Anti-inflammatory effects of clarithromycin in ventilator-induced lung injury

Respiratory Research

Guillermo M Albaiceta³  Emilio García-Prieto¹  Jorge Blazquez-Prieto⁴  Estefanía Batalla-Solís¹  Aurora Astudillo²  Alina Aguirre⁴  Inés López-Alonso⁴  Adrián González-López⁴  Laura Amado-Rodríguez¹ 

[1] Servicio de Medicina Intensiva, Hospital Universitario Central de Asturias, Oviedo, Spain;Departamento de Cirugía y Especialidades Médico-quirúrgicas, IUOPA, Universidad de Oviedo, Oviedo, Spain;CIBER-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain;Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain

关键词: Neutrophil migration;    Macrolides;    E-selectin;    Mechanical ventilation;   

Others  :  794677
DOI  :  10.1186/1465-9921-14-52

 received in 2012-11-20, accepted in 2013-05-07,  发布年份 2013

【 摘 要 】

Background

Mechanical ventilation can promote lung injury by triggering a pro-inflammatory response. Macrolides may exert some immunomodulatory effects and have shown significant benefits over other antibiotics in ventilated patients. We hypothesized that macrolides could decrease ventilator-induced lung injury.

Methods

Adult mice were treated with vehicle, clarithromycin or levofloxacin, and randomized to receive mechanical ventilation with low (12 cmH₂O, PEEP 2 cmH₂O) or high (20 cmH₂O, ZEEP) inspiratory pressures for 150 minutes. Histological lung injury, neutrophil infiltration, inflammatory mediators (NFκB activation, Cxcl2, IL-10) and levels of adhesion molecules (E-selectin, ICAM) and proteases (MMP-9 and MMP-2) were analyzed.

Results

There were no differences among groups after low-pressure ventilation. Clarithromycin significantly decreased lung injury score and neutrophil count, compared to vehicle or levofloxacin, after high-pressure ventilation. Cxcl2 expression and MMP-2 and MMP-9 levels increased and IL-10 decreased after injurious ventilation, with no significant differences among treatment groups. Both clarithromycin and levofloxacin dampened the increase in NFκB activation observed in non-treated animals submitted to injurious ventilation. E-selectin levels increased after high pressure ventilation in vehicle- and levofloxacin-treated mice, but not in those receiving clarithromycin.

Conclusions

Clarithromycin ameliorates ventilator-induced lung injury and decreases neutrophil recruitment into the alveolar spaces. This could explain the advantages of macrolides in patients with acute lung injury and mechanical ventilation.

