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Section 4. Medical science
Abdukajumov Abdumannop Abdumadjidovich, Candidate of Medical Science, Deputy Head Physician, Republican Specialized Scientific-Practical Pediatric Medical Center, Tashkent, Uzbekistan
Amonov Shavkat Ergashevich, Professor, Head of Otorhinolaryngology Department, Tashkent Pediatric Medical Institute, Tashkent, Uzbekistan
Daminov Botir Turgunpulatovich, Professor, Chancellor, Tashkent Pediatric Medical Institute
Haibullina Zarina Ruslanovna, Professor of Biochemistry Department, Tashkent Pediatric Medical Institute E-Mail: aaauz@inbox.ru
The effectiveness of endoscopic sinus-surgery in immunoreactivity recovery, oxidative stress and endothelial dysfunction elimination at chronic rhinosinusitis associated with comorbidity with immunocomprometation
Abstract: One of the most difficult patients' groups is chronic rhinosinusitis patients with nasal polyps (CRSP) with chronic glomerulonephritis (CGN), whose possibility to undergo surgery removing polyps and sites of chronic infection is limited by high incidence of intra- and postoperative complications. Difficulties in selection of therapeutic approach at CRSP + CGN are caused by immunocompromentation, abnormalities of blood rheology, as well as inflammation and oxidative stress (OS) persistence.
Keywords: chronic rhinosinusitis with nasal polyps, chronic glomerulonephritis, oxidative stress.
Importance of an issue. In 2012 the prevalence of nasal polyps was 2.7 % of general population in Sweden, 0.5 % in Korea, 4.3 % in Finland, 2.1 % in France, which points out high enough rate of chronic rhinosinusitis with nasal polyps [9, 25]. Treatment of chronic polypous rhinosinusitis remains an important issue, as rates of disease recurrence vary widely: from 26 to 83 %. This indicates a complexity of CRSP pathogenesis at that the comorbidity assumes particular importance [20]. One of the most difficult patients' groups is chronic rhinosinusitis patients with chronic glomerulonephritis (CGN), whose possibility to undergo surgery removing polyps and sites of chronic infection is limited by high incidence of intra- and postoperative complications [12]. Difficulties in selection of therapeutic approach at CRSP + CGN are caused by immunocomprometation, abnormalities of blood rheology, as well as inflammation and oxidative stress persistence [10, 16].
Immunodeficiency and disregulation of immune response are developed in CRSP + CGN patients, because, regardless the stage of development, morphologic and clinical form of disease, the glomerulonephritis is considered as autoimmune pathologic process with predominant affection of glomerules, as well as tubules of interstitial tissue. Immune inflammation takes place with damage of T-cellular component, inclusion of pro- and anti-inflammatory cytokines, formation of circulating immune complex and/or autoantibodies.
Long period of immunodepressant administration also changes immunoreactivity in CRSP + CGN patients, which requires special management [9, 25].
One of the mechanisms of chronic renal disease (CRD) progression is an oxidative stress (OS) and antioxidative activity decrease in tubules [7]. Probable OS activation factor at CRD is an increase of angiotensin II prooxidant production and a decrease of endogenous renal antioxidant activity — atrial natriuretic peptide (ANP) and renal dopamine [17]. Prooxidative action of angiotensin II (AT-II) consists in activation of phospholipase A2, in such way increasing an intracellular content of arachidonic acid and lysophospholipids, which promotes lipid peroxidation enhancement [24]. AT-II is a factor assisting in nitrogen oxide transformation into highly toxic active form of nitrogen — per-oxynitrite, increasing OS. Through specific nuclear receptors the AT-II directionally activates an expression of TGF-beta1 genes, promoting strong proinflammatory response development, and TGF-beta, in turn, stimulates angiotensinogen gene expression, p-38-dependent MAPK-activation and expression of proapoptotic p53, moreover, by means of ROS-signaling [8]. This mechanism shows an AT-II and TGF-beta impact on nephron damage through ROS regions. It is an activation of TGF-bets and a following me-sangial cells hypertrophy, hyperproduction of mesangial matrix substance that conditions prosclerotic action of AT-II in kidneys. Locally in nephrons the AT-II through NF-kB activation induces
genes, involved in inflammation and fibrosis, infiltration by monocytes and macrophages, lymphocytes, synthesis of proinflammatory factors and adhesion molecules — endothelin-1, V-CAM, I-CAM, chemokines and cytokines [6].
