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Intensive Care Medicine

, Volume 33, Issue 5, pp 863–871 | Cite as

Targeting caspase-1 by inhalation-therapy: effects of Ac-YVAD-CHO on IL-1β, IL-18 and downstream proinflammatory parameters as detected in rat endotoxaemia

  • Kim A. Boost
  • Sandra Hoegl
  • Christian Hofstetter
  • Michael Flondor
  • Klaus Stegewerth
  • Ilka Platacis
  • Josef Pfeilschifter
  • Heiko Muhl
  • Bernhard Zwissler
Experimental

Abstract

Objective

We set out to investigate whether the nebulized and inhaled specific caspase-1 inhibitor Ac-YVAD-CHO has the potential to attenuate the pulmonary and systemic release of the caspase-1-dependent cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as their downstream enzymes iNOS and COX-2 in rat experimental endotoxaemia.

Design and setting

Controlled, randomized animal study in a university research facility.

Subject

Male Sprague–Dawley rats (n = 32) were randomly treated as follows: Inhaled Ac-YVAD-CHO was administered in eight rats at a inhaled total dosage of 5 mg and in eight rats at a inhaled total dose of 0.5 mg before infusion of lipopolysaccharide (LPS; 5 mg/kg, i.v.). Eight animals received LPS only. Eight animals served as controls without endotoxaemia.

Measurements and results

After 4 h of endotoxaemia, levels of IL-1β, IL-18 and TNF-α in plasma and bronchoalveolar fluid (BALF) were analyzed. Nitric oxide (NO) release from alveolar macrophages was measured by Griess assay. Amounts of iNOS protein in alveolar macrophages and COX-2 protein in lung homogenates were determined by Western blotting. Significant reductions in release of IL-1β (–58%, p < 0.05) and IL-18 (–51%, p < 0.05) in plasma and IL-1β (–59%, p < 0.05) in BALF were found in animals pretreated with inhaled caspase-1 inhibitor compared with animals without therapy. Expression of iNOS in alveolar macrophages and COX-2in lung tissue was concurrently decreased in the treatment groups compared with control animals.

Conclusions

Our data demonstrate that administration of the caspase-1 inhibitor Ac-YVAD-CHO by inhalation is able to reduce the pulmonary and systemic release of proinflammatory mediators in rat endotoxaemia. These results further underscore that inhalation may constitute an effective route of anti-inflammatory drug administration, beneficial in the clinical setting of ARDS.

Keywords

Rat Lipopolysaccharide Interleukin-1β IL-1β Interleukin-18 IL-18 Aerosol therapy 

Notes

Acknowledgements

The study was supported by grants from the August-Scheidel-Stiftung and the Heinrich- und Fritz-Riese-Stiftung, University of Frankfurt to K.A.B.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Kim A. Boost
    • 1
  • Sandra Hoegl
    • 1
  • Christian Hofstetter
    • 1
  • Michael Flondor
    • 1
  • Klaus Stegewerth
    • 1
  • Ilka Platacis
    • 1
  • Josef Pfeilschifter
    • 2
  • Heiko Muhl
    • 2
  • Bernhard Zwissler
    • 1
  1. 1.Department of Anaesthesiology, Intensive Care and Pain TherapyUniversity Hospital of Johann Wolfgang Goethe UniversityFrankfurt am MainGermany
  2. 2.Pharmazentrum Frankfurt/ZAFESUniversity Hospital of Johann Wolfgang Goethe-UniversityFrankfurt am MainGermany

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