【 授权许可】

   
2013 Amado-Rodríguez et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 1.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Villar J, Blanco J, Anon JM, Santos-Bouza A, Blanch L, Ambros A, Gandia F, Carriedo D, Mosteiro F, Basaldua S: The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med 2011, 37:1932-1941.
• [2]Albaiceta GM, Blanch L: Beyond volutrauma in ARDS: The critical role of lung tissue deformation. Crit Care 2011, 15:304. BioMed Central Full Text
• [3]Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P: Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009, 151:566-576.
• [4]Rouby JJ, Brochard L: Tidal recruitment and overinflation in acute respiratory distress syndrome: yin and yang. Am J Respir Crit Care Med 2007, 175:104-106.
• [5]Walkey AJ, Wiener RS: Macrolide antibiotics and survival in patients with acute lung injury. Chest 2012, 141:1153-1159.
• [6]Metersky ML, Ma A, Houck PM, Bratzler DW: Antibiotics for bacteremic pneumonia: Improved outcomes with macrolides but not fluoroquinolones. Chest 2007, 131:466-473.
• [7]Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ, Anzueto A: Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia. Eur Respir J 2009, 33:153-159.
• [8]Giamarellos-Bourboulis EJ, Pechere JC, Routsi C, Plachouras D, Kollias S, Raftogiannis M, Zervakis D, Baziaka F, Koronaios A, Antonopoulou A: Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis 2008, 46:1157-1164.
• [9]Kawasaki S, Takizawa H, Ohtoshi T, Takeuchi N, Kohyama T, Nakamura H, Kasama T, Kobayashi K, Nakahara K, Morita Y, Yamamoto K: Roxithromycin inhibits cytokine production by and neutrophil attachment to human bronchial epithelial cells in vitro. Antimicrob Agents Chemother 1998, 42:1499-1502.
• [10]Morikawa K, Zhang J, Nonaka M, Morikawa S: Modulatory effect of macrolide antibiotics on the Th1- and Th2-type cytokine production. Int J Antimicrob Agents 2002, 19:53-59.
• [11]Kanai K, Asano K, Hisamitsu T, Suzaki H: Suppression of matrix metalloproteinase-9 production from neutrophils by a macrolide antibiotic, roxithromycin, in vitro. Mediators Inflamm 2004, 13:313-319.
• [12]Santos CC, Zhang H, Liu M, Slutsky AS: Bench-to-bedside review: Biotrauma and modulation of the innate immune response. Crit Care 2005, 9:280-286. BioMed Central Full Text
• [13]Pedreira PR, Garcia-Prieto E, Parra D, Astudillo A, Diaz E, Taboada F, Albaiceta GM: Effects of melatonin in an experimental model of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2008, 295:L820-L827.
• [14]Nin N, Penuelas O, de Paula M, Lorente JA, Fernandez-Segoviano P, Esteban A: Ventilation-induced lung injury in rats is associated with organ injury and systemic inflammation that is attenuated by dexamethasone. Crit Care Med 2006, 34:1093-1098.
• [15]Nakanishi Y, Kobayashi D, Asano Y, Sakurai T, Kashimura M, Okuyama S, Yoneda Y, Shapiro SD, Takayama K: Clarithromycin prevents smoke-induced emphysema in mice. Am J Respir Crit Care Med 2009, 179:271-278.
• [16]Tagliabue C, Techasaensiri C, Torres JP, Katz K, Meek C, Kannan TR, Coalson JJ, Esposito S, Principi N, Leff R: Efficacy of increasing dosages of clarithromycin for treatment of experimental Mycoplasma pneumoniae pneumonia. J Antimicrob Chemother 2011, 66:2323-2329.
• [17]Albaiceta GM, Gutierrez-Fernandez A, Garcia-Prieto E, Puente XS, Parra D, Astudillo A, Campestre C, Cabrera S, Gonzalez-Lopez A, Fueyo A: Absence or inhibition of matrix metalloproteinase-8 decreases ventilator-induced lung injury. Am J Respir Cell Mol Biol 2010, 43:555-563.
• [18]Osorio FG, Barcena C, Soria-Valles C, Ramsay AJ, de Carlos F, Cobo J, Fueyo A, Freije JM, Lopez-Otin C: Nuclear lamina defects cause ATM-dependent NF-kappaB activation and link accelerated aging to a systemic inflammatory response. Genes Dev 2012, 26:2311-2324.
• [19]Gonzalez-Lopez A, Aguirre A, Lopez-Alonso I, Amado L, Astudillo A, Fernandez-Garcia MS, Suarez MF, Batalla-Solis E, Colado E, Albaiceta GM: MMP-8 deficiency increases TLR/RAGE ligands S100A8 and S100A9 and exacerbates lung inflammation during endotoxemia. PLoS One 2012, 7:e39940.
• [20]Garcia-Prieto E, Gonzalez-Lopez A, Cabrera S, Astudillo A, Gutierrez-Fernandez A, Fanjul-Fernandez M, Batalla-Solis E, Puente XS, Fueyo A, Lopez-Otin C, Albaiceta GM: Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10. PLoS One 2010, 5:e13242.
• [21]dos Santos CC, Slutsky AS: The contribution of biophysical lung injury to the development of biotrauma. Annu Rev Physiol 2006, 68:585-618.
• [22]Belperio JA, Keane MP, Burdick MD, Londhe V, Xue YY, Li K, Phillips RJ, Strieter RM: Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. J Clin Invest 2002, 110:1703-1716.
• [23]Kawano T, Mori S, Cybulsky M, Burger R, Ballin A, Cutz E, Bryan AC: Effect of granulocyte depletion in a ventilated surfactant-depleted lung. J Appl Physiol 1987, 62:27-33.
• [24]Winn R, Maunder R, Chi E, Harlan J: Neutrophil depletion does not prevent lung edema after endotoxin infusion in goats. J Appl Physiol 1987, 62:116-121.
• [25]Martin TR, Pistorese BP, Chi EY, Goodman RB, Matthay MA: Effects of leukotriene B4 in the human lung. Recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J Clin Invest 1989, 84:1609-1619.
• [26]Bosnar M, Bosnjak B, Cuzic S, Hrvacic B, Marjanovic N, Glojnaric I, Culic O, Parnham MJ, Erakovic Haber V: Azithromycin and clarithromycin inhibit lipopolysaccharide-induced murine pulmonary neutrophilia mainly through effects on macrophage-derived granulocyte-macrophage colony-stimulating factor and interleukin-1beta. J Pharmacol Exp Ther 2009, 331:104-113.
• [27]Kawashima M, Yatsunami J, Fukuno Y, Nagata M, Tominaga M, Hayashi S: Inhibitory effects of 14-membered ring macrolide antibiotics on bleomycin-induced acute lung injury. Lung 2002, 180:73-89.
• [28]Ichiyama T, Nishikawa M, Yoshitomi T, Hasegawa S, Matsubara T, Hayashi T, Furukawa S: Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother 2001, 45:44-47.
• [29]Yamaya M, Nishimura H, Hatachi Y, Yasuda H, Deng X, Sasaki T, Mizuta K, Kubo H, Nagatomi R: Levofloxacin inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells. Antimicrob Agents Chemother 2012, 56:4052-4061.
• [30]Kotani M, Kotani T, Li Z, Silbajoris R, Piantadosi CA, Huang YC: Reduced inspiratory flow attenuates IL-8 release and MAPK activation of lung overstretch. Eur Respir J 2004, 24:238-246.
• [31]Sanz MJ, Nabah YN, Cerda-Nicolas M, O'Connor JE, Issekutz AC, Cortijo J, Morcillo EJ: Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression. Br J Pharmacol 2005, 144:190-201.
• [32]Miyao N, Suzuki Y, Takeshita K, Kudo H, Ishii M, Hiraoka R, Nishio K, Tamatani T, Sakamoto S, Suematsu M: Various adhesion molecules impair microvascular leukocyte kinetics in ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2006, 290:L1059-L1068.
• [33]Martin-Loeches I, Lisboa T, Rodriguez A, Putensen C, Annane D, Garnacho-Montero J, Restrepo MI, Rello J: Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med 2010, 36:612-620.
• [34]Friedlander AL, Albert RK: Chronic macrolide therapy in inflammatory airways diseases. Chest 2010, 138:1202-1212.
• [35]Matute-Bello G, Downey G, Moore BB, Groshong SD, Matthay MA, Slutsky AS, Kuebler WM: An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 2011, 44:725-738.
• [36]Gonzalez-Lopez A, Astudillo A, Garcia-Prieto E, Fernandez-Garcia MS, Lopez-Vazquez A, Batalla-Solis E, Taboada F, Fueyo A, Albaiceta GM: Inflammation and matrix remodeling during repair of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2011, 301:L500-L509.
• [37]Gonzalez-Lopez A, Albaiceta GM: Repair after acute lung injury: molecular mechanisms and therapeutic opportunities. Crit Care 2012, 16:209. BioMed Central Full Text
• [38]Dos Santos CC: Advances in mechanisms of repair and remodelling in acute lung injury. Intensive Care Med 2008, 34:619-630.
• [39]Curley GF, Contreras M, Higgins B, O'Kane C, McAuley DF, O'Toole D, Laffey JG: Evolution of the inflammatory and fibroproliferative responses during resolution and repair after ventilator-induced lung injury in the rat. Anesthesiology 2011, 115:1022-1032.