Lipid peroxidation enhancement and membrane destruction also underlies a ciliated epithelium functional failure at CRSP [11]. Excessive production of reactive oxygen species (ROS) result in activation of protein-tyrosine kinase and protein kinase C (PKC), which is accompanied by stimulation, in particular, of mitogen-ac-tivated protein kinases (MAP-kinases) the consequence ofwhich is an activation of proliferation, underlying both nephrosclerosis and polyp formation in paranasal sinuses [21]. Increasing activity of different protein kinases, the ROS participates in regulation of numerous cellular processes, such as cellular adhesion, proliferation, signal transduction, apoptosis, etc. The ROS activates various signal paths, such as path of AP-1 protein and NF-kB transcription factor [4]. Thus, OS participates in fibrosis development both in nephron and paranasal sinuses (PNS).
Both CGN and CRSP are accompanied by endothelial dysfunction (ED) and clotting abnormalities [3]. Under the influence of factors, activating or damaging endothelium (microbial endotoxins, circulating immune complex, cytokines, inflammation mediators, lipid peroxides) a sudden change of para- and autocrine endothelium activity with loss of its native feature of thromboresistance and increase ofprocoagulant and proaggregate effects take place: a formation ofWillebrand factor, plasminogen 1 activator inhibitor (PAI-1), tissue thromboplastin, fibronectin increases, a synthesis of tissue type plasminogen activator, thrombomodulin, antithrombin, pros-tacyclin, nitrogen oxide decreases, endothelium is involved in synthesis of prooxidants, vasoconstrictors [16].
A decrease of nitrogen oxide level was found in nasal cavity [15] at CRSP, which conditions ciliary dyskinesia and decrease of ciliated epithelium transportation function, and local increase of fibrin stabilizing factor results in formation of fibrin deposits in submucosal of nasal polyps, which contributes in remodeling of polyp tissue at CRSP. According to Takabayashi T. et al. (2013), a level of fibrin degradation products, D-dimer was significantly reduced in nasal polyps in CRS patients without polyps and control, which proved fibrinolysis abnormality and noncompletion in polypous tissue. Significant reduction in epithelium and glands at mRNA level and in protein of tissue-type plasminogen activator (t-PA) was noticed in patients with polypous form of chronic rhinosinusitis [23].
As noted from literature data, there is local impaired coagulation at CRSP, which is a reason of microthromb formation and trophism abnormality in mucous membrane, local blood flow degradation.
Work objective: to study immunoreactivity, intensity of OS, systemic inflammation and markers of endothelial dysfunction in CRSP + CGN patients, evaluate effectiveness of endoscopic sinus-surgery with pathogenetically substantiated medication correction for the dynamics of these blood values.
Materials and methods. 102 patients were examined with chronic nasal and paranasal sinuses diseases with chronic glomerulonephritis of nephrotic form (CGN) in the age of18 to 60 years, men — 76, women — 26. 24 of them were CRSP + CGN patients (1st group), and 32 were CRSP patients without comorbidity (2nd group). The duration of CGP in 1st group patients constituted 2.5 ± 0.8 years, proteinuria was 2.44 ± 0.22 g/day, which indicated noncomplete clinical-laboratory remission, CGP stage 2. Endoscopic rhino-sinus-surgery (FESS) combined with medication
correction (MC) was carried out in 1st and 2nd group patients. For comparative evaluation ERSS + MC and traditional treatment a comparison group was separated — CRSP + CGN patients receiving traditional conservative treatment (n = 8). Control group consisted of 9 healthy volunteers of the same age. Surgical intervention — functional endoscopic sinus-surgery — was carried out under standard technique of endonasal microsurgery with diode laser, additional MC included Antibacterial treatment, antifungal agent, antioxidant therapy, irrigating therapy, topical glucocorti-costeroids and oral steroids.
