Lung

, Volume 182, Issue 6, pp 319–330 | Cite as

Drotrecogin Alfa (activated) Prevents Smoke-Induced Increases in Pulmonary Microvascular Permeability and Proinflammatory Cytokine IL-1β in Rats

  • S. S. Wong
  • N. N. Sun
  • J. D. Hyde
  • L. Ruiz
  • E. Meigs
  • B. R. Herrin
  • C. D. Fastje
  • S. J. Macdonald
  • M. L. Witten
Article

Abstract

In an established rat model of smoke inhalation injury, we conducted a dose-response study to examine the protective effects of XigrisTM [drotrecogin alfa (activated) (DrotAA)], a recombinant form of human activated protein C (APC). DrotAA is a serine protease (∼55 kD molecular weight) with the same amino acid sequence and the glycosylation site as human plasma-derived APC. A total of 120 F344/NH rats (half each gender, approximately 175 g body weight) were randomly divided into five groups and exposed nose-only to air or diesel fuel smoke for 20 min. These rats were then i.v. administered with DrotAA in 0, 5, 10, and 20 mg/kg body weight, respectively, immediately following smoke exposure. Treatment with DrotAA significantly attenuated smoke inhalation injury in a dose-dependent manner at 2 hours after insult, as indicated by preserving microvascular permeability and proinflammatory cytokine IL-1β (but not TNF-α and neuropeptide substance P) in bronchoalveolar lavage fluid (BALF). Moreover, the rats treated with 20 mg/kg of DrotAA had an improvement of the expiration phase of pulmonary dynamic compliance. At all dosages, however, DrotAA also significantly increased all phases of pulmonary resistance compared with either the controls or to smoke inhalation alone. Generally, these data suggest that DrotAA may exert an anti-inflammatory effect by inhibiting cytokine-mediated inflammatory amplification. However, additional studies following a clinical course are needed to confirm the maximum efficiency and possible side effects of this recombined human activated protein C.

Keywords

Fire smoke Acute lung injury Activated protein C Substance P Cytokine 

Notes

Acknowledgments

The authors gratefully acknowledge Dr. Martina M. Cartwright for assistance in this project and Dr. Jill S. McCollam for critically reviewing the manuscript. Eli Lilly and Company funded this research and supplied drotrecogin alpha (activated).

References

  1. 1.
    Aditama, TY 2000Impact of haze from forest fire to respiratory health: Indonesian experienceRespirology5169174CrossRefPubMedGoogle Scholar
  2. 2.
    Baud, FJ, Richter, F, Julien, H, Bismuth, C 1992Pre-hospital strategy for therapeutic intervention of fire victimsToxicol Lett64–65 Spec No273281CrossRefPubMedGoogle Scholar
  3. 3.
    Bergstrom, CE, Eklund, A, Skold, M, Tornling, G 1997Bronchoalveolar lavage findings in firefightersAm J Ind Med32332336CrossRefPubMedGoogle Scholar
  4. 4.
    Bernard, A, Hermans, C, Houte, G 1997Transient increase of serum Clara cell protein (CC16) after exposure to smokeOccup Environ Med546365PubMedGoogle Scholar
  5. 5.
    Brain, JD, Long, NC, Wolfthal, SF, Dumyahn, T, Dockery, DW 1998Pulmonary toxicity in hamsters of smoke particles from Kuwaiti oil firesEnviron Health Perspect106141146PubMedGoogle Scholar
  6. 6.
    Demling, RH 1987Smoke inhalation injuryPostgrad Med826368Google Scholar
  7. 7.
    Kimmel, EC, Still, KR 1999Acute lung injury, acute respiratory distress syndrome and inhalation injury: an overviewDrug Chem Toxicol2291128PubMedGoogle Scholar
  8. 8.
    Kirkpatrick, MB, Bass, JB 1979Severe obstructive lung disease after smoke inhalationChest76108110PubMedGoogle Scholar
  9. 9.
    Matthew, E, Warden, G, Dedman, J 2001A murine model of smoke inhalationAm J Physiol Lung Cell Mol Physiol280L716L723PubMedGoogle Scholar
  10. 10.
    Teixidor, HS, Novick, G, Rubin, E 1983Pulmonary complications in burn patientsJ Can Assoc Radiol34264270PubMedGoogle Scholar
  11. 11.
    Terrill, JB, Montgomery, RR, Reinhardt, CF 1978Toxic gases from firesScience20013431347PubMedGoogle Scholar
  12. 12.
    Traber, DL 1995Systemic cardiovascular changes with acute lung injuryCrit Care Med237CrossRefPubMedGoogle Scholar
  13. 13.
    Lin, WY, Kao, CH, Wang, SJ 1997Detection of acute inhalation injury in fire victims by means of technetium-99m DTPA radioaerosol inhalation lung scintigraphyEur J Nucl Med24125129PubMedGoogle Scholar
  14. 14.
    Bernard, GR, Luce, JM, Sprung, CL,  et al. 1987High-dose corticosteroids in patients with the adult respiratory distress syndromeN Engl J Med31715651570PubMedGoogle Scholar
  15. 15.
    Luce, JM, Montgomery, AB, Marks, JD,  et al. 1988Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shockAm Rev Respir Dis1386268PubMedGoogle Scholar
  16. 16.
    Sprung, CL, Caralis, PV, Marcial, EH,  et al. 1984The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled studyN Engl J Med31111371143PubMedGoogle Scholar
  17. 17.
    Esmon, CT, Gu, JM, Xu, J,  et al. 1999Regulation and functions of the protein C anticoagulant pathwayHaematologica84363368PubMedGoogle Scholar
  18. 18.
    Oka, S, Gabazza, EC, Taguchi, Y,  et al. 2000Role of activated protein C in Helicobacter pylori-associated gastritisInfect Immun6828632869CrossRefPubMedGoogle Scholar
  19. 19.
    Gabazza, EC, Taguchi, O, Adachi, Y 2002Bleomycin-induced lung fibrosis: the authors should have used another method to induce pulmonary lesions resembling human idiopathic pulmonary fibrosisAm J Respir Crit Care Med165845846Google Scholar
  20. 20.
    Hataji, O, Taguchi, O, Gabazza, EC,  et al. 2002Activation of protein C pathway in the airwaysLung1804759CrossRefPubMedGoogle Scholar
  21. 21.
    Kobayashi, H, Gabazza, EC, Tagchi, O,  et al. 1998Protein C anticoagulant system in patients with interstitial lung diseaseAm J Respir Crit Care Med15718501854PubMedGoogle Scholar
  22. 22.
    Yasui, H, Gabazza, EC, Taguchi, O,  et al. 2000Decreased protein C activation is associated with abnormal collagen turnover in the intraalveolar space of patients with interstitial lung diseaseClin Appl Thromb Hemost6202205PubMedGoogle Scholar
  23. 23.
    Yasui, H, Gabazza, EC, Tamaki, S,  et al. 2001Intratracheal administration of activated protein C inhibits bleomycin-induced lung fibrosis in the mouseAm J Respir Crit Care Med16316601668PubMedGoogle Scholar
  24. 24.
    Bernard, GR, Vincent, JL, Laterre, PF,  et al. 2001Efficacy and safety of recombinant human activated protein C for severe sepsisN Engl J Med344699709CrossRefPubMedGoogle Scholar
  25. 25.
    Wang, S, Lantz, RC, Chen, GJ,  et al. 1996The prophylactic effects of U75412E pretreatment in a smoke-induced lung injury rabbit modelPharmacol Toxicol79231237PubMedGoogle Scholar
  26. 26.
    Wang, S, Lantz, RC, Robledo, RF,  et al. 1999Early alterations of lung injury following acute smoke exposure and 21-aminosteroid treatmentToxicol Pathol27334341PubMedGoogle Scholar
  27. 27.
    Wang, S, Young, RS, Witten, ML 2001Age-related differences in pulmonary inflammatory responses to JP-8 jet fuel aerosol inhalationToxicol Ind Health172329CrossRefPubMedGoogle Scholar
  28. 28.
    Wang, S, Sun, NN, Zhang, J,  et al. 2002Immunomodulatory effects of high-dose alpha-tocopherol acetate on mice subjected to sidestream cigarette smokeToxicology175235245PubMedGoogle Scholar
  29. 29.
    Yuda, H, Adachi, Y, Taguchi, O,  et al. 2003Activated protein C inhibits bronchial hyperresponsiveness and Th2 cytokine expression in the mouseBlood..Google Scholar
  30. 30.
    Esmon, CT 2001Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammationCrit Care Med29S48S51CrossRefPubMedGoogle Scholar
  31. 31.
    Murakami, K, Okajima, K, Uchiba, M,  et al. 1996Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in ratsBlood87642647PubMedGoogle Scholar
  32. 32.
    Palma, C, Manzini, S 1998Substance P induces secretion of immunomodulatory cytokines by human astrocytoma cellsJ Neuroimmunol81127137CrossRefPubMedGoogle Scholar
  33. 33.
    Lieb, K, Fiebich, BL, Berger, M,  et al. 1997The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cellsJ Immunol15949524958PubMedGoogle Scholar
  34. 34.
    Serra, MC, Calzetti, F, Ceska, M, Cassatella, MA 1994Effect of substance P on superoxide anion and IL-8 production by human PMNLImmunology826369PubMedGoogle Scholar
  35. 35.
    Essen, SG, Rennard, SI, O’Neill, D,  et al. 1992Bronchial epithelial cells release neutrophil chemotactic activity in response to tachykininsAm J Physiol263L226L231PubMedGoogle Scholar
  36. 36.
    Zawacki, BE, Jung, RC, Joyce, J, Rincon, E 1977Smoke, burns, and the natural history of inhalation injury in fire victims: a correlation of experimental and clinical dataAnn Surg185100110PubMedGoogle Scholar
  37. 37.
    Zikria, BA, Weston, GC, Chodoff, M, Ferrer, JM 1972Smoke and carbon monoxide poisoning in fire victimsJ Trauma12641645PubMedGoogle Scholar
  38. 38.
    Conway, EM, Rosenberg, RD 1988Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cellsMol Cell Biol855885592PubMedGoogle Scholar
  39. 39.
    Xu, J, Qu, D, Esmon, NL, Esmon, CT 2000Metalloproteolytic release of endothelial cell protein C receptorJ Biol Chem27560386044CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • S. S. Wong
    • 1
  • N. N. Sun
    • 1
  • J. D. Hyde
    • 1
  • L. Ruiz
    • 1
  • E. Meigs
    • 1
  • B. R. Herrin
    • 1
  • C. D. Fastje
    • 1
  • S. J. Macdonald
    • 1
  • M. L. Witten
    • 1
    • 2
  1. 1.Lung Injury Laboratory, Department of PediatricsThe University of Arizona Health Sciences CenterTucsonUSA
  2. 2.Department of Pediatrics, AHSCB Room #3352University of ArizonaTucsonUSA

Personalised recommendations