral pathogens that affects the lower respiratory tract and could be a reason of bronchiolitis and/or pneumonia. Currently, there are no available effective ways of treating the RSV infection. Attempts to develop preventive vaccine have been unsuccessful. The only therapeutic agent used for RSV treatment is virazole (ribavirin); however, it induces adverse effects. Medications based on neutralizing monoclonal antibodies, such as IGIV (Respigam), palivizumab (Synagis), and MEDI-524 (Numab), are under clinical trials; however, their use will be limited by their high cost. One of the promising approaches for antiviral therapy is the use of natural peptides (defensins and cathelicidins), or their synthetic analogs. The majority of currently described antiviral peptides are developed against the human immunodeficiency virus, the herpes simplex virus, and the influenza virus. At the same time, a body of experimental data evidencing anti-RSV activity of peptides has been accumulated. The main advantages of peptide drugs are their wide spectrum of antiviral activity and low toxicity. However, there are obstacles in implementing peptide-based drugs in clinical practice. Due to their low resistance to the action of serum proteases, most authors consider peptides promising only for local application. Given that RSV affects the epithelium of the respiratory tract, where the protease activity is lower than in the systemic circulation, it is possible to develop locally active peptide drugs, for example, as inhalation forms. Their stability could also be increased by the synthesis of dendrimer peptides and by the development of recombinant peptides as precursor proteins. Anti-RSV peptides can be divided into several groups: (1) attachment and/or fusion blockers; (2) peptides displaying direct virucidal activity, disrupting the viral envelope. Such peptides, which suppress early stages of the viral life cycle, are considered prophylactic agents. However, for several peptides, their immunoregulatory properties have been described, which opens the possibility for therapeutic use. This review summarizes the information on the antiviral properties of such peptides and mechanisms of their action and describes the prospects of the future development of antiviral peptides.