GGTI-2133, an inhibitor of geranylgeranyltransferase, inhibits infiltration of inflammatory cells into airways in mouse experimental asthma.

Abstract

Statins have been proposed as a novel treatment of respiratory diseases including asthma. Although the mechanism of anti-inflammatory effect of statins is still unclear, an inhibition of protein prenylation by depleting the downstream metabolites of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase might be involved. To test the hypothesis, the effects of GGTI-2133, a direct inhibitor of geran ylgeranyltransferase (GGTase), on antigen-induced airway inflammation were investigated in a murine model of allergic bronchial asthma. Mice were sensitized and repeatedly challenged with ovalbumin antigen (OA). Animals were also treated with GGTI-2133 (5 mg/kg/day, i.p.) once a day before and during the antigen inhalation period. Repeated antigen inhalation caused an infiltration of inflammatory cells, especially eosinophils, into airways. Significant increases in interleukin (IL)-4, IL-13, eotaxin, thymus and activation-regulated chemokine (TARC) and leukotriene B4 (LTB4) in bronchoalveolar lavage fluids and total and OA-specific IgE in sera were also found in the antigen-exposed animals. The systemic treatments with GGTI-2133 inhibited the antigen-induced eosinophil infiltration into airways almost completely. However, interestingly, the GGTI-2133 treatment did not affect the levels of these chemotactic factors and IgE. These findings suggest that selective inhibition of GGTase is effective for eosinophilic airway inflammation such as asthma.

• Authors: Y Chiba, S Sato, M Misawa
• Journal: International journal of immunopathology and pharmacology (Int J Immunopathol Pharmacol) 2009 Oct-Dec Vol. 22 Issue 4 Pg. 929-35 ISSN: 0394-6320 [Print] England
• PMID: 20074456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Asthmatic Agents
• Ccl17 protein, mouse
• Chemokine CCL17
• Enzyme Inhibitors
• GGTI-2133
• Imidazoles
• Interleukin-13
• Naphthalenes
• Leukotriene B4
• Interleukin-4
• Immunoglobulin E
• Ovalbumin
• Alkyl and Aryl Transferases
• Leucine

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors, metabolism)
• Animals
• Anti-Asthmatic Agents (administration & dosage, pharmacology)
• Asthma (drug therapy, enzymology, immunology)
• Bronchoalveolar Lavage Fluid (cytology, immunology)
• Chemokine CCL17 (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Imidazoles (administration & dosage, pharmacology)
• Immunoglobulin E (blood)
• Injections, Intraperitoneal
• Interleukin-13 (metabolism)
• Interleukin-4 (metabolism)
• Leucine (administration & dosage, analogs & derivatives, pharmacology)
• Leukotriene B4 (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Naphthalenes (administration & dosage, pharmacology)
• Ovalbumin
• Protein Prenylation
• Pulmonary Eosinophilia (enzymology, immunology, prevention & control)