Macrólidos en enfermedades inflamatorias crónicas de las vías respiratorias

Mauricio Moreno, MD., Oscar Sáenz Morales, MD., Camilo Manrique Martínez, MD., Francisco González Acosta, MD., Erika Paola Vergara Vela, MD., Alberto Mario Pereira Garzón, MD., Rafael Miranda Jiménez, MD.

Resumen


Revisamos la actividad de los macrólidos en la enfermedad inflamatoria crónica de la vía aérea, haciendo énfasis en los efectos inmunomoduladores y antiinflamatorios sobre la célula epitelial. Describimos en detalle los mediadores humorales, celulares y las diferentes interacciones entre estos antibióticos y los mediadores inflamatorios circulantes, incluyendo procesos de apoptosis y oxidación, así como efectos sobre la defensa del epitelio, acciones sobre el moco, movimiento de iones, defensinas, depuración mucociliar y finalmente estabilización epitelial. Debido a estos mecanismos descritos, los macrólidos se convierten en una alternativa coadyuvante en el manejo de las enfermedades pulmonares infecciosas e inflamatorias.


Palabras clave


macrólidos; efectos inmunomodulatorios; célula epitelial; enfermedad inflamatoria de la vía aérea; mediadores inflamatorios

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Referencias


Comité Científico del Estudio IBERPOC. Proyecto IBERPOC: un estudio epidemiológico de la EPOC en España. Arch Bronconeu-mol. 1997;33:293-9.

Manfreda J, Mas Y, Litven W. Morbidity and mortality from chronic obstructive pulmonary disease. Am Rev Respir Dis.1989;140:19-26.

Hurd S. The impact of COPD on lung health worldwide. Epidemiology and incidence. Chest. 2000;117:1-4.

Tateda,T.J. Standiford, J.C. Pechere and K. Yamaguchi,

Regulatory effects of macrolides on bacterial virulence: potential role as quorum-sensing inhibitors, Curr Pharm Des 10 (2004), pp. 3055–3065

B.K. Rubin and M.O. Henke, Immunomodulatory activity and effectiveness of macrolides in chronic airway disease, Chest 125 (2004), pp. 70S–78S.

M. Shinkai and B.K. Rubin, Macrolides and airway inflammation in children, PaediatrRespir Rev 6 (2005), pp. 227–235.

M.O. Henke, S.A. Shah and B.K. Rubin, The role of airway secretions in COPD – clinical applications, COPD 2 (2005), pp.377–390

B.K. Rubin and M.O. Henke, Immunomodulatory activity and effectiveness of macrolides in chronic airway disease, Chest 125 (2004), pp. 70S–78S.

S.L. Johnston, Macrolide antibiotics and asthma treatment, J Allergy ClinImmunol 117 (2006), pp. 1233–1236.

M.J. Parnham, Immunomodulatory effects of antimicrobials in the therapy of respiratory tract infections, CurrOpin Infect Dis 18 (2005), pp. 125–131.

Giamarellos-Bourboulis EJ: Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents2008, 31:12-20.

M. Shinkai, G.H. Foster and B.K. Rubin, Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells, Am J Physiol Lung Cell MolPhysiol 290 (2006), pp. L75–L85.

M. Shinkai, Y.S. Lopez-Boado and B.K. Rubin, Clarithromycin has an immunomodulatory effect on ERK-mediated inflammation induced by Pseudomonas aeruginosaflagellin, J AntimicrobChemother 59 (2007), pp. 1096–1101. This was one of the first papers demonstrating that the effect of low dose macrolides is truly immunomodulatory rather than anti-inflammatory, and that this was mediated, in part, by the ERK pathway, confirming earlier work (reference [10]).

M. Shinkai, J. Tamaoki, H. Kobayashi, S. Kanoh, K. Motoyoshi, T. Kute and B.K. Rubin, Clarithromycin delays progression of bronchial epithelial cells from G1 phase to S phase and delays cell growth via extracellular signal-regulated protein kinase suppression, Antimicrob Agents Chemother 50(2006), pp. 1738–1744.

