GGTI-2133, an inhibitor of geranylgeranyltransferase, inhibits infiltration of inflammatory cells into airways in mouse experimental asthma.
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.
Chiba
Y
Y
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan. chiba@hoshi.ac.jp
Sato
S
S
Misawa
M
M
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D054414:Chemokine CCL17 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007073:Immunoglobulin E / Q000097:blood; D007274:Injections, Intraperitoneal; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D010047:Ovalbumin; D017368:Protein Prenylation; D011657:Pulmonary Eosinophilia / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*
D018927:Anti-Asthmatic Agents; C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; D004791:Enzyme Inhibitors; C547856:GGTI-2133; D007093:Imidazoles; D018793:Interleukin-13; D009281:Naphthalenes; D007975:Leukotriene B4; D015847:Interleukin-4; D007073:Immunoglobulin E; D010047:Ovalbumin; D019883:Alkyl and Aryl Transferases; D007930:Leucine