Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2

Nature Immunology volume 1, pages 42–46 (2000)Cite this article

Abstract

Adult respiratory distress syndrome (ARDS) is characterized by acute lung injury with a high mortality rate and yet its mechanism is poorly understood. Sepsis syndrome and acid aspiration are the most frequent causes of ARDS, leading to increased lung permeability, enhanced polymorphonuclear neutrophil (PMN) sequestration and respiratory failure. Using a murine model of acute lung injury induced by septic syndrome or acid aspiration, we investigated the role of cytosolic phospholipase A2 (cPLA2) in ARDS. We found that disruption of the gene encoding cPLA2 significantly reduced pulmonary edema, PMN sequestration and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. Acute lung injury induced by acid aspiration was similarly reduced in mice with a disrupted cpla2 gene. Our observations suggest that cPLA2 is a mediator of acute lung injury induced by sepsis syndrome or acid aspiration. Thus, the inhibition of cPLA2-initiated pathways may provide a therapeutic approach to acute lung injury, for which no pharmaceutical agents are currently effective.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The time course of response in lung elastance (EL) in LPS/zymosan-treated groups and saline-treated groups (n = 3 for each group).
Figure 2: Role of cpla2 gene in acute lung injury induced by LPS/zymosan treatment.
Figure 3: Photomicrographs of lung tissues.
Figure 4: The time course of response in lung elastance (EL) in HCl- and saline-treated groups.
Figure 5: Role of cPLA2 gene in acid-induced lung injury.
Figure 6: Photomicrograph of lung tissues.

Similar content being viewed by others

References

  1. Eijking, E.P., Gommers, D., So, K.L., Vergeer, M. & Lachmann, B. Surfactant treatment of respiratory failure induced by hydrochloric acid aspiration in rats. Anesthesiology 78, 1145–1151 (1993).

    Article  CAS  Google Scholar 

  2. Goldman, G. et al. Reactive oxygen species and elastase mediate lung permeability after acid aspiration. J. Appl. Physiol. 73, 571–575 (1992).

    Article  CAS  Google Scholar 

  3. Pittet, J.F., Mackersie, R.C., Martin, T.R. & Matthay, M.A. Biological markers of acute lung injury: prognostic and pathogenetic significance. Am. J. Respir. Crit. Care Med. 155, 1187–1205 (1997).

    Article  CAS  Google Scholar 

  4. Fowler, A.A. et al. Adult respiratory distress syndrome: Risk with common predispositions. Ann. Intern. Med. 98, 593–597 (1983).

    Article  CAS  Google Scholar 

  5. Hudson, L.D., Milberg, J.A., Anardi, D. & Maunder, R.J. Clinical risks for development of the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 151, 293–301 (1995).

    Article  CAS  Google Scholar 

  6. Prescott, S.M., Zimmerman, G.A. & McIntyre, T.M. Platelet-activating factor. J. Biol. Chem. 265, 17381–17384 (1990).

    CAS  PubMed  Google Scholar 

  7. Chao, W. & Olson, M.S. Platelet-activating factor: receptors and signal transduction. Biochem. J. 292, 617–629 (1993).

    Article  CAS  Google Scholar 

  8. Izumi, T. & Shimizu, T. Platelet-activating factor receptor: gene expression and signal transduction. Biochim. Biophys. Acta 1259, 317–333 (1995).

    Article  Google Scholar 

  9. Honda, Z.-i et al. Cloning by functional expression of platelet-activating factor receptor from guinea-pig lung. Nature 349, 342–346 (1991).

    Article  CAS  Google Scholar 

  10. Nakamura, M. et al. Molecular cloning and expression of platelet-activating factor receptor from human leukocytes. J. Biol. Chem. 266, 20400–20405 (1991).

    CAS  PubMed  Google Scholar 

  11. Ye, R.D., Prossnitz, E.R., Zou, A.H. & Cochrane, C.G. Characterization of a human cDNA that encodes a functional receptor for platelet activating factor. Biochem. Biophys. Res. Commun. 180, 105–111 (1991).