L. Saiman, B.C. Marshall, N. Mayer-Hamblett, J.L. Burns, A.L. Quittner, D.A. Cibene, S. Coquillette, A.Y. Fieberg, F.J. Accurso and P.W. Campbell III, Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial, JAMA 290 (2003), pp. 1749–1756.

M.J. Schultz, Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis, J AntimicrobChemother. (2004), pp. 21–28.

W.C. Tsai and T.J. Standiford, Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and invivo models, Curr Pharm Des 10(2004), pp. 3081–3093.

Shinkai M, HenkeMO, Rubin BK: Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action. Pharm Therap2008, 117:393-405.

O. Culic, V. Erakovic, I. Cepelak, K. Barisic, K. Brajsa, Z. Ferencic, R. Galovic, I. Glojnaric, Z. Manojlovic and V. Munic et al., Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects, Eur J Pharmacol 450 (2002), pp. 277–289.

M.J. Parnham, O. Culic, V. Erakovic, V. Munic, S. Popovic-Grle, K. Barisic, M. Bosnar, K. Brajsa, I. Cepelak and S. Cuzic et al., Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment, Eur J Pharmacol 517 (2005), pp. 132–143 This study shows that in vivo, azithromycin can initially increase the elaboration of inflammatory mediators followed by a sustained decrease in inflammation, as is characteristic of immunomodulation.

T.V. Ivetic, B. Bosnjak, B. Hrvacic, M. Bosnar, N. Marjanovic, Z. Ferencic, K. Situm, O. Culic, M.J. Parnham and V. Erakovic, Antiinflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice, Eur J Pharmacol 539 (2006), pp. 131–138.

E.J. Giamarellos-Bourboulis, T. Adamis, G. Laoutaris, L. Sabracos, V. Koussoulas, M. Mouktaroudi, D. Perrea, P.E. Karayannacos and H. Giamarellou, Immunomodulatory clarithromycin treatment of experimental sepsis and acute pyelonephritis caused by multidrug-resistantPseudomonasaeruginosa, Antimicrob Agents Chemother 48 (2004), pp. 93–99.

R. Legssyer, F. Huaux, J. Lebacq, M. Delos, E. Marbaix, P. Lebecque, D. Lison, B.J. Scholte, P. Wallemacq and T. Leal, Azithromycin reduces spontaneous and induced inflammation in DeltaF508 cystic fibrosis mice, Respir Res 7 (2006), p. 134. It is thought that CF lung disease is due, in part, to a hyperinflammatory state, with both constitutive inflammation and the induced inflammatory response being increased. This study demonstrates that azithromycin can ‘reset’ (modulate) both the spontaneous and the induced inflammatory response in a mouse model of CF. M. Bosnar, Z. Kelneric, V. Munic, V. Erakovic and M.J. Parnham, Cellular uptake and efflux of azithromycin, erythromycin, clarithromycin, telithromycin, and cethromycin, Antimicrob Agents Chemother 49 (2005), pp. 2372–2377.

M. Bosnar, Z. Kelneric, V. Munic, V. Erakovic and M.J. Parnham, Cellular uptake and efflux of azithromycin, erythromycin, clarithromycin, telithromycin, and cethromycin, Antimicrob Agents Chemother 49 (2005), pp. 2372–2377.

S. Hodge, G. Hodge, S. Brozyna, H. Jersmann, M. Holmes and P.N. Reynolds, Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages, EurRespir J 28 (2006), pp. 486–495.