Determination of total number of peripheral blood lymphocytes was conducted at Automatic Hematology Analyzed MIN-DRAY BC-5800 (China). T-helper/inductor cells (CD4+), Sup-pressor/Cytotoxic T cells (CD8+) were determined by method of Zalyalieva M. V. (2003) using monoclonal antilymphocyte antibodies, produced by Research Institute of Immunology of Russian Federation (Moscow). Immunoregulatory index was determined by ratio CD4+/CD8+. Circulating immune complexes (CIC) were discovered by method of Menshikov V. V., 1987, by precipitation in 3.5 % solution of polyethyleneglycol (PEG), the measurements were taken at spectrometer SF-46 at 280 nm ant expressed in standard units. A neutrophil phagocytic activity of (NPA) was examined by phagocytic index, determined by neutrophil capability to absorb inert particles of melamine-formaldehyde latexes. Used inert particles melamine-formaldehyde latexes were 1.5 to 2.0 ^m in size and produced by Institution of Biological Instrumentation (Moscow), the neutrophils absorbed one or more particles of latex were considered phagocytic, 100 neutrophils were calculated and this way the phagocytic activity was determined.
A concentration of endothelin-1 (ET-1) was determined by immunoenzyme method at the Analyzer ELx808 manufactured by BIO-TEK INSTRUMENTS INC (USA) using sets produced by Biomedica. Using the same analyzer a concentration of immunoglobulin IgE, tumor necrosis factor-alpha (TNFa), D-dimer in blood plasma was determined by EIA method using standard sets produced by CJSC VECTOR-BEST, Novosibirsk, Russia «total IgE — EIA-BEST», D-dimer — EIA-BEST, Alpha-TNF-EIA-BEST respectively.
Determination of activated partial thromboplastin time (APTT) and fibrinogen concentration in plasma was carried out with standard sets of company Cypress Diagnostics, Belgium.
Concentration of C-reactive protein (CRP) was estimated at automatic biochemical analyzer VITROS — 350 with reagents of company ORTO-clinical diagnostic, USA. Determination of malo-ndialdehyde (MDA) in blood serum was carried out by method of Stalnaya I. D. et al. [5]. Determination of superoxide dismutase (SOD) activity in blood was conducted by method of Mirsa P. H., Fridovich I. modified by Brusov O. S. et al. [1, 18]. Catalase activity in blood was studied according to Zubkova S. M. et al. [2].
Results. Initially, before treatment 1st group CRSP + CGN patients showed expressed lymphopenia (a decrease in lymphocyte content by 1.9 times as for the control), a decrease in CD4+ by 1.2 times as for the control and 1.3 as for the 2nd group, as well as an increase by 1.7 times and a decrease of NPA by 1.5 times as for the control. Immunogram in CRSP of 2nd group patients were characterized with proved increase of Suppressor T cells (CD8+) by 1.3 times as for the control at normal content of CD4+ and total lymphocytes. Immunoreguatory index (IRI) of this group was reduced to 1.67 characterizing current chronic inflammatory process. CIC and NPA content in 2nd group of patients were compared to control (Table 1).
Table 1. - Immunoreactivity indices in polypous form chronic rhinosinusitis patients with immunocompromentation before and after treatment
Patients groups Control, n = 9 Before treatment After treatment
1st group (CRSP + CGN), n = 16 2nd group (CRSP), n = 32 1st group (CRSP + CGN), n = 16 2nd group (CRSP), n = 32 Comparison group (CRSP + CGN traditionally), n = 8
Total lymphocytes, % 32.4 ± 1.3 23.8 ± 3.9 29.4 ± 1.6 27.1 ± 0.9*' ** 29.9 ± 0.8 24.2 ± 2.0
CD4+, % 39.1 ± 2.4 32.1 ± 2.7 42.2 ± 1.6 35.4 ± 0.5 41.6 ± 1.1*** 33.7 ± 1.9
CD8+, % 19.5 ± 1.1 29.3 ± 1.8 25.2 ± 1.9* 24.6 ± 0.9*' ** 21.0 ± 0.9**' *** 28.8 ± 0.9***
IRI 2.0 ± 0.1 0.9 ± 0.1 1.7 ± 0.2 1.43 ± 0.2*' ** 1.98 ± 0.2*** 1.17 ± 0.1***
IgE, IU/l 32.0 ± 2.3 299 ± 19 235.0 ± 13.5 99 ± 13*' ** 63 ± 11**' *** 253 ± 13***
NPA, % 61.2 ± 9.1 39.7 ± 1.2 65.2 ± 1.4 55.3 ± 2.2*' ** 65.9 ± 1.9*** 43.6 ± 1.9***
sIgA, |xg/ml 0.81 ± 0.03 0.42 ± 0.03 0.49 ± 0.03* 0.66 ± 0.06*' ** 0.79 ± 0.02**' *** 0.45 ± 0.03***
CIC, SU 69.3 ± 2.4 121.0 ± 11.2 76.2 ± 2.9 92.7 ± 1.1*' ** 71.1 ± 0.8**' *** 114.2 ± 3.3***
D-dimer, ng/ml 130 ± 10 229 ± 18 179 ± 9 147 ± 8 128 ± 7 190 ± 5
APTT 38.1 ± 2.0 21.9 ± 2.0 38.2 ± 1.7 32.3 ± 1.5 37.0 ± 0.7 22.4 ± 0.9
Note: * — proved as for the traditional treatment method, P < 0.05; ** — proved as for before treatment, P < 0.05; *** — proved as for the 1st group, P < 0.05.
As obvious from the Table 1, CRSP + CGN patients have deep T-cellular deficiency combined with allergic component in the form of immonoglobulin E increase with sharp decrease of IRI and CIC increase, showing immune response disregulation. These shifts in T-helper content in CRS + CGN patients are dangerous for deep disregulatory changes in immune status, as T-helper cytokines provide for the development of effective immune response. 1 type T-helpers (Th-1) producing IL-2 and IFN-gamma support cell-mediated immunity formation, and 2 type T-helpers (Th-2) population synthesize IL-4 and IL-10, IL-13 acting to activate humoral immunity, proliferation stimulation and B-lymphocyte differentiation, as well as synthesis of different classes of antibodies. Which path the T helper would follow depends on cytokine background, antigen nature ant its amount [26].
The association of CRSP with Th-2 dominant inflammation is stated in Nagarkar D. R. et al., 2013, as these authors found thymic stromal lymphopoietin (TSL) and its RNA in nasal polyps' content. TSL is a trigger of Th-2 inflammatory response in dendrite cells and an inductor of IL-1-dependent production of Th-2 profile cytokines by mast cells. Nasal polyps extract increased IL-5 concentration in mast cells induced by IL-1 beta [19]. The study of epithelial cytokine expression, involved in Th-2 inflammation, IL-25, IL-33, TSL, as well as chemoattractant properties of eosinophils in polyp tissue and mucous membrane showed the high level of them at CRSP, correlated with CT and endoscopy data [13], which proves Th-2 response prevalence at CRSP [14].
Therefore, immunologic peculiarities of CRSP include CD8+ reduce without proved IRI change, while CGN comorbidity patients have deep T-cellular deficiency with immune response disregulation.
After ERSS 1st group patients showed statistically proved as for the index before treatment increase of IRI owing to CD8 reduce, total amount of lymphocytes also proved to increase. This indicates immunoreactivity restoration resulting from secondary immunodeficiency arresting in CRSP + CGN patients. An increase of NPA and secretory immunoglobulin A shows local immunity competence after complex treatment completion in 1st patients group. It must be noted, that immunogram parameters in 1 patients group had positive dynamics, but didn't reach the control level. Thus, the CIC level reduced by 1.3 times as for before treatment content, but it exceeded control level by 1.32 times, the IgE concentration decreased by 3.0 times compared to before treatment index, by it exceeded
control level by 3.1 times. Despite this all, immunogram indices reasonably differed between the 1st and the comparison groups. Traditional treatment did not show significant influence on immune state at CRSP + CGN, immunodeficiency state remained at the level corresponding to the beginning of treatment. Thus, immunogram parameters in 1st patients group before the treatment show positive shifts in cellular immunity increasing CD4+ and decreasing CD8+, which promotes an IRI increase up to 1.43. This is lower than in control group, but reasonably higher than before treatment index. Furthermore, restoration of lymphocytes regulatory functions assisted NPA increase as well as growth of secretory immunoglobulin A amount, which is an important factor of local immunity.
One of the peculiarities of CRSP + CGN progression is development of hypercoagulation syndrome, appeared as APTT shortening, tendency to increase D-dimer and fibrinogen. After traditional treatment, these indices were not significantly different from the level before treatment. After endoscopic sinus-surgery the D-dimer concentration reduced by 1.6 times and basic haemostatic profile ofAPTT elongated by 1.5 times in 1st patients group. We believe that positive dynamics of hypercoagulation syndrome is conditioned by decrease of endothelial dysfunction manifestations and OS when using offered method of treatment. It must be noted that blood rheological properties restoration is a favorable factor of CGN progression.
Biochemical research showed that MDA and endothelin-1 levels at CRS + CGN significantly exceeded the ones in CRSP patients, and were reasonably higher than control, which proves endothelium activation as the result of its damage and systemic oxidative stress. These shifts were accompanied by sharp suppression of antioxidative system (AOS) in terms of noncompensated oxidative stress. Thus, CRSP + CGN patients before treatment had an elevated level of MDA by 11.6 times as for control and by 1.4 times as for CRSP patients. They had SOD activity suppressed by 3.0 times and catalase by 1.5 times as for control, and by 2.0 and 1.2 times respectively as for CRSP patients. CRP concentration in 1st patients group was increased by 3.2 times as for control and by 1.2 times as for the 2nd patients group.
The results of laboratory monitoring at CRSP + CGN and CRSP after 1 month of therapy showed positive dynamics of oxidative stress parameters increasing the activity of enzymatic component of AOS, decreasing MDA, as well as reduction of systemic inflammation response syndrome in the course of complex treatment using radical polyp removal and modified sections of mucous membrane of sinuses (Table 2).
Table 2. - Indices of oxidative stress, inflammation and endothelial dysfunction in chronic rhinosinusitis patients before and after treatment
Patients groups Control, n = 9 Before treatment After treatment
1st group (CRSP + CGN), n = 16 2nd group (CRSP), n = 32 1st group (CRSP + CGN), n = 16 2nd group (CRSP), n = 32 Comparison group (CRSP + CGN traditionally), n = 8
MDA, (nmol/mg of protein*min) 0.51 ± 0.01 5.92 ± 1.21 4.16 ± 0.21 2.33 ± 0.5*' ** 0.84 ± 0.05*, **, *** 3.78 ± 0.33***
SOD (U/l) 4.62 ± 0.23 1.56 ± 0.13 3.12 ± 0.11 3.46 ± 0.2*, ** 4.1 ± 0.3* 2.15 ± 0.42***
Catalase, (mmol H2 02/mln. of er.*min) 38.1 ± 0.4 26.2 ± 1.3 32.1 ± 1.0 34.2 ± 1.1*, ** 37.3 ± 0.5*, ** 29.4 ± 1.4***
CRP, mg/l 4.4 ± 0.8 14.1 ± 1.5 12.1 ± 2.0 8.4 ± 0.9*, ** 6.0 ± 1.2*, ** 12.3 ± 0.7***
TNF-alpha, pg/ml 0.56 ± 0.02 29.5 ± 1.7 10.8 ± 0.9 15.3 ± 0.4*, ** 7.2 ± 1.1* ** *** 27.6 ± 1.3***
Endothelin, pg/ml 1.91 ± 0.20 19.3 ± 0.41 14.13 ± 0.62 9.7 ± 0.5*, ** 4.4 ± 0.4*, **, *** 17.3 ± 0.9***
Note: * — proved as for the traditional treatment method, P < 0.05; ** — proved as for before treatment, P < 0.05; *** — proved as for the 1stgroup, P < 0.05.
As the Table 2 shows, all parameters of systemic inflammation (CRP, TNFa) endothelial dysfunction (endothelin-1) and OS after the treatment by offered method were reasonably different from indices of comparison group, which was treated traditionally without operative intervention application. Furthermore, all the above parameters in 1st group were reasonably different from indices before treatment.
