title: Targeting caspase-1 by inhalation-therapy: effects of Ac-YVAD-CHO on IL-1 beta, IL-18 and downstream proinflammatory parameters as detected in rat endotoxaemia.
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-1 beta (IL-1 beta) and interleukin-18 (IL-18) as well as their downstream enzymes iNOS and COX-2 in rat experimental endotoxaemia.
  
  
  METHODS
  Controlled, randomized animal study in a university research facility.
  
  
  METHODS
  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.
  
  
  RESULTS
  After 4h of endotoxaemia, levels of IL-1 beta, IL-18 and TNF-alpha 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-1 beta (-58%, p<0.05) and IL-18 (-51%, p<0.05) in plasma and IL-1 beta (-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-2 in 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.
authors: Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany. k.boost@med.uni-frankfurt.de.
authors: Kim A
authors: KA
authors: Boost
authors: Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Sandra
authors: S
authors: Hoegl
authors: Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Christian
authors: C
authors: Hofstetter
authors: Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Michael
authors: M
authors: Flondor
authors: Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Klaus
authors: K
authors: Stegewerth
authors: Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Ilka
authors: I
authors: Platacis
authors: Pharmazentrum Frankfurt/ZAFES, University Hospital of Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Josef
authors: J
authors: Pfeilschifter
authors: Pharmazentrum Frankfurt/ZAFES, University Hospital of Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Heiko
authors: H
authors: Muhl
authors: Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Bernhard
authors: B
authors: Zwissler
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D020382:Interleukin-18 / Q000097:blood*; D053583:Interleukin-1beta / Q000097:blood*; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D000336:Aerosols; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D020382:Interleukin-18; D053583:Interleukin-1beta; D009842:Oligopeptides; D048069:Tumor Necrosis Factors; C096429:L 709049