T. Yamaryo, K. Oishi, H. Yoshimine, Y. Tsuchihashi, K. Matsushima and T. Nagatake, Fourteen-member macrolides promote the phosphatidylserine receptor-dependent phagocytosis of apoptotic neutrophils by alveolar macrophages, Antimicrob Agents Chemother 47 (2003), pp. 48–53These two interesting papers postulate a new effect of macrolides in resolution of lung inflammation. Macrolides can improve phagocytosis of apoptotic cells by alveolar macrophages, a critical component of resolution of chronic inflammation (refs. [

S. Hodge, G. Hodge, R. Scicchitano, P.N. Reynolds and M. Holmes, Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells, Immunol Cell Biol 81 (2003), pp. 289–296

S. Hodge, G. Hodge, J. Ahern, H. Jersmann, M. Holmes and P.N. Reynolds, Smoking alters alveolar macrophage recognition and phagocytic ability: implications in COPD, Am J Respir Cell MolBiol 37 (2007), pp. 748–755

Y.J. Li, A. Azuma, J. Usuki, S. Abe, K. Matsuda, T. Sunazuka, T. Shimizu, Y. Hirata, H. Inagaki and T. Kawada et al., EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-beta signaling in lung fibroblasts, Respir Res 7 (2006), p. 16. This study demonstrates that a powerfully immunomodulatory 14-member macrolide derivative can actually hasten resolution of bleomycin-induced lipid peroxidation injury and fibrosis. This is also a remarkable paper because EM703 is a derivative of erythromycin A that has no identifiable antimicrobial properties.

Ikeda H, Sunazuka T, Suzuki H, Hamasaki Y, Yamazaki S, Omura S, Hatamochi A: EM703, the new derivative of erythromycin, inhibits transcription of type I collagen in normal and scleroderma fibroblasts. J DermatolSci 2008, 49:195-205.

C. Cigana, B.M. Assael and P. Melotti, Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial cells,Antimicrob Agents Chemother 51 (2007), pp. 975-981.

C. Cigana, E. Nicolis, M. Pasetto, B.M. Assael and P. Melotti, Antiinflammatory effects of azithromycin in cystic fibrosis airway epithelial cells,BiochemBiophys Res Commun 350 (2006), pp. 977–982

M. Desaki, H. Okazaki, T. Sunazuka, S. Omura, K. Yamamoto and H. Takizawa, Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation, Antimicrob Agents Chemother 48 (2004), pp. 1581–1585. This paper illustrates the molecular mechanisms of macrolide activity in a lung epithelial cells line, including the non-antimicrobial erythromycin derivative EM703.

H. Yamasawa, K. Oshikawa, S. Ohno and Y. Sugiyama, Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating granulocyte macrophage colony-stimulating factor release, Am J Respir Cell MolBiol 30 (2004), pp. 569–575.

H. Takizawa, M. Desaki, T. Ohtoshi, S. Kawasaki, T. Kohyama, M. Sato, M. Tanaka, T. Kasama, K. Kobayashi and J. Nakajima et al., Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells, Am J RespirCrit Care Med 156 (1997), pp. 266–271.

T. Sunazuka, H. Takizawa, M. Desaki, K. Suzuki, R. Obata, K. Otoguro and S. Omura, Effects of erythromycin and its derivatives on interleukin-8 release by human bronchial epithelial cell line BEAS-2B cells, J Antibiot (Tokyo) 52 (1999), pp. 71–74.

S.H. Randell and R.C. Boucher, Effective mucus clearance is essential for respiratory health, Am J Respir Cell MolBiol 35 (2006), pp. 20–28. This is an excellent recent review on mucociliary clearance and its critical role for normal lung function.

T. Shimizu, S. Shimizu, R. Hattori, E.C. Gabazza and Y. Majima, In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells, Am J RespirCrit Care Med 168 (2003), pp. 581–587. 38. Y. Kaneko, K. Yanagihara, M. Seki, M. Kuroki, Y. Miyazaki, Y. Hirakata, H. Mukae, K. Tomono, J. Kadota and S. Kohno, Clarithromycin inhibits overproduction of muc5ac core protein in murine model of diffuse panbronchiolitis, Am J Physiol Lung Cell MolPhysiol 285 (2003), pp. L847–L853.

V. Sperandio, Novel approaches to bacterial infection therapy by interfering with bacteria-to-bacteria signaling, Expert Rev Anti Infect Ther 5 (2007), pp. 271–276

W.E. Swords and B.K. Rubin, Macrolide antibiotics, bacterial populations and inflammatory airway disease, Neth J Med 61 (2003), pp. 242–248.

Y. Imamura, K. Yanagihara, Y. Mizuta, M. Seki, H. Ohno, Y. Higashiyama, Y. Miyazaki, K. Tsukamoto, Y. Hirakata and K. Tomono et al., Azithromycin inhibits MUC5AC production induced by the Pseudomonas aeruginosaautoinducer N-(3-Oxododecanoyl) homoserine lactone in NCI-H292 Cells, Antimicrob Agents Chemother 48 (2004), pp. 3457–3461.

D.Y. Kim, K. Takeuchi, H. Ishinaga, C. Kishioka, S. Suzuki, C. Basbaum and Y. Majima, Roxithromycin suppresses mucin gene expression in epithelial cells, Pharmacology 72 (2004), pp. 6–11.

U. Pradal, A. Delmarco, M. Morganti, M. Cipolli, E. Mini and G. Cazzola, Long-term azithromycin in cystic fibrosis: another possible mechanism of action?, J Chemother 17 (2005), pp. 393-400.

N. Ge, Y. Nakamura, Y. Nakaya and S. Sone, Interferon-gamma activates outwardly rectifying chloride channels in the human bronchial epithelial cell line BEAS-2B, J Med Invest 48 (2001), pp. 97–101.

P.M. Barker, D.J. Gillie, M.S. Schechter and B.K. Rubin, Effect of macrolides on in vivo ion transport across cystic fibrosis nasal epithelium, Am J RespirCrit Care Med 171 (2005), pp. 868–871

D.M. Laube, S. Yim, L.K. Ryan, K.O. Kisich and G. Diamond, Antimicrobial peptides in the airway, Curr Top MicrobiolImmunol 306 (2006), pp. 153–182.

K. Ishizawa, T. Suzuki, M. Yamaya, Y.X. Jia, S. Kobayashi, S. Ida, H. Kubo, K. Sekizawa and H. Sasaki, Erythromycin increases bactericidal activity of surface liquid in human airway epithelial cells, Am J Physiol Lung Cell MolPhysiol 289 (2005), pp. L565-L573.

This report shows that macrolides can increase epithelial antimicrobial activity in the absence of inflammation, suggesting that macrolide treatment may contribute to improvement of the epithelial barrier function and defense against microorganisms by this mechanism.

T. Hiratsuka, H. Mukae, H. Iiboshi, J. Ashitani, K. Nabeshima, T. Minematsu, N. Chino, T. Ihi, S. Kohno and M. Nakazato, Increased concentrations of human beta-defensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis, Thorax 58 (2003), pp. 425–430

X. Gao, R. Ray, Y. Xiao, P.E. Barker and P. Ray, Inhibition of sulfur mustard-induced cytotoxicity and inflammation by the macrolide antibiotic roxithromycin in human respiratory epithelial cells, BMC Cell Biol 8 (2007), p. 17

Timothy R. Pasquale and James S. Tan, Nonantimicrobial effects of antibacterial agents, clinical infectious diseases 2005;40;127-135.

Jun Tamaoki, The effects of Macrolides on Inflammatory Cells, CHEST,2004;125;41s-51s.

Esterly NB, Furey NL, Flanagan LE. The effect of antimicrobial agents on leukocyte chemotaxis. J Invest Dermatol 1978; 70:51-55.

Nelson S, Summer WR, Terry PB, et al. Erythromycininduced suppression of pulmonary antibacterial defenses: a potential mechanism of superinfection in the lung. Am Rev Respir Dis 1987; 136:1207–1212.

Kawasaki S, Takizawa H, Takayuki O, et al. Roxithromycin inhibits cytokine production by and neutrophil attachment to human bronchial epithelial cells in vitro. Antimicrob Agents Chemother 1998; 42:1499 –1502.




DOI: http://dx.doi.org/10.30789/rcneumologia.v23.n2.2011.178

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