Consilium MedicumConsilium MedicumConsilium MedicumConsilium Medicum2075-17532542-2170Consilium Medicum93509ArticlesСтатьиResearch ArticleImmunomoduliruyushchie svoystva azitromitsina: ot eksperimental'nykh dannykh k klinicheskomu primeneniyu pri khronicheskikh vospalitel'nykh zabolevaniyakh respiratornogo traktaИммуномодулирующие свойства азитромицина: от экспериментальных данных к клиническому применению при хронических воспалительных заболеваниях респираторного трактаRvachevaA. VРвачеваА. В

Лаборатория пульмонологии

StetsyukO. UСтецюкО. УAndreevaI. VАндрееваИ. ВГОУ ВПО МГМСУНаучно-исследовательский институт антимикробной химиотерапии ГБОУ ВПО Смоленская государственная медицинская академия Минздравсоцразвития РФ15032012143VOL 14, NO3 (2012)ТОМ 14, №3 (2012)121928122021Copyright ©; 2012, Consilium MedicumCopyright ©; 2012, ООО "Консилиум Медикум"2012Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://consilium.orscience.ru/2075-1753/article/view/93509

Предположения о наличии иммуномодулирующих свойств у макролидных антибиотиков впервые были высказаны японскими исследователями еще в 60-х годах прошлого века. Основанием для подобных предположений послужили результаты применения эритромицина у пациентов с диффузным панбронхиолитом (ДПБ). Назначение эритромицина при данном заболевании существенно улучшило показатели выживаемости пациентов, в том числе больных с колонизацией дыхательных путей Pseudomonas aeruginosa, несмотря на то, что данный микроорганизм не входит в спектр активности макролидов. Дальнейшие исследования показали, что эффективность макролидов при ДПБ и некоторых других хронических воспалительных заболеваниях респираторного тракта обусловлена иммуномодулирующими свойствами представителей данного класса антибиотиков, в частности эритромицина, кларитромицина, рокситромицина и азитромицина. В настоящем обзоре рассмотрены иммуномодулирующие свойства 15-членного макролида азитромицина, выявленные в экспериментах in vitro, ex vivo и на животных, а также клинические данные об эффективности его применения при тяжелых хронических воспалительных заболеваниях респираторного тракта.

воспалительные заболевания респираторного трактамакролидыантибиотикииммуномодуляторыTanimoto H. A review of the recent progress in treatment of patients with diffuse panbronchiolitis associated with Pseudomonas aeruginosa infection in Japan. Antibiot Chemother 1991; 44: 94–8.López-Boado Y.S., Rubin B.K. Macrolides as immunomodulatory medications for the therapy of chronic lung diseases. Curr Opin Pharmacol 2008; 8 (3): 286–91.Friedlander A.L., Albert R.K. Chronic macrolide therapy in inflammatory airways diseases. Chest 2010; 138 (5): 1202–12.Kanoh S, Rubin B.K. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev 2010; 23 (3): 590–615.Culić O, Eraković V, Cepelak I et al. Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. Eur J Pharmacol 2002; 450 (3): 277–89.Parnham M.J., Culić O, Eraković V et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short - term azithromycin treatment. Eur J Pharmacol 2005; 517 (1–2): 132–43.Legssyer R, Huaux F, Lebacq J et al. Azithromycin reduces spontaneous and induced inflammation in DeltaF508 cystic fibrosis mice. Respir Res 2006; 7: 134.Cigana C, Assael B.M., Melotti P. Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial cells. Antimicrob Agents Chemother 2007; 51 (3): 975–81.Cigana C, Nicolis E, Pasetto M et al. Anti - inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells. Biochem Biophys Res Commun 2006; 350 (4): 977–82.Bergamini G, Cigana C, Sorio C et al. Effects of azithromycin on glutathione S - transferases in cystic fibrosis airway cells. Am J Respir Cell Mol Biol 2009; 41 (2): 199–206.Murphy D.M., Forrest I.A., Corris P.A. et al. Azithromycin attenuates effects of lipopolysaccharide on lung allograft bronchial epithelial cells. J. Heart Lung Transplant 2008; 27: 1210–6.Tsai W.C., Rodriguez M.L., Young K.S. et al. Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med 2004; 170: 1331–9.Murphy B.S., Sundareshan V, Cory T.J. et al. Azithromycin alters macrophage phenotype. Antimicrob Chemother 2008; 61: 554–60.Sugiyama K, Shirai R, Mukae H, et al. Differing effects of clarithromycin and azithromycin on cytokine production by murine dendritic cells. Clin Exp Immunol 2007; 147: 540–6.Koch С.С., Esteban D.J., Chin A.C. et al. Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae. J Antimicrob Chemother 2000; 46 (1): 19–26.Hodge S, Hodge G, Brozyna S et al. Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages. Eur Respir J 2006; 28: 486–95.Hodge S, Hodge G, Jersmann H et al. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 178 (2): 139–48.Asgrimsson V, Gudjonsson T, Gudmundsson G.H., Baldursson O. Novel effects of azithromycin on tight junction proteins in human airway epithelia. Antimicrob Agents Chemother 2006, 50: 1805–12.Halldorsson S, Gudjonsson T, Gottfredsson M et al. Azithromycin maintains airway epithelial integrity during Pseudomonas aeruginosa infection. Am J Respir Cell Mol Biol 2010; 42 (1): 62–8.Imamura Y, Yanagihara K, Mizuta Y et al. Azithromycin inhibits MUC5AC production induced by the Pseudomonas aeruginosa autoinducer N-(3-Oxododecanoyl) homoserine lactone in NCI-H292 Cells. Antimicrob Agents Chemother 2004; 48: 3457–61.Araki N, Yanagihara K, Morinaga Y et al. Azithromycin inhibits nontypeable Haemophilus influenzae - induced MUC5AC expression and secretion via inhibition of activator protein-1 in human airway epithelial cells. Eur J Pharmacol 2010; 644 (1–3): 209–14.Baumann U, Fischer J.J., Gudowius P et al. Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long - term therapy with azithromycin. Infection 2001; 29: 7–11.Mizukane R, Hirakata Y, Kaku M et al. Comparative in vitro exoenzyme - suppressing activities of azithromycin and other macrolide antibiotics against Pseudomonas aeruginosa. Antimicrob Agents Chemother 1994; 38: 528–33.Molinari G, Guzma´n C.A., Pesce A, Schito G.C. Inhibition of Pseudomonas aeruginosa virulence factors by subinhibitory concentrations of azithromycin and other macrolide antibiotics. J Antimicrob Chemother 1993; 31: 681–8.Kawamura-Sato K, Iinuma T, Hasegawa T et al. Effect of subinhibitory concentrations of macrolides on expression of flagellin in Pseudomonas aeruginosa and Proteus mirabilis. Antimicrob Agents Chemother 2000; 44: 2869–72.Aparna M.S., Yadav S. Biofilms: microbes and disease. Braz J Infect Dis 2008; 12 (6): 526–30.Грузина В.Д. Коммуникативные сигналы бактерий. Антибиотики и химиотерапия. 2003; 48 (10): 32–9.Tateda K, Comte R, Pechere J.C. et al. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2001; 45 (6): 1930–3.Favre-Bonte S, Kohler T, Van Delden C. Biofilm formation by Pseudomonas aeruginosa: role of the C4-HSL cell - to - cell signal and inhibition by azithromycin. J Antimicrob Chemother 2003; 52: 598–604.Gillis R.J., Iglewski B.H. Azithromycin retards Pseudomonas aeruginosa biofilm formation. J Clin Microbiol 2004; 42 (12): 5842–5.Hoffmann N, Lee B, Hentzer M et al. Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary - growth - phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice. Antimicrob Agents Chemother 2007; 51 (10): 3677–87.Howe R.A., Spencer R.C. Macrolides for the treatment of Pseudomonas aeruginosa infections? J Antimicrob Chemother 1997; 40: 153–5.Rubin B.K., Henke M.O. Immunomodulatory activity and effectiveness of macrolides in chronic airway disease. Chest 2004; 125 (Suppl.): 70S–78S.Moskowitz S.M., Foster J.M., Emerson J, Burns J.L. Clinically feasible biofilm susceptibility assay for isolates of Pseudomonas aeruginosa from patients with cystic fibrosis. J Clin Microbiol 2004; 42: 1915–22.Eldika N, Sethi S. Role of nontypeable Haemophilus influenzae in exacerbations and progression of chronic obstructive pulmonary disease. Curr Opin Pulm Med 2006; 12: 118–24.Starner T.D., Shrout J.D., Parsek M.R. et al. Subinhibitory concentrations of azithromycin decrease nontypeable Haemophilus influenzae biofilm formation and diminish established biofilms. Antimicrob Agents Chemother 2008; 52 (1): 137–45.Kudoh S. Applying lessons learned in the treatment of diffuse panbronchiolitis to other chronic inflammatory diseases. Am J Med 2004; 117 (Suppl. 