, 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. WittenEmail author


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.


Fire smoke Acute lung injury Activated protein C Substance P Cytokine 



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).


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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
    Email author
  1. 1.Lung Injury Laboratory, Department of PediatricsThe University of Arizona Health Sciences CenterTucsonUSA
  2. 2.Department of Pediatrics, AHSCB Room #3352University of ArizonaTucsonUSA

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