A broad-spectrum caspase inhibitor attenuates allergic airway inflammation in murine asthma model.
Asthma is characterized by acute and chronic airway inflammation, and the severity of the airway hyperreactivity correlates with the degree of inflammation. Many of the features of lung inflammation observed in human asthma are reproduced in OVA-sensitized/challenged mice. T lymphocytes, particularly Th2 cells, are critically involved in the genesis of the allergic response to inhaled Ag. In addition to antiapoptotic effects, broad-spectrum caspase inhibitors inhibit T cell activation in vitro. We investigated the effect of the broad-spectrum caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), on airway inflammation in OVA-sensitized/challenged mice. OVA-sensitized mice treated with z-VAD-fmk immediately before allergen challenge showed marked reduction in inflammatory cell infiltration in the airways and pulmonary blood vessels, mucus production, and Th2 cytokine production. We hypothesized that the caspase inhibitor prevented T cell activation, resulting in the reduction of cytokine production and eosinophil infiltration. Treatment with z-VAD-fmk in vivo prevented subsequent T cell activation ex vivo. We propose that caspase inhibitors may offer a novel therapeutic approach to T cell-dependent inflammatory airway diseases.
Iwata
Akiko
A
Department of Surgery, University of Washington, Seattle, WA 98104, USA. aiwata@u.washington.edu
Nishio
Kazumi
K
Winn
Robert K
RK
Chi
Emil Y
EY
Henderson
William R
WR
Harlan
John M
JM
D000336:Aerosols; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D061945:Caspase Inhibitors; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D007442:Intubation, Intratracheal; D007962:Leukocytes / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000336:Aerosols; D000485:Allergens; D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D015848:Interleukin-5; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D016210:Methacholine Chloride; D015847:Interleukin-4; D010047:Ovalbumin