Intensive Care Medicine

, Volume 36, Issue 11, pp 1935–1945 | Cite as

Pulmonary-derived phosphoinositide 3-kinase gamma (PI3Kγ) contributes to ventilator-induced lung injury and edema

  • Vito Fanelli
  • Valeria Puntorieri
  • Barbara Assenzio
  • Erica L. Martin
  • Vincenzo Elia
  • Martino Bosco
  • Luisa Delsedime
  • Lorenzo Del Sorbo
  • Andrea Ferrari
  • Stefano Italiano
  • Alessandra Ghigo
  • Arthur S. Slutsky
  • Emilio Hirsch
  • V. Marco Ranieri
Experimental

Abstract

Background

Ventilator-induced lung injury (VILI) occurs in part by increased vascular permeability and impaired alveolar fluid clearance. Phosphoinositide 3-kinase gamma (PI3Kγ) is activated by mechanical stress, induces nitric oxide (NO) production, and participates in cyclic adenosine monophosphate (cAMP) hydrolysis, each of which contributes to alveolar edema. We hypothesized that lungs lacking PI3Kγ or treated with PI3Kγ inhibitors would be protected from ventilation-induced alveolar edema and lung injury.

Methods

Using an isolated and perfused lung model, wild-type (WT) and PI3Kγ-knockout (KO) mice underwent negative-pressure cycled ventilation at either −25 cmH2O and 0 cmH2O positive end-expiratory pressure (PEEP) (HIGH STRESS) or −10 cmH2O and −3 cmH2O PEEP (LOW STRESS).

Results

Compared with WT, PI3Kγ-knockout mice lungs were partially protected from VILI-induced derangement of respiratory mechanics (lung elastance) and edema formation [bronchoalveolar lavage (BAL) protein concentration, wet/dry ratio, and lung histology]. In PI3Kγ-knockout mice, VILI induced significantly less phosphorylation of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), production of nitrate and nitrotyrosine, as well as hydrolysis of cAMP, compared with wild-type animals. PI3Kγ wild-type lungs treated with AS605240, an inhibitor of PI3Kγ kinase activity, in combination with enoximone, an inhibitor of phosphodiesterase-3 (PDE3)-induced cAMP hydrolysis, were protected from VILI at levels comparable to knockout lungs.

Conclusions

Phosphoinositide 3-kinase gamma in resident lung cells mediates part of the alveolar edema induced by high-stress ventilation. This injury is mediated via altered Akt, eNOS, NO, and/or cAMP signaling. Anti-PI3Kγ therapy aimed at resident lung cells represents a potential pharmacologic target to mitigate VILI.

Keywords

Ventilator-induced lung injury Nitric oxide Permeability Lung edema cAMP ARDS 

Supplementary material

134_2010_2018_MOESM1_ESM.doc (4.3 mb)
Supplementary material 1 (DOC 4432 kb)