    Article  CAS  Google Scholar 

  12. Kunz, D., Gerard, N.P. & Gerard, C. The human leukocyte platelet-activating factor receptor. cDNA cloning, cell surface expression, and construction of a novel epitope-bearing analog. J. Biol. Chem. 267, 9101–9106 (1992).

    CAS  PubMed  Google Scholar 

  13. Sugimoto, T. et al. Molecular cloning and characterization of the platelet-activating factor receptor gene expressed in the human heart. Biochem. Biophys. Res. Commun. 189, 617–624 (1992).

    Article  CAS  Google Scholar 

  14. Bito, H., Honda, Z.-i, Nakamura, M. & Shimizu, T. Cloning, expression and tissue distribution of rat platelet-activating-factor-receptor cDNA. Eur. J. Biochem. 221, 211–218 (1994).

    Article  CAS  Google Scholar 

  15. Ishii, S. et al. A murine platelet-activating factor receptor gene: cloning, chromosomal localization and up-regulation of expression by lipopolysaccharide in peritoneal resident macrophages. Biochem. J. 314, 671–678 (1996).

    Article  CAS  Google Scholar 

  16. Ishii, S. et al. Bronchial hyperreactivity, increased endotoxin lethality and melanocytic tumorigenesis in transgenic mice overexpressing platelet-activating factor receptor. EMBO J. 16, 133–142 (1997).

    Article  CAS  Google Scholar 

  17. Ishii, S. et al. Impaired anaphylactic responses but intact sensitivity to endotoxin in mice lacking a platelet-activating factor receptor. J. Exp. Med. 187, 1779–1788 (1998).

    Article  CAS  Google Scholar 

  18. Leslie, C.C. Properties and regulation of cytosolic phospholipase A2 . J. Biol. Chem. 272, 16709–16712 (1997).

    Article  CAS  Google Scholar 

  19. Clark, J.D. et al. A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65, 1043–1051 (1991).

    Article  CAS  Google Scholar 

  20. Sharp, J.D. et al. Molecular cloning and expression of human Ca2+-sensitive cytosolic phospholipase A2 . J. Biol. Chem. 266, 14850–14853 (1991).

    CAS  PubMed  Google Scholar 

  21. Lin, L.L. et al. cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269–278 (1993).

    Article  CAS  Google Scholar 

  22. Kramer, R.M. et al. p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. J. Biol. Chem. 271, 27723–27729 (1996).

    Article  CAS  Google Scholar 

  23. Uozumi, N. et al. Roles of cytosolic phospholipase A2 in allergic response and parturition. Nature 390, 618–622 (1997).

    Article  CAS  Google Scholar 

  24. Donnelly, S.C. & Haslett, C. Cellular mechanisms of acute lung injury: implications for future treatment in the adult respiratory distress syndrome. Thorax 47, 260–263 (1992)

    Article  CAS  Google Scholar 

  25. Miotla, J.M., Williams, T.J., Hellewell, P.G. & Jeffery, P.K. A role for the β2 integrin CD11b in mediating experimental lung injury in mice. Am. J. Respir. Cell Mol. Biol. 14, 363–373 (1996).

    Article  CAS  Google Scholar 

  26. Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y. & Shimizu, T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387, 620–624 (1997).

    Article  CAS  Google Scholar 

  27. Chiang, N. et al. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J. Clin. Invest. 104, 309–316 (1999).

    Article  CAS  Google Scholar 

  28. Levy, R. et al. Elevated cytosolic phospholipase A2 expression and activity in human neutrophils during sepsis. Blood 95, 660–665 (2000).

    CAS  PubMed  Google Scholar 

  29. Hardman, J.G. & O'Connor, P.J. Predicting gastric contents following trauma: an evaluation of current practice. Eur. J. Anaesthesiol. 16, 404–409 (1999).

