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Inhaled milrinone attenuates experimental acute lung injury

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Abstract

Purpose

To test whether inhalation of the phosphodiesterase 3 inhibitor milrinone may attenuate experimental acute lung injury (ALI).

Methods

In rats, ALI was induced by infusion of oleic acid (OA). After 30 min, milrinone was inhaled either as single dose, or repeatedly in 30 min intervals. In mice, ALI was induced by intratracheal instillation of hydrochloric acid, followed by a single milrinone inhalation.

Results

Four hours after OA infusion, ALI was evident as lung inflammation, protein-rich edema and hypoxemia. A single inhalation of milrinone attenuated the increase in lung wet-to-dry weight ratio and myeloperoxidase activity, and reduced protein concentration, neutrophil counts and TNF-α levels in bronchoalveolar lavage. This effect was further pronounced when milrinone was repeatedly inhaled. In mice with acid-induced ALI, milrinone attenuated hypoxemia and prevented the increase in lung myeloperoxidase activity.

Conclusions

Inhalation of aerosolized milrinone may present a novel therapeutic strategy for the treatment of ALI.

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References

  1. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353:1685–1693

    Article  PubMed  CAS  Google Scholar 

  2. Zambon M, Vincent JL (2008) Mortality rates for patients with acute lung injury/ARDS have decreased over time. Chest 133:1120–1127

    Article  PubMed  Google Scholar 

  3. Bachofen M, Weibel ER (1982) Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med 3:35–56

    PubMed  CAS  Google Scholar 

  4. Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:1334–1349

    Article  PubMed  CAS  Google Scholar 

  5. Moore TM, Chetham PM, Kelly JJ, Stevens T (1998) Signal transduction and regulation of lung endothelial cell permeability. Interaction between calcium and cAMP. Am J Physiol 275:L203–L222

    PubMed  CAS  Google Scholar 

  6. Matthay MA, Clerici C, Saumon G (2002) Active fluid clearance from the distal air spaces of the lung. J Appl Physiol 93:1533–1541

    PubMed  CAS  Google Scholar 

  7. Derian CK, Santulli RJ, Rao PE, Solomon HF, Barrett JA (1995) Inhibition of chemotactic peptide-induced neutrophil adhesion to vascular endothelium by cAMP modulators. J Immunol 154:308–317

    PubMed  CAS  Google Scholar 

  8. Elferink JG, de Koster BM (2000) Inhibition of interleukin-8-activated human neutrophil chemotaxis by thapsigargin in a calcium- and cyclic AMP-dependent way. Biochem Pharmacol 59:369–375

    Article  PubMed  CAS  Google Scholar 

  9. Dhanakoti SN, Gao Y, Nguyen MQ, Raj JU (2000) Involvement of cGMP-dependent protein kinase in the relaxation of ovine pulmonary arteries to cGMP and cAMP. J Appl Physiol 88:1637–1642

    PubMed  CAS  Google Scholar 

  10. McAuley DF, Matthay MA (2005) Is there a role for β-adrenoceptor agonists in the management of acute lung injury and the acute respiratory distress syndrome? Treat Respir Med 4:297–307

    Article  PubMed  CAS  Google Scholar 

  11. Haddad JJ, Land SC, Tarnow-Mordi WO, Zembala M, Kowalczyk D, Lauterbach R (2002) Immunopharmacological potential of selective phosphodiesterase inhibition. I. Differential regulation of lipopolysaccharide-mediated proinflammatory cytokine (interleukin-6 and tumor necrosis factor-α) biosynthesis in alveolar epithelial cells. J Pharmacol Exp Ther 300:559–566

    Article  PubMed  CAS  Google Scholar 

  12. Hayashida N, Tomoeda H, Oda T, Tayama E, Chihara S, Kawara T, Aoyagi S (1999) Inhibitory effect of milrinone on cytokine production after cardiopulmonary bypass. Ann Thorac Surg 68:1661–1667

    Article  PubMed  CAS  Google Scholar 

  13. Howell RE, Jenkins LP, Howell DE (1995) Inhibition of lipopolysaccharide-induced pulmonary edema by isozyme-selective phosphodiesterase inhibitors in guinea pigs. J Pharmacol Exp Ther 275:703–709

    PubMed  CAS  Google Scholar 

  14. Lamarche Y, Malo O, Thorin E, Denault A, Carrier M, Roy J, Perrault LP (2005) Inhaled but not intravenous milrinone prevents pulmonary endothelial dysfunction after cardiopulmonary bypass. J Thorac Cardiovasc Surg 130:83–92

    Article  PubMed  CAS  Google Scholar 

  15. Hentschel T, Yin N, Riad A, Habbazettl H, Weimann J, Koster A, Tschope C, Kuppe H, Kuebler WM (2007) Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure. Anesthesiology 106:124–131

    Article  PubMed  CAS  Google Scholar 

  16. Tanaka H, Tajimi K, Matsumoto A, Kobayashi K (1992) Effects of milrinone on lung water content in dogs with acute pulmonary hypertension. J Pharmacol Toxicol Methods 28:201–208

    Article  PubMed  CAS  Google Scholar 

  17. Tabuchi A, Mertens M, Kuppe H, Pries AR, Kuebler WM (2008) Intravital microscopy of the murine pulmonary microcirculation. J Appl Physiol 104:338–346

    Article  PubMed  Google Scholar 

  18. Kuebler WM, Abels C, Schuerer L, Goetz AE (1996) Measurement of neutrophil content in brain and lung tissue by a modified myeloperoxidase assay. Int J Microcirc Clin Exp 16:89–97

    Article  PubMed  CAS  Google Scholar 

  19. Lamarche Y, Perrault LP, Maltais S, Tetreault K, Lambert J, Denault AY (2007) Preliminary experience with inhaled milrinone in cardiac surgery. Eur J Cardiothorac Surg 31:1081–1087

    Article  PubMed  Google Scholar 

  20. Sablotzki A, Starzmann W, Scheubel R, Grond S, Czeslick EG (2005) Selective pulmonary vasodilation with inhaled aerosolized milrinone in heart transplant candidates. Can J Anaesth 52:1076–1082

    Article  PubMed  Google Scholar 

  21. Matute-Bello G, Frevert CW, Martin TR (2008) Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 295:L379–L399

    Article  PubMed  CAS  Google Scholar 

  22. Schuster DP (1994) ARDS: clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med 149:245–260

    PubMed  CAS  Google Scholar 

  23. Bursten SL, Federighi DA, Parsons P, Harris WE, Abraham E, Moore EE Jr, Moore FA, Bianco JA, Singer JW, Repine JE (1996) An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. Crit Care Med 24:1129–1136

    Article  PubMed  CAS  Google Scholar 

  24. Schmidt R, Meier U, Yabut-Perez M, Walmrath D, Grimminger F, Seeger W, Gunther A (2001) Alteration of fatty acid profiles in different pulmonary surfactant phospholipids in acute respiratory distress syndrome and severe pneumonia. Am J Respir Crit Care Med 163:95–100

    PubMed  CAS  Google Scholar 

  25. Hussain N, Wu F, Zhu L, Thrall RS, Kresch MJ (1998) Neutrophil apoptosis during the development and resolution of oleic acid-induced acute lung injury in the rat. Am J Respir Cell Mol Biol 19:867–874

    PubMed  CAS  Google Scholar 

  26. Ito K, Mizutani A, Kira S, Mori M, Iwasaka H, Noguchi T (2005) Effect of Ulinastatin, a human urinary trypsin inhibitor, on the oleic acid-induced acute lung injury in rats via the inhibition of activated leukocytes. Injury 36:387–394

    Article  PubMed  Google Scholar 

  27. Quintel M, Pelosi P, Caironi P, Meinhardt JP, Luecke T, Herrmann P, Taccone P, Rylander C, Valenza F, Carlesso E, Gattinoni L (2004) An increase of abdominal pressure increases pulmonary edema in oleic acid-induced lung injury. Am J Respir Crit Care Med 169:534–541

    Article  PubMed  Google Scholar 

  28. Gust R, Kozlowski J, Stephenson AH, Schuster DP (1998) Synergistic hemodynamic effects of low-dose endotoxin and acute lung injury. Am J Respir Crit Care Med 157:1919–1926

    PubMed  CAS  Google Scholar 

  29. Haraldsson A, Kieler-Jensen N, Ricksten SE (2001) The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Anesth Analg 93:1439–1445

    Article  CAS  Google Scholar 

  30. Suttorp N, Weber U, Welsch T, Schudt C (1993) Role of phosphodiesterases in the regulation of endothelial permeability in vitro. J Clin Invest 91:1421–1428

    Article  PubMed  CAS  Google Scholar 

  31. Degerman E, Belfrage P, Manganiello VC (1997) Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3). J Biol Chem 272:6823–6826

    Article  PubMed  CAS  Google Scholar 

  32. Sayner SL, Alexeyev M, Dessauer CW, Stevens T (2006) Soluble adenylyl cyclase reveals the significance of cAMP compartmentation on pulmonary microvascular endothelial cell barrier. Circ Res 98:675–681

    Article  PubMed  CAS  Google Scholar 

  33. Eiermann GJ, Dickey BF, Thrall RS (1983) Polymorphonuclear leukocyte participation in acute oleic-acid-induced lung injury. Am Rev Respir Dis 128:845–850

    PubMed  CAS  Google Scholar 

  34. Knight PR, Druskovich G, Tait AR, Johnson KJ (1992) The role of neutrophils, oxidants, and proteases in the pathogenesis of acid pulmonary injury. Anesthesiology 77:772–778

    Article  PubMed  CAS  Google Scholar 

  35. Miyakawa H, Oishi K, Hagiwara S, Kira S, Kitano T, Iwasaka H, Noguchi T (2004) Olprinone improves diaphragmatic contractility and fatigability during abdominal sepsis in a rat model. Acta Anaesthesiol Scand 48:637–641

    Article  PubMed  CAS  Google Scholar 

  36. Yamaura K, Okamoto H, Akiyoshi K, Irita K, Taniyama T, Takahashi S (2001) Effect of low-dose milrinone on gastric intramucosal pH and systemic inflammation after hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 15:197–203

    Article  PubMed  CAS  Google Scholar 

  37. Schudt C, Winder S, Forderkunz S, Hatzelmann A, Ullrich V (1991) Influence of selective phosphodiesterase inhibitors on human neutrophil functions and levels of cAMP and Cai. Naunyn Schmiedebergs Arch Pharmacol 344:682–690

    Article  PubMed  CAS  Google Scholar 

  38. Blease K, Burke-Gaffney A, Hellewell PG (1998) Modulation of cell adhesion molecule expression and function on human lung microvascular endothelial cells by inhibition of phosphodiesterases 3 and 4. Br J Pharmacol 124:229–237

    Article  PubMed  CAS  Google Scholar 

  39. Davidson KG, Bersten AD, Barr HA, Dowling KD, Nicholas TE, Doyle IR (2000) Lung function, permeability, and surfactant composition in oleic acid-induced acute lung injury in rats. Am J Physiol Lung Cell Mol Physiol 279:L1091–L1102

    PubMed  CAS  Google Scholar 

  40. Denault AY, Lamarche Y, Couture P, Haddad F, Lambert J, Tardif JC, Perrault LP (2006) Inhaled milrinone: a new alternative in cardiac surgery? Semin Cardiothorac Vasc Anesth 10:346–360

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Sylvia May for excellent technical assistance. This study was supported by grants from the Deutsche Forschungsgemeinschaft (Ku1218/4) and the Kaiserin-Friedrich Foundation, Berlin, Germany.

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Authors and Affiliations

  1. Department of Anesthesiology, German Heart Institute, Berlin, Germany

    Moritz Bueltmann, Xiang Kong, Ning Yin, Jun Yin, Andreas Koster, Hermann Kuppe & Wolfgang M. Kuebler

  2. Department of Cardiothoracic Surgery, Shanghai East Hospital, Tongji University, Shanghai, People’s Republic of China

    Xiang Kong & Zhongmin Liu

  3. Institute of Physiology, Charité-Universitätsmedizin, Berlin, Germany

    Michael Mertens, Ning Yin, Jun Yin & Wolfgang M. Kuebler

  4. Institute for Human Biology and Anthropology, Free University, Berlin, Germany

    Michael Mertens

  5. The Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 30 Bond Street, Bond Wing 2-021, Toronto, ON, M5B 1W8, Canada

    Jun Yin & Wolfgang M. Kuebler

  6. Department of Surgery, University of Toronto, Toronto, ON, USA

    Wolfgang M. Kuebler

Authors
  1. Moritz Bueltmann
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  2. Xiang Kong
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  3. Michael Mertens
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  4. Ning Yin
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  7. Andreas Koster
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  9. Wolfgang M. Kuebler
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Corresponding author

Correspondence to Wolfgang M. Kuebler.

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Bueltmann, M., Kong, X., Mertens, M. et al. Inhaled milrinone attenuates experimental acute lung injury. Intensive Care Med 35, 171–178 (2009). https://doi.org/10.1007/s00134-008-1344-9

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  • DOI: https://doi.org/10.1007/s00134-008-1344-9

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