References

  1. 1.
    Slutsky AS (1999) Lung injury caused by mechanical ventilation. Chest 116:9S–15SCrossRefPubMedGoogle Scholar
  2. 2.
    Dos Santos CC, Slutsky AS (2000) Invited review: mechanisms of ventilator-induced lung injury: a perspective. J Appl Physiol 89:1645–1655PubMedGoogle Scholar
  3. 3.
    Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, Bruno F, Slutsky AS (1999) Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 282:54–61CrossRefPubMedGoogle Scholar
  4. 4.
    Lachmann RA, van Kaam AH, Haitsma JJ, Lachmann B (2007) High positive end-expiratory pressure levels promote bacterial translocation in experimental pneumonia. Intensive Care Med 33:1800–1804CrossRefPubMedGoogle Scholar
  5. 5.
    Uhlig U, Haitsma JJ, Goldmann T, Poelma DL, Lachmann B, Uhlig S (2002) Ventilation-induced activation of the mitogen-activated protein kinase pathway. Eur Respir J 20:946–956CrossRefPubMedGoogle Scholar
  6. 6.
    Matthay MA, Robriquet L, Fang X (2005) Alveolar epithelium: role in lung fluid balance and acute lung injury. Proc Am Thorac Soc 2:206–213CrossRefPubMedGoogle Scholar
  7. 7.
    de Prost N, Roux D, Dreyfuss D, Ricard JD, Le Guludec D, Saumon G (2007) Alveolar edema dispersion and alveolar protein permeability during high volume ventilation: effect of positive end-expiratory pressure. Intensive Care Med 33:711–717CrossRefPubMedGoogle Scholar
  8. 8.
    Broccard AF, Feihl F, Vannay C, Markert M, Hotchkiss J, Schaller MD (2004) Effects of L-NAME and inhaled nitric oxide on ventilator-induced lung injury in isolated, perfused rabbit lungs. Crit Care Med 32:1872–1878CrossRefPubMedGoogle Scholar
  9. 9.
    Peng X, Abdulnour RE, Sammani S, Ma SF, Han EJ, Hasan EJ, Tuder R, Garcia JG, Hassoun PM (2005) Inducible nitric oxide synthase contributes to ventilator-induced lung injury. Am J Respir Crit Care Med 172:470–479CrossRefPubMedGoogle Scholar
  10. 10.
    Choi WI, Quinn DA, Park KM, Moufarrej RK, Jafari B, Syrkina O, Bonventre JV, Hales CA (2003) Systemic microvascular leak in an in vivo rat model of ventilator-induced lung injury. Am J Respir Crit Care Med 167:1627–1632CrossRefPubMedGoogle Scholar
  11. 11.
    Frank JA, Pittet JF, Lee H, Godzich M, Matthay MA (2003) High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance. Am J Physiol 284:L791–L798Google Scholar
  12. 12.
    Ader F, Le Berre R, Lancel S, Faure K, Viget NB, Nowak E, Neviere R, Guery BP (2007) Inhaled nitric oxide increases endothelial permeability in Pseudomonas aeruginosa pneumonia. Intensive Care Med 33:503–510CrossRefPubMedGoogle Scholar
  13. 13.
    Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624CrossRefPubMedGoogle Scholar
  14. 14.
    Haddad IY, Pataki G, Hu P, Galliani C, Beckman JS, Matalon S (1994) Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. J Clin Invest 94:2407–2413CrossRefPubMedGoogle Scholar
  15. 15.
    Zsengeller ZK, Ross GF, Trapnell BC, Szabo C, Whitsett JA (2001) Adenovirus infection increases iNOS and peroxynitrite production in the lung. Am J Physiol 280:L503–L511Google Scholar
  16. 16.
    Michel CC, Curry FE (1999) Microvascular permeability. Physiol Rev 79:703–761PubMedGoogle Scholar
  17. 17.
    de Prost N, Dreyfuss D, Ricard JD, Saumon G (2008) Terbutaline lessens protein fluxes across the alveolo-capillary barrier during high-volume ventilation. Intensive Care Med 34:763–770CrossRefPubMedGoogle Scholar
  18. 18.
    Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S, Mantovani A, Altruda F, Wymann MP (2000) Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287:1049–1053CrossRefPubMedGoogle Scholar
  19. 19.
    Uhlig U, Fehrenbach H, Lachmann RA, Goldmann T, Lachmann B, Vollmer E, Uhlig S (2004) Phosphoinositide 3-OH kinase inhibition prevents ventilation-induced lung cell activation. Am J Respir Crit Care Med 169:201–208CrossRefPubMedGoogle Scholar
  20. 20.
    Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E (2004) PI3 Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118:375–387CrossRefPubMedGoogle Scholar
  21. 21.
    Perino A, Ghigo A, Damilano F, Hirsch E (2006) Identification of the macromolecular complex responsible for PI3 Kgamma-dependent regulation of cAMP levels. Biochem Soc Trans 34:502–503CrossRefPubMedGoogle Scholar
  22. 22.
    Lionetti V, Lisi A, Patrucco E, De Giuli P, Milazzo MG, Ceci S, Wymann M, Lena A, Gremigni V, Fanelli V, Hirsch E, Ranieri VM (2006) Lack of phosphoinositide 3-kinase-gamma attenuates ventilator-induced lung injury. Crit Care Med 34:134–141CrossRefPubMedGoogle Scholar
  23. 23.