    Article  CAS  Google Scholar 

  30. Marion, D.W. Complications of head injury and their therapy. Neurosurg. Clin. N. Am. 2, 411–424 (1991).

    Article  CAS  Google Scholar 

  31. Goldman, G. et al. Synergism between leukotriene B4 and thromboxane A2 in mediating acid-aspiration injury. Surgery 111, 55–61 (1992).

    CAS  PubMed  Google Scholar 

  32. Utsunomiya, T. et al. Modification of inflammatory response to aspiration with ibuprofen. Am. J. Physiol. 243, H903–H910 (1982).

    CAS  PubMed  Google Scholar 

  33. Nagase, T. et al. Intravenous bolus of prednisolone decreases 15–hydroxyeicosatetraenoic acid formation in the rat model of acid aspiration. Crit. Care Med. 19, 950–954 (1991).

    Article  CAS  Google Scholar 

  34. Stewart, A.G., Dubbin, P.N., Harris, T. & Dusting, G.J. Platelet-activating factor may act as a second messenger in the release of icosanoids and superoxide anions from leukocytes and endothelial cells. Proc. Natl Acad. Sci. USA 87, 3215–3219 (1990).

    Article  CAS  Google Scholar 

  35. Lynch, K.R. et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399, 789–793 (1999).

    Article  CAS  Google Scholar 

  36. Dahlen, S.E. et al. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules; in vitro effects with relevance to the acute inflammatory response. Proc. Natl Acad. Sci. USA 78, 3887–3891 (1981).

    Article  CAS  Google Scholar 

  37. Nagase, T. et al. Intercellular adhesion molecule-1 mediates acid aspiration-induced lung injury. Am. J. Respir. Crit. Care Med. 154, 504–510 (1996).

    Article  CAS  Google Scholar 

  38. Folkesson, H.G., Matthay, M.A., Hebert, C.A. & Broaddus, V.C. Acid aspiration-induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms. J. Clin. Invest. 96, 107–116 (1995).

    Article  CAS  Google Scholar 

  39. Nagase, T., Aoki, T., Oka, T., Fukuchi, Y. & Ouchi, Y. ET-1-induced bronchoconstriction is mediated via ETB receptor in mice. J. Appl. Physiol. 83, 46–51 (1997).

    Article  CAS  Google Scholar 

  40. Nagase, T. et al. Airway hyperresponsiveness to methacholine in mutant mice deficient in endothelin-1. Am. J. Respir. Crit. Care Med. 157, 560–564 (1998).

    Article  CAS  Google Scholar 

  41. Nagase, T. et al. Airway responsiveness in transgenic mice overexpressing platelet-activating factor receptor: roles of thromboxanes and leukotrienes. Am. J. Respir. Crit. Care Med. 156, 1621–1627 (1997).

    Article  CAS  Google Scholar 

  42. Nagase, T. et al. Platelet-activating factor mediates acid-induced lung injury in genetically engineered mice. J. Clin. Invest. 104, 1071–1076 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y. Suzuki, K. Ishihara, K. Izumisawa, R. Mitsuzono, M. Yoshino, C. Jin, M. Hata and M. Ito (The University of Tokyo) for their technical assistance. We are also grateful to F. Takaku (Jichi Medical School), T. Yokomizo, N. Ito, and D. A.Wong (The University of Tokyo) for valuable suggestions. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan, and grants from the Human Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research.

Author information

Authors and Affiliations

  1. Department of Geriatric Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, 113, Tokyo, Japan

    Takahide Nagase & Yasuyoshi Ouchi

  2. Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, 113, Tokyo, Japan

    Naonori Uozumi, Satoshi Ishii, Kazuhiko Kume, Takashi Izumi & Takao Shimizu

  3. CREST of Japan Science and Technology Corporation, Japan

    Takao Shimizu

Authors
  1. Takahide Nagase
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naonori Uozumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satoshi Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhiko Kume
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takashi Izumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasuyoshi Ouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takao Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takao Shimizu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagase, T., Uozumi, N., Ishii, S. et al. Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2. Nat Immunol 1, 42–46 (2000). https://doi.org/10.1038/76897

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/76897

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing