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The involvement of nitric oxide, nitric oxide synthase, neutrophil elastase, myeloperoxidase and proinflammatory cytokines in the acute lung injury caused by phorbol myristate acetate

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Journal of Biomedical Science

Abstract

Phorbol myristate acetate (PMA) causes acute lung injury (ALI). The present study was designed to elucidate the role of nitric oxide (NO), inducible NO synthase (iNOS), neutrophil elastase (NE) and other mediators in the ALI caused by PMA. In isolated rat’s lungs, PMA at various doses (1, 2 and 4 μg/g lung weight) was added into the lung perfusate. Vehicle group received dimethyl sulfoxide (the solvent for PMA) 100 μg/g. We measured the lung weight changes, pulmonary arterial pressure, capillary filtration coefficient, exhaled NO, protein concentration in bronchoalveolar lavage (PCBAL) and Evan blue dye leakage. Nitrate/nitrite, methyl guanidine, proinflammatory cytokines, NE and myeloperoxidase (MPO) in lung perfusate were determined. Histopathological examination was performed. We detected the iNOS mRNA expression in lung tissue. PMA caused dose-dependent increases in variables for lung changes, and nitrate/nitrite, methyl guanidine, proinflammatory cytokines, NE and MPO in lung perfusate. The pathology was characterized by alveolar hemorrhagic edema with inflammatory cell infiltration. Scanning electron microscopy revealed endothelial damage. PMA upregulated the expression of iNOS mRNA. Our results suggest that neutrophil activation by PMA causes release of NE, upregulation of iNOS and a series of inflammatory responses leading to endothelial damage and ALI.

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References

  1. Chu SJ, Chang DM, Wang D, Hsu K, Chiang CH (2001) Protective effect of lipophilic antioxidants on phorbol-induced acute lung injury in rats. Crit Care Med 29:819–824

    Article  PubMed  CAS  Google Scholar 

  2. Creamer KM, McCloud LL, Fisher LE, Ehrhart IC (2001) Pentoxifylline rescue preserves lung function in isolated canine lungs injured with phorbol myristate acetate. Chest 119:1893–1900

    Article  PubMed  CAS  Google Scholar 

  3. Evgenov OV, Hevrøy O, Bremnes KE, Bjertnaes LJ (2000) Effect of aminoguanidine on lung fluid filtration after endotoxin in awake sheep. Am J Respir Crit Care Med 162:465–470

    PubMed  CAS  Google Scholar 

  4. Razavi HM, Wang le F, Weicker S, Rohan M, Law C, McCormack DG, Mehta S (2004) Pulmonary neutrophil infiltration in murine sepsis: role of inducible nitric oxide synthase. Am J Respir Crit Care Med 170:227–233

    Article  PubMed  Google Scholar 

  5. Kao SJ, Yang FL, Hsu YH, Chen HI (2004) Mechanism of fulminant pulmonary edema caused by enterovirus 71. Clin Infect Dis 38:1784–1788

    Article  PubMed  Google Scholar 

  6. Lee WL, Downey GP (2001) Leukocyte elastase: Physiological functions and role in acute lung injury. Am J Respir Crit Care Med 164:896–904

    PubMed  CAS  Google Scholar 

  7. Kuraki T, Ishibashi M, Takayama M, Shiraishi M, Yoshida M (2002) A novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysema in rats. Am J Respir Crit Care Med 166:496–500

    Article  PubMed  Google Scholar 

  8. Murakami K, Okajima K, Uchiba M (2000) The prevention of lipopolysaccharide-induced pulmonary vascular injury by pretreatment with cepharanthine in rats. Am J Respir Crit Care Med 161:57–63

    PubMed  CAS  Google Scholar 

  9. Inoue Y, Seiyama A, Tanaka H, Ukai I, Akimau P, Nishino M, Shimazu T, Sugimoto H (2005) Protective effects of a selective neutrophil elastase inhibitor (sivelestat) on lipopolysaccharide-induced acute dysfunction of the pulmonary microcirculation. Crit Care Med 33:1814–1822

    Article  PubMed  CAS  Google Scholar 

  10. Koshika T, Ishizaka A, Nagatomi I, Sudo Y, Hasegawa N, Goto T (2001) Pretreatment with FK506 improves survival rate and gas exchange in canine model of acute lung injury. Am J Respir Crit Care Med 163:79–84

    PubMed  CAS  Google Scholar 

  11. Murakami K, Cox RA, Hawkins HK, Schmalstieg FC, McGuire RW, Jodoin JM, Traber LD, Traber DL (2003) Cepharanthin, an alkaloid from Stephania cepharantha, inhibits increased pulmonary vascular permeability in an ovine model of sepsis. Shock 20:46–51

    Article  PubMed  CAS  Google Scholar 

  12. Kao SJ, Wang D, Yeh DY, Hsu K, Hsu YH, Chen HI (2004) Static inflation attenuates ischemia/reperfusion injury in an isolated rat lung in situ. Chest 126:552–558

    Article  PubMed  Google Scholar 

  13. Chen HI, Yeh DY, Liou HL, Kao SJ (2006) Insulin attenuates endotoxin-induced acute lung injury in conscious rats. Crit Care Med 34:758–764

    Article  PubMed  CAS  Google Scholar 

  14. Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD (2000) Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6:460–463

    Article  PubMed  CAS  Google Scholar 

  15. Lee RP, Wang D, Lin NT, Chen HI (2002) Physiological and chemical indicators for early and late stages of sepsis in conscious rats. J Biomed Sci 9:613–621

    Article  PubMed  CAS  Google Scholar 

  16. Nakamura K, Ienaga K, Yokozawa T, Fujitsuka N, Oura H (1991) Production of methylguanidine from creatinine via creatol by active oxygen species: analyses of the catabolism in vitro. Nephron 58:42–46

    Article  PubMed  CAS  Google Scholar 

  17. Yoshimura K, Nakagawa S, Koyama S, Kobayashi T, Homma T (1994) Roles of neutrophil elastase and superoxide anion in leukotriene B4-induced lung injury in rabbit. J Appl Physiol 76:91–96

    PubMed  CAS  Google Scholar 

  18. Kinoshita M, Ono S, Mochizuki H (2000) Neutrophils mediate acute lung injury in rabbits: role of neutrophil elastase. Eur Surg Res 32:337–346

    Article  PubMed  CAS  Google Scholar 

  19. Lin NT, Yang FL, Lee RP, Peng TC, Chen HI (2006) Inducible nitric oxide synthase mediates cytokine release: the time course in conscious and septic rats. Life Sci 78:1038–1043

    Article  PubMed  CAS  Google Scholar 

  20. Abraham E (2003) Neutrophils and acute lung injury. Crit Care Med 31:S195–S199

    Article  PubMed  Google Scholar 

  21. Suzuki T, Moraes TJ, Vachon E, Ginzberg HH, Huang TT, Matthay MA, Hollenberg MD, Marshall J, McCulloch CA, Abreu MT, Chow CW, Downey GP (2005) Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cells. Am J Respir Cell Mol Biol 33:231–247

    Article  PubMed  CAS  Google Scholar 

  22. Delacourt C, Herigault S, Delclaux C, Poncin A, Levame M, Harf A, Saudubray F, Lafuma C (2002) Protection against acute lung injury by intravenous or intratracheal pretreatment with EPI-HNE-4, a new potent neutrophil elastase inhibitor. Am J Respir Cell Mol Biol 26:290–297

    PubMed  CAS  Google Scholar 

  23. Hagio T, Nakao S, Matsuoka H, Matsumoto S, Kawabata K, Ohno H (2001) Inhibition of neutrophil elastase activity attenuates complement-mediated lung injury in the hamster. Eur J Pharmacol 426:131–138

    Article  PubMed  CAS  Google Scholar 

  24. Lee RP, Wang D, Kao SJ, Chen HI (2001) The lung is the major site that produces nitric oxide to induce acute pulmonary oedema in endotoxin shock. Clin Exp Pharmacol Physiol 28:315–320

    Article  PubMed  CAS  Google Scholar 

  25. Inoue H, Aizawa H, Nakano H, Matsumoto K, Kuwano K, Nadel JA, Hara N (2000) Nitric oxide synthase inhibitors attenuate ozone-induced airway inflammation in guinea pigs. Possible role of interleukin-8. Am J Respir Crit Care Med 161:249–256

    PubMed  CAS  Google Scholar 

  26. Cuzzocrea S, Mazzon E, Calabro G, Dugo L, De Sarro A, van De Loo FA, Caputi AP (2000) Inducible nitric oxide synthase-knockout mice exhibit resistance to pleurisy and lung injury caused by carrageenan. Am J Respir Crit Care Med 162:1859–1866

    PubMed  CAS  Google Scholar 

  27. Agorreta J, Garayoa M, Montuenga LM, Zulueta JJ (2003) Effects of acute hypoxia and lipopolysaccharide on nitric oxide synthase-2 expression in acute lung injury. Am J Respir Crit Care Med 168:287–296

    Article  PubMed  Google Scholar 

  28. Chen HI, Kao SJ, Wang D, Lee RP, Su CF (2003) Acute respiratory distress syndrome. J Biomed Sci 10:588–592

    Article  PubMed  Google Scholar 

  29. Kao SJ, Peng TC, Lee RP, Hsu K, Chen CF, Hung YK, Wang D, Chen HI (2003) Nitric oxide mediates lung injury induced by ischemia-reperfusion in rats. J Biomed Sci 10:58–64

    Article  PubMed  CAS  Google Scholar 

  30. Su CF, Yang FL, Chen HI (2007) Inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in rats. Clin Exp Pharmacol Physiol 34:339–346

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported, in part, by grants from the National Science Council (NSC 95-2320-B-320-004 and NSC 95-2320-B-320-008).

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Authors and Affiliations

  1. Institute of Biotechnology, National Chia-Yi University, Chiayi, Taiwan

    Yi-Ling Yang

  2. Institute of Undersea and Hyperbaric Medicine, National Defense Medical Center, Taipei, Taiwan

    Kun-Lun Huang

  3. Department of Nursing, Taipei Veteran General Hospital, Taipei, Taiwan

    Huey-Ling Liou

  4. Institute of Integrative Physiology and Clinical Sciences and of Medical Sciences, Tzu Chi University, No. 701, Sec. 3, Jhongyang Rd., Hualien, 97004, Taiwan

    Hsing I. Chen

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  1. Yi-Ling Yang
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  2. Kun-Lun Huang
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Correspondence to Hsing I. Chen.

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Yang, YL., Huang, KL., Liou, HL. et al. The involvement of nitric oxide, nitric oxide synthase, neutrophil elastase, myeloperoxidase and proinflammatory cytokines in the acute lung injury caused by phorbol myristate acetate. J Biomed Sci 15, 499–507 (2008). https://doi.org/10.1007/s11373-008-9238-y

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  • DOI: https://doi.org/10.1007/s11373-008-9238-y

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