    von Bethmann AN, Brasch F, Nusing R, Vogt K, Volk HD, Muller KM, Wendel A, Uhlig S (1998) Hyperventilation induces release of cytokines from perfused mouse lung. Am J Respir Crit Care Med 157:263–272Google Scholar
  24. 24.
    Ranieri VM, Zhang H, Mascia L, Aubin M, Lin CY, Mullen JB, Grasso S, Binnie M, Volgyesi GA, Eng P, Slutsky AS (2000) Pressure-time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model. Anesthesiology 93:1320–1328CrossRefPubMedGoogle Scholar
  25. 25.
    Muscedere JG, Mullen JB, Gan K, Slutsky AS (1994) Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 149:1327–1334PubMedGoogle Scholar
  26. 26.
    Martin EL, Sheikh TA, Leco KJ, Lewis JF, Veldhuizen RA (2007) Contribution of alveolar macrophages to the response of the TIMP-3 null lung during a septic insult. Am J Physiol 293:L779–L789CrossRefGoogle Scholar
  27. 27.
    Camps M, Ruckle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B, Martin T, Gretener D, Perrin D, Leroy D, Vitte PA, Hirsch E, Wymann MP, Cirillo R, Schwarz MK, Rommel C (2005) Blockade of PI3 Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 11:936–943PubMedGoogle Scholar
  28. 28.
    Eckle T, Grenz A, Laucher S, Eltzschig HK (2008) A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J Clin Invest 118:3301–3315PubMedGoogle Scholar
  29. 29.
    Mehta D, Malik AB (2006) Signaling mechanisms regulating endothelial permeability. Physiol Rev 86:279–367CrossRefPubMedGoogle Scholar
  30. 30.
    Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012CrossRefPubMedGoogle Scholar
  31. 31.
    Song W, Matalon S (2007) Modulation of alveolar fluid clearance by reactive oxygen-nitrogen intermediates. Am J Physiol 293:L855–L858CrossRefGoogle Scholar
  32. 32.
    Kuebler WM, Uhlig U, Goldmann T, Schael G, Kerem A, Exner K, Martin C, Vollmer E, Uhlig S (2003) Stretch activates nitric oxide production in pulmonary vascular endothelial cells in situ. Am J Respir Crit Care Med 168:1391–1398CrossRefPubMedGoogle Scholar
  33. 33.
    Takenaka K, Nishimura Y, Nishiuma T, Sakashita A, Yamashita T, Kobayashi K, Satouchi M, Ishida T, Kawashima S, Yokoyama M (2006) Ventilator-induced lung injury is reduced in transgenic mice that overexpress endothelial nitric oxide synthase. Am J Physiol 290:L1078–L1086Google Scholar
  34. 34.
    Miyahara T, Hamanaka K, Weber DS, Drake DA, Anghelescu M, Parker JC (2007) Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs. Am J Physiol 293:L11–L21Google Scholar
  35. 35.
    Kooy NW, Royall JA, Ye YZ, Kelly DR, Beckman JS (1995) Evidence for in vivo peroxynitrite production in human acute lung injury. Am J Respir Crit Care Med 151:1250–1254PubMedGoogle Scholar
  36. 36.
    Tremblay LN, Slutsky AS (1998) Ventilator-induced injury: from barotrauma to biotrauma. Proc Assoc Am Physicians 110:482–488PubMedGoogle Scholar
  37. 37.
    Chiumello D, Pristine G, Slutsky AS (1999) Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med 160:109–116PubMedGoogle Scholar
  38. 38.
    Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS (1997) Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 99:944–952CrossRefPubMedGoogle Scholar
  39. 39.
    Kaestle SM, Reich CA, Yin N, Habazettl H, Weimann J, Kuebler WM (2007) Nitric oxide-dependent inhibition of alveolar fluid clearance in hydrostatic lung edema. Am J Physiol 293:L859–L869Google Scholar
  40. 40.
    Martin EL, Souza DG, Fagundes CT, Amaral FA, Assenzio B, Puntorieri V, Del Sorbo L, Fanelli V, Bosco M, Delsedime L, Pinho JF, Lemos VS, Souto FO, Alves-Filho JC, Cunha FQ, Slutsky AS, Ruckle T, Hirsch E, Teixeira MM, Ranieri VM (2010) PI3Kγ kinase activity contributes to sepsis and organ damage by altering neutrophil recruitment. Am J Respir Crit Care Med, online firstGoogle Scholar

Copyright information

© Copyright jointly held by Springer and ESICM 2010

Authors and Affiliations

  • Vito Fanelli
    • 1
  • Valeria Puntorieri
    • 1
  • Barbara Assenzio
    • 1
  • Erica L. Martin
    • 1
  • Vincenzo Elia
    • 1
  • Martino Bosco
    • 2
  • Luisa Delsedime
    • 2
  • Lorenzo Del Sorbo
    • 1
  • Andrea Ferrari
    • 1
  • Stefano Italiano
    • 1
  • Alessandra Ghigo
    • 3
  • Arthur S. Slutsky
    • 4
  • Emilio Hirsch
    • 3
  • V. Marco Ranieri
    • 1
  1. 1.Department of Anesthesia and Critical Care, Ospedale S. Giovanni Battista-MolinetteUniversity of TorinoTurinItaly
  2. 2.Department of Pathology, Ospedale S. Giovanni Battista-MolinetteUniversity of TorinoTurinItaly
  3. 3.Molecular Biotechnology CenterUniversity of TurinTurinItaly
  4. 4.Keenan Research Center at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Interdepartmental Division of Critical Care Medicine, Department of MedicineUniversity of TorontoTorontoCanada

Personalised recommendations