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Clinical implications of the immunomodulatory effects of macrolides
Clinical Implications of the Immunomodulatory Effects of Macrolides Jun Tamaoki, MD, PhD, Junichi Kadota, MD, Hajime Takizawa, MD
Macrolide antibiotics are known for their efficacy in treating acute airway infections, but just as importantly, they are also effective anti-inflammatory agents. Their anti-inflammatory properties have been studied most thoroughly in chronic inflammatory airway diseases, particularly diffuse panbronchiolitis (DPB). Erythromycin, azithromycin, clarithromycin, and roxithromycin inhibit chemotaxis and infiltration of neutrophils into the airway and, subsequently, decrease mucus secretion. Mucus formation, a significant cause of morbidity and mortality in patients with chronic airway inflammation, is directly inhibited by macrolides and suppressed by decreased inflammation in the airway. The mechanisms of action for the anti-inflammatory properties of the macrolides are still being investigated, but they are clearly multifactorial. Macrolides inhibit the production of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor–␣, perhaps by suppressing the transcription factor nuclear factor–B or activator protein–1. Inhibition of cytokine production has been seen in vitro and also in bronchoalveolar lavage fluid, which contains less IL-8 and fewer neutrophils after treatment with macrolides. Macrolides also inhibit formation of leukotriene B4, which attracts neutrophils, and inhibit the release of superoxide anion by neutrophils that may be present in the airway. An important aspect of inflammation is extravasation of neutrophils into the tissues. Macrolides block formation of adhesion molecules necessary for neutrophil migration. Together, these anti-inflammatory effects result in improved pulmonary functions and fewer airway infections. In patients with DPB, the anti-inflammatory effects lead to a significant increase in survival. Further work is needed to characterize the clinical benefits of macrolides in patients with other chronic inflammatory airway diseases. Am J Med. 2004;117(9A): 5S–11S. © 2004 by Elsevier Inc.
From the First Department of Medicine, Tokyo Women’s Medical University, Tokyo, Japan (JT); the Second Department of Medicine, Oita Medical University, Oita, Japan (JK); and the Department of Respiratory Medicine, Tokyo University School of Medicine, Tokyo, Japan (HT). Requests for reprints should be addressed to Jun Tamaoki, MD, PhD, First Department of Medicine, Tokyo Women’s Medical University, 8-1 Kawada-Cho, Shiinjuku, Tokyo 162-8666, Japan. © 2004 by Elsevier Inc. All rights reserved.
T
he nonantimicrobial, anti-inflammatory properties of macrolides were first identified when patients receiving troleandomycin for the treatment of asthma had a reduction in their requirement for steroids.1– 6 Most of the subsequent work on the immunomodulatory effects of macrolides has been in patients with diffuse panbronchiolitis (DPB),7–11 a chronic inflammatory airway disease characterized by cough, persistent sinus disease, and neutrophilic airway inflammation. Other chronic inflammatory diseases of the airways affected by macrolides include cystic fibrosis, chronic bronchitis, and asthma. The anti-inflammatory effects of macrolides are clinically significant. Use of macrolides in patients with DPB has resulted in an increase in 10-year survival from 12% to ⬎90%.12 This review summarizes many of the in vivo and in vitro effects of macrolides, which lead to clinical improvement in patients with chronic inflammatory lung diseases. These anti-inflammatory effects include decreased production of proinflammatory cytokines, such as interleukin (IL)-8, IL-1, tumor necrosis factor (TNF)-␣, reduced neutrophil infiltration into airways, reduced secretion of mucus, and modulation of defensin and adhesion molecule expression.13,14
EFFECTS ON MUCUS HYPERSECRETION Many respiratory diseases, such as acute and chronic bronchitis, bronchiectasis, DPB, asthma, and cystic fibrosis, are characterized by hypersecretion of mucus in the airways. Mucus hypersecretion increases morbidity and mortality, particularly from pulmonary infections, in patients with chronic inflammation of the airways.15–17 Infiltration of neutrophils, lymphocytes, and eosinophils into the tissues of the airways leads to chronic inflammation. This inflammation causes damage to the airway epithelium and goblet cell hyperplasia leading to hypersecretion of mucus. Mediators of mucus hypersecretion include inflammatory cell-derived cytokines, chemokines, and oxygen radicals. It is important to control airway mucus secretion for the management of chronic airway diseases. Mucus hypersecretion is a common cause of acute exacerbations of chronic airway diseases. In fact, mucus hypersecretion is associated with a decreased forced expiratory volume in 1 second and increased risk of hospitalization in patients with chronic obstructive pulmonary disease.17 In patients 1548-2766/04/$22.00 5S doi:10.1016/j.amjmed.2004.07.023
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with chronic inflammatory diseases of the airways, the presence of viscous mucus in the airway lumen causes impairment of mucociliary clearance, which may promote bacterial colonization and recurrent respiratory infection. Bacteria-derived substances then stimulate airway mucus secretion, which results in further disturbance of airway clearance of mucus. Obstruction or narrowing of small airways by mucus may produce atelectasis or V˙/Q˙ mismatch, which can result in respiratory failure. Both in vitro and in vivo studies show that macrolides reduce mucus and sputum secretion. An in vitro study showed a direct effect of macrolides on the secretion of respiratory glycoconjugate, a component of mucus. Erythromycin inhibited the secretion of radiolabeled glucosamine from human airway explants and endometrial adenocarcinoma cells in a concentration-dependent manner.18 In this study, penicillin, ampicillin, tetracycline, and cephalosporin had no effect on mucus secretion. The inhibitory effects of clarithromycin and erythromycin on mucus production in airway epithelial cells were also shown in cultures of human mucoepidermoid carcinoma cells and from cultured human nasal epithelial cells.19 As suggested in a study of guinea pig airways,20 macrolides may reduce the volume of mucus secreted by goblet cells through the inhibition of neutrophil accumulation. In this study, clarithromycin and erythromycin both significantly reduced mucus secretion, whereas amoxicillin and cefaclor had no effect. In a rat model of mucus hypersecretion, clarithromycin (5–10 mg/kg) significantly inhibited ovalbumin and lipopolysaccharideinduced mucus production by epithelial cells and mucosal neutrophil infiltration in goblet cells in rat nasal epithelium.19 Macrolides also inhibit the expression of MUC5AC, a mucus glycoprotein localized primarily in airway goblet cells.19,20 Clarithromycin 500 mg twice daily was administered to 10 patients with purulent rhinitis for 2 weeks. When compared with healthy subjects, these clarithromycintreated patients showed a reduction of mucus volume and improvement of the properties of nasal mucus such as viscoelasticity, cohesion, hydration, and transportability.21 Clarithromycin decreased the volume of secretions (500 mg vs. 28 mg, P ⫽ 0.01) and increased mucus clearance by 30% (P ⫽ 0.005). The rheology, hydration, cohesion, and transportability of mucus secretions in these patients were similar to secretions from healthy subjects. A double-blind, placebo-controlled, parallel-group trial of 31 patients with chronic bronchitis, bronchiectasis, or DPB showed that clarithromycin 100 mg twice daily for 8 weeks significantly reduced the amount of sputum produced from 51 g/day to 24 g/day without altering bacterial density or sputum flora, and also increased sputum elasticity.22 Treatment with clarithromycin signifi6S