Positive dynamics of MDA in 1st group expressed in its reduction by 2.5 times as for the index before treatment, with that SOD and catalase activity increased by 2.2 and 1.3 times respectively. The level of OS indices in this group was reasonably lower than the control after 1 month of therapy, however, this significant reduction (by 2-2.5 times) from the original data allows to state the expressed positive effect of the developed method of CRSP + CGN treatment, which wasn't shown by the comparison group, where the intensity of OS was similar to the one before treatment.
The endothelin-1 level in 1st group reduced by 1.98 times, TNFa — by 1.93 times as for the content before treatment, and CRP decreased by 1.7 times, pointing out significant reduction of systemic inflammation and endothelial dysfunction, while appropriate aeration of sinuses was restored and abnormal focus was eliminated by sinus-surgery, which wasn't noted in comparison group. In traditionally treated patients, these parameters were not reasonably different from the values before treatment.
I. e. conservative therapy without elimination of one of the focuses of chronic infection and sensibilization does not result in objective improvement ofpathochemical processes underlying systemic oxidative stress and inflammation at CRSP + CGN.
Comparative analysis of the results in 1st and 2nd groups demonstrated that application of ERSS + MC promotes blood antioxidant activity restoration in CRSP + CGN patients to the CRSP level. Thus, we managed to approximate the effectiveness of impact on AOS to the results of patients without comorbidity, as the parameters of SOD and blood catalase were not reasonably different between 1st and 2nd groups. MDA concentration, TNFa and endothelin-1 levels differed in statistically proved limits in 1st and 2nd groups, showing a contribution of CRD into systemic increase of these parameters, which is characteristic for CGN rather than for CRSP. At the same time, the concentration of systemic inflammation marker was not reasonably different in 1st and 2nd groups, demonstrating high efficiency of ERSS + MC.
Abnormal focus removal, aeration restoration, sinus drainage provision coupled with therapy optimization in the form of administration of small doses of topical steroids and antioxidant-mucolytics
allowed significantly reduce the intensity of ROS generation in blood, signs of endothelial dysfunction and inflammation.
The above stated proves absolute necessity of endoscopic sinus-surgery in CRSP + CGN. With that, the conservative part of therapy is directed to improve drainage function of ciliated epithelium, gives anti-inflammatory, immunomodulatory and antioxidant action. Cumulative impact of abnormal immunostimulation focus eradication and pathogenetic symptomatic treatment results in objective improvement of cellular, humoral and local immunity parameters.
Comparative analysis of treatment results in 1st and 2nd groups showed that application of complex therapy in the group without comorbidity leads to complete restoration of IRI, and OL, CD-4, CD-8, NPA, CIC, sIgA parameters were not significantly different from the controls. This proves high effectiveness of this offered method of polypous rhinosinusitis treatment.
Abnormal focus removal, aeration restoration, sinus drainage provision coupled with therapy optimization in the form of administration of small doses of topical steroids and antioxidant-mucolytics allowed to restore immunoreactivity, significantly reduce the intensity of ROS generation in blood, signs of endothelial dysfunction and inflammation. This also promoted local immunity restoration, positively affected the immunoreactivity in general.
Conclusions:
1. CGN contributes in chronic rhinosinusitis progress in the form of endothelial dysfunction, hypercoagulation syndrome, OS enhancement and AOS reduction, T-cellular immunodeficiency with immune response disregulation, systemic inflammation.
2. CRS at CGN progresses much worse than without comorbidity, accompanied by MDA increase by 3.3 times, CRP — by 1.4 times, TNF-alpha — by 5.3 times, endothelin-1 — by 4.5 times, SOD suppression by 2.9 times as for the CRS group without CGN.
3. Comparative analysis of CRSP + CGN and CRSP showed that ERSS + MC application promotes restoration ofblood antioxidant activity in CRS + CGN patients up to the CRSP level, decrease of endothelial dysfunction by 1.9 times, systemic inflammation by 1.7 times, OS by 4.2 times as for the level before treatment, which the traditional conservative therapy does not show.
4. Comparative analysis of CRSP + CGN and CRSP showed that ERSS + MC application promotes restoration ofblood antioxidant activity in CRS + CGN patients up to the CRSP level, decrease of endothelial dysfunction by 1.9 times, systemic inflammation by 1.7 times, OS by 4.2 times as for the level before treatment, which the traditional conservative therapy does not show.
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