9A): 12S–19S.Li H, Zhou Y, Fan F et al. Effect of azithromycin on patients with diffuse panbronchiolitis: retrospective study of 51 cases. Intern Med 2011; 50 (16): 1663–9.Муковисцидоз в РФ. Электронный доступ: www.cf-rf.ru.Southern K.W., Barker P.M., Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2011; 12: CD002203.Clement A, Tamalet A, Leroux E et al. Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial. Thorax 2006; 61: 895–902.Equi A, Balfour-Lynn I.M., Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo - controlled crossover trial. Lancet 2002; 360: 978–84.Hansen C.R., Presslera T, Koch C, Høiby N. Long - term azithromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection: an observational cohort study. J Cyst Fibros 2005; 4: 35–40.Saiman L, Marshall B.C., Mayer-Hamblett N et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290: 1749–56.Wolter J, Seeney S, Bell S et al. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002; 57: 212–6.Steinkamp G, Schmitt-Grohe S, Döring G et al. Once - weekly azithromycin in cystic fibrosis with chronic Pseudomonas aeruginosa infection. Respir Med 2008; 102 (11): 1643–53.Власова А.В., Ашерова И.К. Влияние длительной терапии азитромицином в субингибирующей дозе на развитие повторных обострений хронического бронхита, показатели функции внешнего дыхания, нутритивный статус и микробиологический спектр мокроты у детей, больных муковисцидозом в течение двух лет. VII Национальный конгресс по муковисцидозу. Воронеж, 5–6 апреля, 2005. Сборник статей и тезисов; с. 35–6.Saiman L, Anstead M, Mayer-Hamblett N et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2010; 303 (17): 1707–15.Martinez F.J., Curtis J.L., Albert R. Role of macrolide therapy in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2008; 3 (3): 331–50.Gómez J, Baños V, Simarro E et al. Prospective, comparative study (1994–1998) of the influence of short - term prophylactic treatment with azithromycin on patients with advanced COPD. Rev Esp Quimioter 2000; 13 (4): 379–83.Albert R.K., Connett J, Bailey W.C. et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011; 365 (8): 689–98.Pomares X, Montón C, Espasa M et al. Long - term azithromycin therapy in patients with severe COPD and repeated exacerbations. Int J Chron Obstruct Pulmon Dis 2011; 6: 449–56.Blasi F, Bonardi D, Aliberti S et al. Long - term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy. Pulm Pharmacol Ther 2010; 23 (3): 200–7.Davies G, Wilson R. Prophylactic antibiotic treatment of bronchiectasis with azithromycin. Thorax 2004; 59: 540–1.Cymbala A.A., Edmonds L.C., Bauer M.A. et al. The disease - modifying effects of twice - weekly oral azithromycin in patients with bronchiectasis. Treat Respir Med 2005; 4 (2): 117–22.Anwar G.A., Bourke S. C, Afolabi G et al. Effects of long - term low - dose azithromycin in patients with non - CF bronchiectasis. Respir Med 2008; 102 (10): 1494–6.Gerhardt S.G., Mc Dyer J.F., Girgis R.E. et al. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Resp Crit Care Med 2003; 168: 121–5.Jain R, Hachem R.R., Morrell M.R. et al. Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant 2010; 29 (5): 531–7.Richeldi L, Ferrara G, Fabbri L.M. et al. Macrolides for chronic asthma. Cochrane Database Syst Rev 2005; 4: CD002997.Ekici A, Ekici M, Erdemoglu A.K. Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma. J Asthma 2002; 39: 181–5.Piacentini G.L., Peroni D.G., Bodini A et al. Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report. Allergy Asthma Proc 2007; 28: 194–8.Hahn D.L., Plane M.B., Mahdi O.S., Byrne G.I. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials 2006; 1 (2): e11.Dokic D, Goseva Z, Trajkovska-Dokic E et al. Chlamydia pneumoniae infection in asthmatic patients. World Allergy Organization J 2007; p. S248–S249.