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cantly improved hypoxia, hypercapnia, pulmonary function, and quality of life in these patients. The mechanism by which macrolides decrease mucus hypersecretion is unclear. Macrolides may decrease the volume of mucus secreted in patients with chronic airway disease by direct actions on mucus-producing cells in the airways or indirectly by decreasing bacterial adhesion, cytokine production, inflammatory cell recruitment, or the generation of free radicals.23–29 Macrolides may also decrease sputum production by inhibiting water secretion into the airway lumen by inhibiting secretion of chloride.30,31 Macrolides directly inhibit acetylcholineevoked Cl– channels in vitro, which may explain the activity of these drugs even in patients with cystic fibrosis who have a defect in the cystic fibrosis transmembrane conductance regulator, a cyclic adenosine monophosphate–regulated chloride channel.31
EFFECTS ON NEUTROPHIL ACCUMULATION AND THE INFLAMMATORY RESPONSE Neutrophils are key mediators of the inflammatory response in patients with chronic airway disease (Figure 1). Neutrophils release oxidative and proteolytic products, such as neutrophil elastase, which can cause damage to the lower respiratory tract. These cytotoxic products damage the lung parenchyma and epithelial cells. Patients with chronic airway disease such as asthma have significantly higher percentages of neutrophils and higher neutrophil chemotactic activity in bronchoalveolar lavage fluid (BALF) compared with healthy subjects.32,33 Erythromycin significantly reduces the percentage of neutrophils (P ⬍0.01) and neutrophil chemotactic activity (P ⬍0.001) in BALF from patients with chronic diseases of the airways.23,28,32,34 Erythromycin is effective in reducing the percentage of neutrophils in BALF regardless of infection with Pseudomonas aeruginosa or bacterial clearance in patients (Figure 2).28 Erythromycin also suppresses the influx of neutrophils into the airways despite the presence of chemotactic factors, such as IL-8, in the lungs.32 Both the concentration of IL-8 and the percentage of neutrophils in BALF in patients with DPB are reduced after treatment with erythromycin or roxithromycin (P ⬍0.05).23 A study of erythromycin therapy for the treatment of bronchiolitis showed that the number of neutrophils and the neutrophil-derived elastolytic-like activity in BALF in patients was significantly reduced after the treatment and corresponded to an improvement in pulmonary function in these patients.35 In this study, another antibiotic, ampicillin, had no effect on the function or number of neutrophils in these patients. By reducing the intrapulmonary chemotactic gradient or the ability of neutrophils to respond to chemotactic factors, erythromycin reduces the migration and, therefore, the
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Figure 1. Role of neutrophil accumulation in chronic inflammation of airway disease. Chronic inflammation of the airways is characterized by airway epithelial damage, goblet cell hyperplasia, and mucociliary dysfunction. The increased airway mucus layer may cause mucociliary dysfunction and recurrent airway infection. Chronic inflammation is mediated by cytokines, chemokines, oxygen radicals, and chemical mediators, all of which are targets of macrolide therapy. EM ⫽ erythromycin; ICAM-1 ⫽ intercellular cell adhesion molecule–1; IL ⫽ interleukin; LTB4 ⫽ leukotriene B4; Mac-1 ⫽ neutrophil adhesion molecule Mac-1.
Figure 2. Number of neutrophils (left), concentration of interleukin (IL)-8 (middle), and concentration of neutrophil elastase in the bronchoalveolar lavage fluid (right) from patients (N ⫽ 5) with diffuse panbronchiolitis (DPB) or bronchiectasis (BE) before (open symbols) and after treatment with erythromycin 600 mg/day for 3 months (closed symbols). The effect was independent of infection with Pseudomonas aeruginosa. (Adapted from Infect Immun.27)
accumulation of neutrophils in the lower respiratory tract, which in turn reduces pulmonary inflammation.32,36 However, these effects are unclear in patients with cystic fibrosis. In an in vitro study, erythromycin did
not inhibit the migration of neutrophils isolated from patients with cystic fibrosis.37 Macrolides reduce the accumulation of neutrophils not only by impairing the migration of neutrophils to
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sites of inflammation but also by inhibiting the expression of neutrophil adhesion molecules. Adhesion molecules are necessary for extravasation of neutrophils from blood vessels into the interstitial space. A reduction in adhesion molecules will decrease neutrophil-mediated inflammation in tissues. Macrolides reduce the expression of the neutrophil adhesion molecule Mac-1 and the serum concentrations of the soluble adhesion molecules sL-, sE-, and sP-selectin; intercellular adhesion molecule–1; vascular cell adhesion molecule–1; and lymphocyte function-associated antigen.24,38 – 41 The concentrations of these neutrophil adhesion molecules correlate with the concentrations of IL-8 and IL-1 in BALF.41 In vitro incubation of neutrophils with macrolides does not directly affect adhesion molecule release from neutrophils after stimulation with IL-8.41 Therefore, the effect of macrolides on the neutrophil adhesion molecules may be secondary to inhibition of the release of cytokines and other proinflammatory molecules involved in the upregulation of neutrophil adhesion molecules. Macrolides inhibit oxygen radical production by neutrophils and degranulation of neutrophils. This effect may be explained in part by the inhibition of the phospholipase-D phosphatidate phosphohydrolase pathway by macrolides.42 Levert and coworkers26 showed that azithromycin inhibited superoxide anion production by human neutrophils even at drug concentrations unlikely to have antimicrobial effects. The effect was not related to cellular toxicity or superoxide scavenging properties. Likewise, Kadota and colleagues25 showed that erythromycin significantly suppressed superoxide anion production by primed neutrophils. Macrolides also enhance the activity of superoxide dismutase, an antioxidant enzyme in alveolar macrophages of patients with DPB.43 Some studies show an inhibitory effect of macrolides on neutrophil elastase, which stimulates mucus hypersecretion in patients with chronic airway diseases.27,44 However, other investigators have reported the stimulation of neutrophil elastase by erythromycin.45 Whether any of the effects of macrolides on neutrophil functions observed in vitro are clinically relevant in vivo requires further study.
EFFECTS ON THE INFLAMMATORY CASCADE, TRANSCRIPTION, AND CYTOKINES The inflammatory cascade is composed of a network of cytokines and chemokines that modulate the initiation and progression of the inflammatory response.46 Proinflammatory cytokines include IL-1, IL-6, IL-8, and TNF-␣. Modulation of these cytokines can decrease inflammation. Although the mechanism by which macrolides inhibit the accumulation of neutrophils and reduce inflammation is not clear, studies show that macrolides 8S
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significantly affect a variety of these immune mediators and transcription factors.13,14,23,25,29,47,48 Expression of IL-8 messenger RNA in alveolar macrophages, epithelial cells, and endothelial cells suggests that IL-8 is produced in the lung and is an important mediator in the accumulation of neutrophils and the inflammatory response. In vitro studies suggest that macrolides impair the production of IL-8 by human alveolar macrophages, which results in the reduction of neutrophil accumulation.29 Only the 14-member macrolides— erythromycin, clarithromycin, and roxithromycin—were effective in inhibiting the production of IL-8. The 16-member macrolides—josamycin and midecamycin—and the nonmacrolide drugs—piperacillin, clindamycin, and ciprofloxacin—had no effect on the production of IL-8. Similarly, the concentrations of IL-8, as well as the concentrations of IL-1 and TNF-␣, were reduced in the BALF of patients with DPB after treatment with either erythromycin or roxithromycin.23 Erythromycin suppresses the expression of IL-6 in human bronchial epithelial cells.49 Similarly, clarithromycin and azithromycin inhibit the production of IL-1␣, IL-1, IL-6, IL-10, TNF-␣, and granulocyte–macrophage colony-stimulating factors (GM-CSF).47 Macrolides reduce the concentrations of cytokines by suppressing transcription factors such as nuclear factor (NF)–B and activator protein (AP)–1 in human bronchial epithelial cells in vitro.50 –54 These transcription factors are important in the inflammatory response, and inhibition of these factors can decrease the expression of IL-8 and other cytokines. Both erythromycin and clarithromycin were shown to suppress IL-8 production by human monocytes through inhibitory effects on NF-B and AP-1 activation.51,52 Erythromycin modulates the lipoxygenase pathway of arachidonic acid metabolism in neutrophils and macrophages.55 Leukotriene (LT) B4, a metabolite of arachidonic acid, is an important chemotactic factor for neutrophils and is elevated in patients with chronic airway disease. Erythromycin reduces the concentrations of LTB4 in BALF from patients with DPB, which significantly correlates with reductions in the percentage of neutrophils and neutrophil chemotactic activity.55 Macrolides also act on defensins. Defensins are endogenous antimicrobial peptides that attach to epithelial cells and potentially cause injury to the lungs. Defensins are present in the azurophil granules of neutrophils, the mucinous exudates of the airways, and on the surface of bronchiolar epithelial cells. Macrolide therapy reduces defensin concentrations, which correlates with the percentage of neutrophils, the concentration of IL-8, and improvement in pulmonary function in patients with DPB.56
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Figure 3. Summary of the effects of macrolides for the treatment of chronic airway diseases. The anti-inflammatory and antisecretory properties of macrolides collectively decrease the inflammation and hypersecretion associated with chronic airway diseases. ROS ⫽ reactive oxygen species.
CONCLUSION The anti-inflammatory properties of macrolides are well established, although the mechanisms for these actions are still being investigated. At the molecular level there are many effects that, in combination, provide clinical benefits to the patient (Figure 3). For example, hypersecretion of mucus complicates many chronic inflammatory airway diseases and has been shown to significantly contribute to morbidity and mortality.15,16 Macrolides directly inhibit secretion of mucus by preventing the release of glycoproteins but also decrease neutrophil accumulation in the airways by inhibiting expression of proinflammatory cytokines, such as IL-1, IL-8, and TNF-␣, and by inhibiting secretion of adhesion molecules that allow extravasation of neutrophils. As a result of these biologic effects, patients with chronic inflammatory airway disease have improvement in their pulmonary function tests and experience fewer airway infections when taking a macrolide. Macrolides reduce the number of airway infections in patients with chronic airway disease not only by their direct effects on bacteria but also by their ability to reduce inflammation, a common cause of infection in these patients. The reduction in neutrophils in the airway of these patients also leads to decreased release of superoxide anion, LTB4, and defensins from these cells. Although further studies are needed to fully assess the benefits of macrolides in many inflammatory airway dis-
eases, the clinical benefits of these drugs in DPB are profound. Before macrolide therapy, patients with DPB had progressive loss of pulmonary function, recurrent pulmonary infections, and a 10-year survival rate of just 12%.12 Now, with long-term macrolide therapy, patients with DPB have improved pulmonary functions, fewer infections, and, most importantly, a 10-year survival rate of ⬎90%. Patients with cystic fibrosis also report a decreased rate of airway infection, improved pulmonary function, and improved quality of life after treatment with macrolides. Questions that remain include which macrolide has the best efficacy and fewest adverse effects, duration of the anti-inflammatory effect with long-term macrolide therapy, and the long-term impact of continuous antimicrobial coverage.
REFERENCES 1. Flotte TR, Loughlin GM. Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma. Pediatr Pulmonol. 1991;10:178 –182. 2. Kamada AK, Hill MR, Ikle DN, Brenner AM, Szefler SJ. Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma. J Allergy Clin Immunol. 1993;91:873–882. 3. Siracusa A, Brugnami G, Fiordi T, Areni S, Severini C, Marabini A. Troleandomycin in the treatment of difficult asthma. J Allergy Clin Immunol. 1993;92:677–682. 4. Spector S, Katz F, Farr R. Troleandomycin: effectiveness in steroid-dependent asthma and bronchitis. J Allergy Clin Immunol. 1974;54:367–379.
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A Symposium: Clinical Implications of Macrolide Immunomodulation/Tamaoki et al. 5. Wald JA, Friedman BF, Farr RS. An improved protocol for the use of troleandomycin (TAO) in the treatment of steroidrequiring asthma. J Allergy Clin Immunol. 1986;78(Pt 1):36 – 43. 6. Zeiger RS, Schatz M, Sperling W, Simon RA, Stevenson DD. Efficacy of troleandomycin in outpatients with severe, corticosteroid-dependent asthma. J Allergy Clin Immunol. 1980;66:438 –446. 7. Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration. 1991;58:145–149. 8. Kudoh S, Uetake T, Hagiwara K, et al. Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis [in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1987;25:632–642. 9. Kadota J, Mukae H, Ishii H, et al. Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis. Respir Med. 2003;97:844 –850. 10. Brugiere O, Milleron B, Antoine M, Carette MF, Philippe C, Mayaud C. Diffuse panbronchiolitis in an Asian immigrant. Thorax. 1996;51:1065–1067. 11. Takeda H, Miura H, Kawahira M, Kobayashi H, Otomo S, Nakaike S. Long-term administration study on TE-031 (A56268) in the treatment of diffuse panbronchiolitis [in Japanese]. Kansenshogaku Zasshi. 1989;63:71–78. 12. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med. 1998;157(Pt 1):1829 –1832. 13. Rubin BK, Tamaoki J. Macrolide antibiotics as biological response modifiers. Curr Opin Investig Drugs. 2000;1:169 – 172. 14. Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. 2001;429:209 – 229. 15. Puchelle E, Bajolet O, Abely M. Airway mucus in cystic fibrosis. Paediatr Respir Rev. 2002;3:115–119. 16. Prescott E, Lange P, Vestbo J. Chronic mucus hypersecretion in COPD and death from pulmonary infection. Eur Respir J. 1995;8:1333–1338. 17. Vestbo J, Prescott E, Lange P, for the Copenhagen City Heart Study Group. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Am J Respir Crit Care Med. 1996; 153:1530 –1535. 18. Goswami SK, Kivity S, Marom Z. Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro. Am Rev Respir Dis. 1990;141:72–78. 19. Shimizu T, Shimizu S, Reiko H, Gabazza EC, Majima Y. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med. 2003;168:581–587. 20. Tamaoki J, Nakata J, Takeda Y, Takemura H, Tagaya E, Konno K. Effect of macrolide antibiotics on airway goblet hypersecretion in guinea pigs [in Japanese]. Kansenshogaku Zasshi. 1996;70:591–596. 21. Rubin BK, Druce H, Ramirez OE, Palmer R. Effect of clarithromycin on nasal mucus properties in healthy subjects and in patients with purulent rhinitis. Am J Respir Crit Care Med. 1997;155:2018 –2023. 22. Tamaoki J, Takeyama K, Tagaya E, Konno K. Effect of clarithromycin on sputum production and its rheological properties in chronic respiratory tract infections. Antimicrob Agents Chemother. 1995;39:1688 –1690. 10S
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23. Sakito O, Kadota J, Kohno S, Abe K, Shirai R, Hara K. Interleukin 1 beta, tumor necrosis factor alpha, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy. Respiration. 1996;63:42–48. 24. Khair OA, Devalia JL, Abdelaziz MM, Sapsford RJ, Davies RJ. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells. Eur Respir J. 1995; 8:1451–1457. 25. Kadota J, Iwashita T, Matsubara Y, et al. Inhibitory effect of erythromycin on superoxide anion production by human neutrophils primed with granulocyte-colony stimulating factor. Antimicrob Agents Chemother. 1998;42:1866 – 1867. 26. Levert H, Gressier B, Moutard I, et al. Azithromycin impact on neutrophil oxidative metabolism depends on exposure time. Inflammation. 1998;22:191–201. 27. Oishi K, Sonoda F, Kobayashi S, et al. Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients with chronic airway diseases. Infect Immun. 1994;62:4145–4152. 28. Fujii T, Kadota J, Kawakami K, et al. Long-term effect of erythromycin therapy in patients with chronic Pseudomonas aeruginosa infection. Thorax. 1995;50:1246 –1252. 29. Fujii T, Kadota J, Morikawa T, et al. Inhibitory effect of erythromycin on interleukin-8 production by 1 alpha,25dihydroxyvitamin D3-stimulated THP-1 cells. Antimicrob Agents Chemother. 1996;40:1548 –1551. 30. Tagaya E, Tamaoki J, Kondo M, Nagai A. Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion. Chest. 2002; 122:213–218. 31. Ikeda K, Wu D, Takasaka T. Inhibition of acetylcholineevoked Cl– currents by 14-membered macrolide antibiotics in isolated acinar cells of the guinea pig nasal gland. Am J Respir Cell Mol Biol. 1995;13:449 –454. 32. Kadota J, Sakito O, Kohno S, et al. A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. Am Rev Respir Dis. 1993;147:153–159. 33. Ordonez CL, Shaughnessy TE, Matthay MA, Fahy JV. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: clinical and biologic significance. Am J Respir Crit Care Med. 2000;161(Pt 1):1185– 1190. 34. Oda H, Kadota J, Sakito O, et al. Determination of the neutrophil chemotactic factor in bronchoalveolar lavage fluid in patients with diffuse panbronchiolitis [in Japanese]. Kansenshogaku Zasshi. 1992;66:441–447. 35. Ichikawa Y, Ninomiya H, Koga H, et al. Erythromycin reduces neutrophils and neutrophil-derived elastolytic-like activity in the lower respiratory tract of bronchiolitis patients. Am Rev Respir Dis. 1992;146:196 –203. 36. Oda H, Kadota J, Kohno S, Hara K. Erythromycin inhibits neutrophil chemotaxis in bronchoalveoli of diffuse panbronchiolitis. Chest. 1994;106:1116 –1123. 37. Brennan S, Cooper D, Sly PD. Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin. Thorax. 2001;56:62–64. 38. Isono K, Tamaoki J, Nishimura K, Takeyama R, Nagai A. Effects of macrolide antibiotics on neutrophil infiltration into the airway mucosa and ICAM-1 expression [in Japanese]. Jpn J Antibiot. 1998;51(Suppl):34 –37. 39. Kusano S, Kadota J, Kohno S, et al. Effect of roxithromycin on peripheral neutrophil adhesion molecules in patients Volume 117 (9A)
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40.
41.
42.
43.
44.
45.
46.
47.
with chronic lower respiratory tract disease. Respiration. 1995;62:217–222. Matsuoka N, Eguchi K, Kawakami A, et al. Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells. Clin Exp Immunol. 1996;104:501–508. Mukae H, Kadota J, Ashitani J, et al. Elevated levels of soluble adhesion molecules in serum of patients with diffuse panbronchiolitis. Chest. 1997;112:1615–1621. Abdelghaffar H, Vazifeh D, Labro MT. Erythromycin A– derived macrolides modify the functional activities of human neutrophils by altering the phospholipase D-phosphatidate phosphohydrolase transduction pathway: L-cladinose is involved both in alterations of neutrophil functions and modulation of this transductional pathway. J Immunol. 1997;159:3995–4005. Morikawa T, Kadota JI, Kohno S, Kondo T. Superoxide dismutase in alveolar macrophages from patients with diffuse panbronchiolitis. Respiration. 2000;67:546 –551. Sommerhoff CP, Nadel JA, Basbaum CB, Caughey GH. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J Clin Invest. 1990;85:682–689. Jones A, Elphick H, Pettitt E, Everard ML, Evans GS. Colistin stimulates the activity of neutrophil elastase and Pseudomonas aeruginosa elastase. Eur Respir J. 2002;19: 1136 –1141. Liles WC, Van Voorhis WC. Review: nomenclature and biologic significance of cytokines involved in inflammation and the host immune response. J Infect Dis. 1995;172: 1573–1580. Khan AA, Slifer TR, Araujo FG, Remington JS. Effect of clarithromycin and azithromycin on production of cytokines by human monocytes. Int J Antimicrob Agents. 1999;11: 121–132.
48. Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells. Am J Respir Crit Care Med. 1997;156: 266 –271. 49. Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin suppresses interleukin-6 expression by human bronchial epithelial cells: a potential mechanism of its anti-inflammatory action. Biochem Biophys Res Commun. 1995;210:781– 786. 50. Miyanohara T, Ushikai M, Matsune S, Ueno K, Katahira S, Kurono Y. Effects of clarithromycin on cultured human nasal epithelial cells and fibroblasts. Laryngoscope. 2000; 110:126 –131. 51. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. 2002;49: 745–755. 52. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 2000;267:124 –128. 53. Abe S, Nakamura H, Inoue S, et al. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;22:51–60. 54. Ichiyama T, Nishikawa M, Yoshitomi T, et al. Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother. 2001;45:44 –47. 55. Oda H, Kadota J, Kohno S, Hara K. Leukotriene B4 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Chest. 1995;108:116 –122. 56. Ashitani J, Mukae H, Nakazato M, et al. Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis. Eur Respir J. 1998;11:104 –111.
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Macrolide antibiotics are known for their efficacy in treating acute airway infections, but just as importantly, they are also effective anti-inflammatory agents. Their anti-inflammatory properties have been studied most thoroughly in chronic inflammatory airway diseases, particularly diffuse panbronchiolitis (DPB). Erythromycin, azithromycin, clarithromycin, and roxithromycin inhibit chemotaxis and infiltration of neutrophils into the airway and, subsequently, decrease mucus secretion. Mucus formation, a significant cause of morbidity and mortality in patients with chronic airway inflammation, is directly inhibited by macrolides and suppressed by decreased inflammation in the airway. The mechanisms of action for the anti-inflammatory properties of the macrolides are still being investigated, but they are clearly multifactorial. Macrolides inhibit the production of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor–␣, perhaps by suppressing the transcription factor nuclear factor–B or activator protein–1. Inhibition of cytokine production has been seen in vitro and also in bronchoalveolar lavage fluid, which contains less IL-8 and fewer neutrophils after treatment with macrolides. Macrolides also inhibit formation of leukotriene B4, which attracts neutrophils, and inhibit the release of superoxide anion by neutrophils that may be present in the airway. An important aspect of inflammation is extravasation of neutrophils into the tissues. Macrolides block formation of adhesion molecules necessary for neutrophil migration. Together, these anti-inflammatory effects result in improved pulmonary functions and fewer airway infections. In patients with DPB, the anti-inflammatory effects lead to a significant increase in survival. Further work is needed to characterize the clinical benefits of macrolides in patients with other chronic inflammatory airway diseases. Am J Med. 2004;117(9A): 5S–11S. © 2004 by Elsevier Inc.
From the First Department of Medicine, Tokyo Women’s Medical University, Tokyo, Japan (JT); the Second Department of Medicine, Oita Medical University, Oita, Japan (JK); and the Department of Respiratory Medicine, Tokyo University School of Medicine, Tokyo, Japan (HT). Requests for reprints should be addressed to Jun Tamaoki, MD, PhD, First Department of Medicine, Tokyo Women’s Medical University, 8-1 Kawada-Cho, Shiinjuku, Tokyo 162-8666, Japan. © 2004 by Elsevier Inc. All rights reserved.
T
he nonantimicrobial, anti-inflammatory properties of macrolides were first identified when patients receiving troleandomycin for the treatment of asthma had a reduction in their requirement for steroids.1– 6 Most of the subsequent work on the immunomodulatory effects of macrolides has been in patients with diffuse panbronchiolitis (DPB),7–11 a chronic inflammatory airway disease characterized by cough, persistent sinus disease, and neutrophilic airway inflammation. Other chronic inflammatory diseases of the airways affected by macrolides include cystic fibrosis, chronic bronchitis, and asthma. The anti-inflammatory effects of macrolides are clinically significant. Use of macrolides in patients with DPB has resulted in an increase in 10-year survival from 12% to ⬎90%.12 This review summarizes many of the in vivo and in vitro effects of macrolides, which lead to clinical improvement in patients with chronic inflammatory lung diseases. These anti-inflammatory effects include decreased production of proinflammatory cytokines, such as interleukin (IL)-8, IL-1, tumor necrosis factor (TNF)-␣, reduced neutrophil infiltration into airways, reduced secretion of mucus, and modulation of defensin and adhesion molecule expression.13,14
EFFECTS ON MUCUS HYPERSECRETION Many respiratory diseases, such as acute and chronic bronchitis, bronchiectasis, DPB, asthma, and cystic fibrosis, are characterized by hypersecretion of mucus in the airways. Mucus hypersecretion increases morbidity and mortality, particularly from pulmonary infections, in patients with chronic inflammation of the airways.15–17 Infiltration of neutrophils, lymphocytes, and eosinophils into the tissues of the airways leads to chronic inflammation. This inflammation causes damage to the airway epithelium and goblet cell hyperplasia leading to hypersecretion of mucus. Mediators of mucus hypersecretion include inflammatory cell-derived cytokines, chemokines, and oxygen radicals. It is important to control airway mucus secretion for the management of chronic airway diseases. Mucus hypersecretion is a common cause of acute exacerbations of chronic airway diseases. In fact, mucus hypersecretion is associated with a decreased forced expiratory volume in 1 second and increased risk of hospitalization in patients with chronic obstructive pulmonary disease.17 In patients 1548-2766/04/$22.00 5S doi:10.1016/j.amjmed.2004.07.023
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with chronic inflammatory diseases of the airways, the presence of viscous mucus in the airway lumen causes impairment of mucociliary clearance, which may promote bacterial colonization and recurrent respiratory infection. Bacteria-derived substances then stimulate airway mucus secretion, which results in further disturbance of airway clearance of mucus. Obstruction or narrowing of small airways by mucus may produce atelectasis or V˙/Q˙ mismatch, which can result in respiratory failure. Both in vitro and in vivo studies show that macrolides reduce mucus and sputum secretion. An in vitro study showed a direct effect of macrolides on the secretion of respiratory glycoconjugate, a component of mucus. Erythromycin inhibited the secretion of radiolabeled glucosamine from human airway explants and endometrial adenocarcinoma cells in a concentration-dependent manner.18 In this study, penicillin, ampicillin, tetracycline, and cephalosporin had no effect on mucus secretion. The inhibitory effects of clarithromycin and erythromycin on mucus production in airway epithelial cells were also shown in cultures of human mucoepidermoid carcinoma cells and from cultured human nasal epithelial cells.19 As suggested in a study of guinea pig airways,20 macrolides may reduce the volume of mucus secreted by goblet cells through the inhibition of neutrophil accumulation. In this study, clarithromycin and erythromycin both significantly reduced mucus secretion, whereas amoxicillin and cefaclor had no effect. In a rat model of mucus hypersecretion, clarithromycin (5–10 mg/kg) significantly inhibited ovalbumin and lipopolysaccharideinduced mucus production by epithelial cells and mucosal neutrophil infiltration in goblet cells in rat nasal epithelium.19 Macrolides also inhibit the expression of MUC5AC, a mucus glycoprotein localized primarily in airway goblet cells.19,20 Clarithromycin 500 mg twice daily was administered to 10 patients with purulent rhinitis for 2 weeks. When compared with healthy subjects, these clarithromycintreated patients showed a reduction of mucus volume and improvement of the properties of nasal mucus such as viscoelasticity, cohesion, hydration, and transportability.21 Clarithromycin decreased the volume of secretions (500 mg vs. 28 mg, P ⫽ 0.01) and increased mucus clearance by 30% (P ⫽ 0.005). The rheology, hydration, cohesion, and transportability of mucus secretions in these patients were similar to secretions from healthy subjects. A double-blind, placebo-controlled, parallel-group trial of 31 patients with chronic bronchitis, bronchiectasis, or DPB showed that clarithromycin 100 mg twice daily for 8 weeks significantly reduced the amount of sputum produced from 51 g/day to 24 g/day without altering bacterial density or sputum flora, and also increased sputum elasticity.22 Treatment with clarithromycin signifi6S
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cantly improved hypoxia, hypercapnia, pulmonary function, and quality of life in these patients. The mechanism by which macrolides decrease mucus hypersecretion is unclear. Macrolides may decrease the volume of mucus secreted in patients with chronic airway disease by direct actions on mucus-producing cells in the airways or indirectly by decreasing bacterial adhesion, cytokine production, inflammatory cell recruitment, or the generation of free radicals.23–29 Macrolides may also decrease sputum production by inhibiting water secretion into the airway lumen by inhibiting secretion of chloride.30,31 Macrolides directly inhibit acetylcholineevoked Cl– channels in vitro, which may explain the activity of these drugs even in patients with cystic fibrosis who have a defect in the cystic fibrosis transmembrane conductance regulator, a cyclic adenosine monophosphate–regulated chloride channel.31
EFFECTS ON NEUTROPHIL ACCUMULATION AND THE INFLAMMATORY RESPONSE Neutrophils are key mediators of the inflammatory response in patients with chronic airway disease (Figure 1). Neutrophils release oxidative and proteolytic products, such as neutrophil elastase, which can cause damage to the lower respiratory tract. These cytotoxic products damage the lung parenchyma and epithelial cells. Patients with chronic airway disease such as asthma have significantly higher percentages of neutrophils and higher neutrophil chemotactic activity in bronchoalveolar lavage fluid (BALF) compared with healthy subjects.32,33 Erythromycin significantly reduces the percentage of neutrophils (P ⬍0.01) and neutrophil chemotactic activity (P ⬍0.001) in BALF from patients with chronic diseases of the airways.23,28,32,34 Erythromycin is effective in reducing the percentage of neutrophils in BALF regardless of infection with Pseudomonas aeruginosa or bacterial clearance in patients (Figure 2).28 Erythromycin also suppresses the influx of neutrophils into the airways despite the presence of chemotactic factors, such as IL-8, in the lungs.32 Both the concentration of IL-8 and the percentage of neutrophils in BALF in patients with DPB are reduced after treatment with erythromycin or roxithromycin (P ⬍0.05).23 A study of erythromycin therapy for the treatment of bronchiolitis showed that the number of neutrophils and the neutrophil-derived elastolytic-like activity in BALF in patients was significantly reduced after the treatment and corresponded to an improvement in pulmonary function in these patients.35 In this study, another antibiotic, ampicillin, had no effect on the function or number of neutrophils in these patients. By reducing the intrapulmonary chemotactic gradient or the ability of neutrophils to respond to chemotactic factors, erythromycin reduces the migration and, therefore, the
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Figure 1. Role of neutrophil accumulation in chronic inflammation of airway disease. Chronic inflammation of the airways is characterized by airway epithelial damage, goblet cell hyperplasia, and mucociliary dysfunction. The increased airway mucus layer may cause mucociliary dysfunction and recurrent airway infection. Chronic inflammation is mediated by cytokines, chemokines, oxygen radicals, and chemical mediators, all of which are targets of macrolide therapy. EM ⫽ erythromycin; ICAM-1 ⫽ intercellular cell adhesion molecule–1; IL ⫽ interleukin; LTB4 ⫽ leukotriene B4; Mac-1 ⫽ neutrophil adhesion molecule Mac-1.
Figure 2. Number of neutrophils (left), concentration of interleukin (IL)-8 (middle), and concentration of neutrophil elastase in the bronchoalveolar lavage fluid (right) from patients (N ⫽ 5) with diffuse panbronchiolitis (DPB) or bronchiectasis (BE) before (open symbols) and after treatment with erythromycin 600 mg/day for 3 months (closed symbols). The effect was independent of infection with Pseudomonas aeruginosa. (Adapted from Infect Immun.27)
accumulation of neutrophils in the lower respiratory tract, which in turn reduces pulmonary inflammation.32,36 However, these effects are unclear in patients with cystic fibrosis. In an in vitro study, erythromycin did
not inhibit the migration of neutrophils isolated from patients with cystic fibrosis.37 Macrolides reduce the accumulation of neutrophils not only by impairing the migration of neutrophils to
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sites of inflammation but also by inhibiting the expression of neutrophil adhesion molecules. Adhesion molecules are necessary for extravasation of neutrophils from blood vessels into the interstitial space. A reduction in adhesion molecules will decrease neutrophil-mediated inflammation in tissues. Macrolides reduce the expression of the neutrophil adhesion molecule Mac-1 and the serum concentrations of the soluble adhesion molecules sL-, sE-, and sP-selectin; intercellular adhesion molecule–1; vascular cell adhesion molecule–1; and lymphocyte function-associated antigen.24,38 – 41 The concentrations of these neutrophil adhesion molecules correlate with the concentrations of IL-8 and IL-1 in BALF.41 In vitro incubation of neutrophils with macrolides does not directly affect adhesion molecule release from neutrophils after stimulation with IL-8.41 Therefore, the effect of macrolides on the neutrophil adhesion molecules may be secondary to inhibition of the release of cytokines and other proinflammatory molecules involved in the upregulation of neutrophil adhesion molecules. Macrolides inhibit oxygen radical production by neutrophils and degranulation of neutrophils. This effect may be explained in part by the inhibition of the phospholipase-D phosphatidate phosphohydrolase pathway by macrolides.42 Levert and coworkers26 showed that azithromycin inhibited superoxide anion production by human neutrophils even at drug concentrations unlikely to have antimicrobial effects. The effect was not related to cellular toxicity or superoxide scavenging properties. Likewise, Kadota and colleagues25 showed that erythromycin significantly suppressed superoxide anion production by primed neutrophils. Macrolides also enhance the activity of superoxide dismutase, an antioxidant enzyme in alveolar macrophages of patients with DPB.43 Some studies show an inhibitory effect of macrolides on neutrophil elastase, which stimulates mucus hypersecretion in patients with chronic airway diseases.27,44 However, other investigators have reported the stimulation of neutrophil elastase by erythromycin.45 Whether any of the effects of macrolides on neutrophil functions observed in vitro are clinically relevant in vivo requires further study.
EFFECTS ON THE INFLAMMATORY CASCADE, TRANSCRIPTION, AND CYTOKINES The inflammatory cascade is composed of a network of cytokines and chemokines that modulate the initiation and progression of the inflammatory response.46 Proinflammatory cytokines include IL-1, IL-6, IL-8, and TNF-␣. Modulation of these cytokines can decrease inflammation. Although the mechanism by which macrolides inhibit the accumulation of neutrophils and reduce inflammation is not clear, studies show that macrolides 8S
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significantly affect a variety of these immune mediators and transcription factors.13,14,23,25,29,47,48 Expression of IL-8 messenger RNA in alveolar macrophages, epithelial cells, and endothelial cells suggests that IL-8 is produced in the lung and is an important mediator in the accumulation of neutrophils and the inflammatory response. In vitro studies suggest that macrolides impair the production of IL-8 by human alveolar macrophages, which results in the reduction of neutrophil accumulation.29 Only the 14-member macrolides— erythromycin, clarithromycin, and roxithromycin—were effective in inhibiting the production of IL-8. The 16-member macrolides—josamycin and midecamycin—and the nonmacrolide drugs—piperacillin, clindamycin, and ciprofloxacin—had no effect on the production of IL-8. Similarly, the concentrations of IL-8, as well as the concentrations of IL-1 and TNF-␣, were reduced in the BALF of patients with DPB after treatment with either erythromycin or roxithromycin.23 Erythromycin suppresses the expression of IL-6 in human bronchial epithelial cells.49 Similarly, clarithromycin and azithromycin inhibit the production of IL-1␣, IL-1, IL-6, IL-10, TNF-␣, and granulocyte–macrophage colony-stimulating factors (GM-CSF).47 Macrolides reduce the concentrations of cytokines by suppressing transcription factors such as nuclear factor (NF)–B and activator protein (AP)–1 in human bronchial epithelial cells in vitro.50 –54 These transcription factors are important in the inflammatory response, and inhibition of these factors can decrease the expression of IL-8 and other cytokines. Both erythromycin and clarithromycin were shown to suppress IL-8 production by human monocytes through inhibitory effects on NF-B and AP-1 activation.51,52 Erythromycin modulates the lipoxygenase pathway of arachidonic acid metabolism in neutrophils and macrophages.55 Leukotriene (LT) B4, a metabolite of arachidonic acid, is an important chemotactic factor for neutrophils and is elevated in patients with chronic airway disease. Erythromycin reduces the concentrations of LTB4 in BALF from patients with DPB, which significantly correlates with reductions in the percentage of neutrophils and neutrophil chemotactic activity.55 Macrolides also act on defensins. Defensins are endogenous antimicrobial peptides that attach to epithelial cells and potentially cause injury to the lungs. Defensins are present in the azurophil granules of neutrophils, the mucinous exudates of the airways, and on the surface of bronchiolar epithelial cells. Macrolide therapy reduces defensin concentrations, which correlates with the percentage of neutrophils, the concentration of IL-8, and improvement in pulmonary function in patients with DPB.56
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Figure 3. Summary of the effects of macrolides for the treatment of chronic airway diseases. The anti-inflammatory and antisecretory properties of macrolides collectively decrease the inflammation and hypersecretion associated with chronic airway diseases. ROS ⫽ reactive oxygen species.
CONCLUSION The anti-inflammatory properties of macrolides are well established, although the mechanisms for these actions are still being investigated. At the molecular level there are many effects that, in combination, provide clinical benefits to the patient (Figure 3). For example, hypersecretion of mucus complicates many chronic inflammatory airway diseases and has been shown to significantly contribute to morbidity and mortality.15,16 Macrolides directly inhibit secretion of mucus by preventing the release of glycoproteins but also decrease neutrophil accumulation in the airways by inhibiting expression of proinflammatory cytokines, such as IL-1, IL-8, and TNF-␣, and by inhibiting secretion of adhesion molecules that allow extravasation of neutrophils. As a result of these biologic effects, patients with chronic inflammatory airway disease have improvement in their pulmonary function tests and experience fewer airway infections when taking a macrolide. Macrolides reduce the number of airway infections in patients with chronic airway disease not only by their direct effects on bacteria but also by their ability to reduce inflammation, a common cause of infection in these patients. The reduction in neutrophils in the airway of these patients also leads to decreased release of superoxide anion, LTB4, and defensins from these cells. Although further studies are needed to fully assess the benefits of macrolides in many inflammatory airway dis-
eases, the clinical benefits of these drugs in DPB are profound. Before macrolide therapy, patients with DPB had progressive loss of pulmonary function, recurrent pulmonary infections, and a 10-year survival rate of just 12%.12 Now, with long-term macrolide therapy, patients with DPB have improved pulmonary functions, fewer infections, and, most importantly, a 10-year survival rate of ⬎90%. Patients with cystic fibrosis also report a decreased rate of airway infection, improved pulmonary function, and improved quality of life after treatment with macrolides. Questions that remain include which macrolide has the best efficacy and fewest adverse effects, duration of the anti-inflammatory effect with long-term macrolide therapy, and the long-term impact of continuous antimicrobial coverage.
REFERENCES 1. Flotte TR, Loughlin GM. Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma. Pediatr Pulmonol. 1991;10:178 –182. 2. Kamada AK, Hill MR, Ikle DN, Brenner AM, Szefler SJ. Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma. J Allergy Clin Immunol. 1993;91:873–882. 3. Siracusa A, Brugnami G, Fiordi T, Areni S, Severini C, Marabini A. Troleandomycin in the treatment of difficult asthma. J Allergy Clin Immunol. 1993;92:677–682. 4. Spector S, Katz F, Farr R. Troleandomycin: effectiveness in steroid-dependent asthma and bronchitis. J Allergy Clin Immunol. 1974;54:367–379.
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A Symposium: Clinical Implications of Macrolide Immunomodulation/Tamaoki et al. 5. Wald JA, Friedman BF, Farr RS. An improved protocol for the use of troleandomycin (TAO) in the treatment of steroidrequiring asthma. J Allergy Clin Immunol. 1986;78(Pt 1):36 – 43. 6. Zeiger RS, Schatz M, Sperling W, Simon RA, Stevenson DD. Efficacy of troleandomycin in outpatients with severe, corticosteroid-dependent asthma. J Allergy Clin Immunol. 1980;66:438 –446. 7. Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration. 1991;58:145–149. 8. Kudoh S, Uetake T, Hagiwara K, et al. Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis [in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1987;25:632–642. 9. Kadota J, Mukae H, Ishii H, et al. Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis. Respir Med. 2003;97:844 –850. 10. Brugiere O, Milleron B, Antoine M, Carette MF, Philippe C, Mayaud C. Diffuse panbronchiolitis in an Asian immigrant. Thorax. 1996;51:1065–1067. 11. Takeda H, Miura H, Kawahira M, Kobayashi H, Otomo S, Nakaike S. Long-term administration study on TE-031 (A56268) in the treatment of diffuse panbronchiolitis [in Japanese]. Kansenshogaku Zasshi. 1989;63:71–78. 12. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med. 1998;157(Pt 1):1829 –1832. 13. Rubin BK, Tamaoki J. Macrolide antibiotics as biological response modifiers. Curr Opin Investig Drugs. 2000;1:169 – 172. 14. Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. 2001;429:209 – 229. 15. Puchelle E, Bajolet O, Abely M. Airway mucus in cystic fibrosis. Paediatr Respir Rev. 2002;3:115–119. 16. Prescott E, Lange P, Vestbo J. Chronic mucus hypersecretion in COPD and death from pulmonary infection. Eur Respir J. 1995;8:1333–1338. 17. Vestbo J, Prescott E, Lange P, for the Copenhagen City Heart Study Group. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Am J Respir Crit Care Med. 1996; 153:1530 –1535. 18. Goswami SK, Kivity S, Marom Z. Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro. Am Rev Respir Dis. 1990;141:72–78. 19. Shimizu T, Shimizu S, Reiko H, Gabazza EC, Majima Y. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med. 2003;168:581–587. 20. Tamaoki J, Nakata J, Takeda Y, Takemura H, Tagaya E, Konno K. Effect of macrolide antibiotics on airway goblet hypersecretion in guinea pigs [in Japanese]. Kansenshogaku Zasshi. 1996;70:591–596. 21. Rubin BK, Druce H, Ramirez OE, Palmer R. Effect of clarithromycin on nasal mucus properties in healthy subjects and in patients with purulent rhinitis. Am J Respir Crit Care Med. 1997;155:2018 –2023. 22. Tamaoki J, Takeyama K, Tagaya E, Konno K. Effect of clarithromycin on sputum production and its rheological properties in chronic respiratory tract infections. Antimicrob Agents Chemother. 1995;39:1688 –1690. 10S
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23. Sakito O, Kadota J, Kohno S, Abe K, Shirai R, Hara K. Interleukin 1 beta, tumor necrosis factor alpha, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy. Respiration. 1996;63:42–48. 24. Khair OA, Devalia JL, Abdelaziz MM, Sapsford RJ, Davies RJ. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells. Eur Respir J. 1995; 8:1451–1457. 25. Kadota J, Iwashita T, Matsubara Y, et al. Inhibitory effect of erythromycin on superoxide anion production by human neutrophils primed with granulocyte-colony stimulating factor. Antimicrob Agents Chemother. 1998;42:1866 – 1867. 26. Levert H, Gressier B, Moutard I, et al. Azithromycin impact on neutrophil oxidative metabolism depends on exposure time. Inflammation. 1998;22:191–201. 27. Oishi K, Sonoda F, Kobayashi S, et al. Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients with chronic airway diseases. Infect Immun. 1994;62:4145–4152. 28. Fujii T, Kadota J, Kawakami K, et al. Long-term effect of erythromycin therapy in patients with chronic Pseudomonas aeruginosa infection. Thorax. 1995;50:1246 –1252. 29. Fujii T, Kadota J, Morikawa T, et al. Inhibitory effect of erythromycin on interleukin-8 production by 1 alpha,25dihydroxyvitamin D3-stimulated THP-1 cells. Antimicrob Agents Chemother. 1996;40:1548 –1551. 30. Tagaya E, Tamaoki J, Kondo M, Nagai A. Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion. Chest. 2002; 122:213–218. 31. Ikeda K, Wu D, Takasaka T. Inhibition of acetylcholineevoked Cl– currents by 14-membered macrolide antibiotics in isolated acinar cells of the guinea pig nasal gland. Am J Respir Cell Mol Biol. 1995;13:449 –454. 32. Kadota J, Sakito O, Kohno S, et al. A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. Am Rev Respir Dis. 1993;147:153–159. 33. Ordonez CL, Shaughnessy TE, Matthay MA, Fahy JV. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: clinical and biologic significance. Am J Respir Crit Care Med. 2000;161(Pt 1):1185– 1190. 34. Oda H, Kadota J, Sakito O, et al. Determination of the neutrophil chemotactic factor in bronchoalveolar lavage fluid in patients with diffuse panbronchiolitis [in Japanese]. Kansenshogaku Zasshi. 1992;66:441–447. 35. Ichikawa Y, Ninomiya H, Koga H, et al. Erythromycin reduces neutrophils and neutrophil-derived elastolytic-like activity in the lower respiratory tract of bronchiolitis patients. Am Rev Respir Dis. 1992;146:196 –203. 36. Oda H, Kadota J, Kohno S, Hara K. Erythromycin inhibits neutrophil chemotaxis in bronchoalveoli of diffuse panbronchiolitis. Chest. 1994;106:1116 –1123. 37. Brennan S, Cooper D, Sly PD. Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin. Thorax. 2001;56:62–64. 38. Isono K, Tamaoki J, Nishimura K, Takeyama R, Nagai A. Effects of macrolide antibiotics on neutrophil infiltration into the airway mucosa and ICAM-1 expression [in Japanese]. Jpn J Antibiot. 1998;51(Suppl):34 –37. 39. Kusano S, Kadota J, Kohno S, et al. Effect of roxithromycin on peripheral neutrophil adhesion molecules in patients Volume 117 (9A)
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40.
41.
42.
43.
44.
45.
46.
47.
with chronic lower respiratory tract disease. Respiration. 1995;62:217–222. Matsuoka N, Eguchi K, Kawakami A, et al. Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells. Clin Exp Immunol. 1996;104:501–508. Mukae H, Kadota J, Ashitani J, et al. Elevated levels of soluble adhesion molecules in serum of patients with diffuse panbronchiolitis. Chest. 1997;112:1615–1621. Abdelghaffar H, Vazifeh D, Labro MT. Erythromycin A– derived macrolides modify the functional activities of human neutrophils by altering the phospholipase D-phosphatidate phosphohydrolase transduction pathway: L-cladinose is involved both in alterations of neutrophil functions and modulation of this transductional pathway. J Immunol. 1997;159:3995–4005. Morikawa T, Kadota JI, Kohno S, Kondo T. Superoxide dismutase in alveolar macrophages from patients with diffuse panbronchiolitis. Respiration. 2000;67:546 –551. Sommerhoff CP, Nadel JA, Basbaum CB, Caughey GH. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J Clin Invest. 1990;85:682–689. Jones A, Elphick H, Pettitt E, Everard ML, Evans GS. Colistin stimulates the activity of neutrophil elastase and Pseudomonas aeruginosa elastase. Eur Respir J. 2002;19: 1136 –1141. Liles WC, Van Voorhis WC. Review: nomenclature and biologic significance of cytokines involved in inflammation and the host immune response. J Infect Dis. 1995;172: 1573–1580. Khan AA, Slifer TR, Araujo FG, Remington JS. Effect of clarithromycin and azithromycin on production of cytokines by human monocytes. Int J Antimicrob Agents. 1999;11: 121–132.
48. Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells. Am J Respir Crit Care Med. 1997;156: 266 –271. 49. Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin suppresses interleukin-6 expression by human bronchial epithelial cells: a potential mechanism of its anti-inflammatory action. Biochem Biophys Res Commun. 1995;210:781– 786. 50. Miyanohara T, Ushikai M, Matsune S, Ueno K, Katahira S, Kurono Y. Effects of clarithromycin on cultured human nasal epithelial cells and fibroblasts. Laryngoscope. 2000; 110:126 –131. 51. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. 2002;49: 745–755. 52. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 2000;267:124 –128. 53. Abe S, Nakamura H, Inoue S, et al. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;22:51–60. 54. Ichiyama T, Nishikawa M, Yoshitomi T, et al. Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother. 2001;45:44 –47. 55. Oda H, Kadota J, Kohno S, Hara K. Leukotriene B4 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Chest. 1995;108:116 –122. 56. Ashitani J, Mukae H, Nakazato M, et al. Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis. Eur Respir J. 1998;11:104 –111.
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