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Objective. Reprogramming of M1 macrophage phenotype with inhibited M2 phenotype transcription factors, such as STAT3, STAT6 and SMAD and assess their impact on the development of Ehrlich carcinoma (EC) in vitro and in vivo. Methods. Tumor growth in vitro was initiated by addition of EC cells in RPMI-1640 culture medium and in vivo by intraperitoneal of EC cell injection into mice. Results. It was found that M1-STAT3/6- SMAD3 macrophages have a pronounced anti-tumor effect in vitro, and in vivo, which was greater than anti-tumor effects of M1, M1-STAT 3/6, M1-SMAD3 macrophages and cisplatin. Conclusion. M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 effectively restrict tumor growth. The findings justify the development of new anti-tumor cell therapy technology.

Predisposition to tumors is often determined by how effectively the genotype of an individual forms an immune defense. An important factor of such protection is macrophage NO. We assumed that the body's vulnerability to the development of tumors may depend from the characteristics of the NO generating systems. The content of NO in the tumor changed by ITU, inhibitor of iNOS, c-PTIO, traps and SNP, donor NO. Production of macrophage NO were evaluated by nitrites in the culture media. iNOS was assessed using the Western blot analysis. Phenotype of macrophages was assessed using cytometry for CD labels. Life span of mice C57BL/6N with Ehrlich tumor was 25% greater than that of the C57BL/6J. Reducing the content of NO in the tumor reduced life expectancy of high-resistance to tumor subline C57BL/6N at 23%. Increase of NO increased life expectancy of low-resistance subline C57BL/6J at 26%. Macrophages of C57BL/6N were 1.5 times higher contents of iNOS and NO production, as compared with macrophages of C57BL/6J. CD phenotype markers determined the macrophage phenotype C57BL/6N as M1 and C57BL/6J mice macrophage phenotype as M2. Thus, the body's vulnerability to the development of tumors may depend from the characteristics of the NO generating systems. C57BL/6J, unlike C57BL/6N does not synthesize NNT (nicotinamide nucleotide transhydrogenase) and have differences in the single nucleotide polymorphism (SNP). The important role of NO in the resistance to Carcinoma, NNT and SNP deserve attention in the development of new methods of antitumor therapy.

Combination of bronchial asthma (BA) and gastroesophageal reflux disease (GERD) is a widespread clinical situation. The two pathologies are known to influence each other leading to disturbances in immune responsiveness. We studied phenotypes and phenotypic plasticity of immune cells (alveolar macrophages) in patients with BA and GERD. It was shown that BA and GERD are largely associated with AM of proinflammatory M2 and anti-inflammatory M1 phenotypes respectively. Population of AM with MI phenotype increases in patients having both BA and GERD compared with that in BA alone. In vitro experiments showed that acidic milieu promotes shifting the phenotype toward the predominance of M1, i.e. simulates the situation characteristic of GERD. Combination of BA and GERD narrows the interval within which AM can change MI phenotype (i.e. makes them more "rigid") but broadens the range in which they can change M2 phenotype. Also, GERD promotes the development of morphological rigidity of AM. Patients with BA given steroid therapy undergo inversion of phenotypic plasticity of AM. These data characterize the immunological component of BA and/or GERD pathogenesis. They help to better understand mechanisms of development of broncho-pulmonary pathology in GERD patients and can be used to work out new methods for the treatment of these diseases.

The study of pathogenesis of bronchial asthma (BA) and gastroesophageal reflux disease (GERD) or their combination showed that the intensity of inflammation and the choice between Thl and Th2 immune responses are determined by macrophages (elements of congenital immunity). Lung surfactant protein D (SP-D) existing in various oligomneric forms (as monomer trimer, dodecamer, multimer) plays an important role in the mechanism of transformation ofalveolar macrophage phenotype. Patients with BA+GERD have higher SP-D level in the bronchoalveolar lavage fluid than those with GERD alone but lower than patients with BA. SP-D dodecamers were found only in BA patients given basaLtherapy with inhaled glucocorticoids (IGC). It suggests that the presence of dodecamers in the lavage fluid may result firom anti-inflammatory action of IGC. They are absent in patients with BA+GERD treated with IGC probably because GERD enhances inflammatoly changes in the lungs of BA patients despite basal therapy These data together with results of experimental acidification of lavage fluid from BA patients give reason to hypothesize that microaspiration of acidic gastric contents frequently associated with GERD is a cause of local decrease of pH in different segments of the bronchial tree triggering two pathogenetic mechanisms: (I) programming proinflammatory MI phenotype of alveolar macrophages, increased production of nitric oxide, nitrosation of SP-D and destruction of its anti-inflammatory multimers ; (b) direct destruction ofSP-D oligomers in the acid medium. Both mechanisms reduce the level of anti-inflammatory SP-D multimers and increase the level ofproinflammatory monomers. Thus, decreased pH in lower airways is a real pathogenetic factor of anti-inflammatory shift in the oligomeric SP-D composition accounting for the inflammatory reaction of lungs in GERD.

The aim of study was to investigate the effect of hypoxia on the macrophage phenotype and phenotypic plasticity and to determine the resistance to acute hypoxia in C57/BL mice, which have the pro-inflammatory M1 macrophage phenotype, and in BALB/c mice, which have the anti-inflammatory M2 macrophage phenotype. The following results were obtained. 1) The response of macrophages to acute hypoxia has two successive phases, the immediate, anti-inflammatory phase, and the delayed, pro-inflammatory phase. This response was more distinctly inverted in C57/BL6 M1 macrophages than in BALB/c M2 macrophages; 2) the effect of acute hypoxia on macrophage phenotypic plasticity depends on the genetically predetermined, original macrophage phenotype. In this process, a clear regularity was observed: hypoxia increased the capability of macrophages for changing into the pro-inflammatory M1 phenotype, while their capability for changing into the anti-inflammatory M2 phenotype remained virtually unaffected. 3) BALB/c mice were more resistant to acute hypoxia than C57/BL6 mice. Taken together, these data expand our understanding of mechanisms for pathogenetic effects of hypoxia.