8-oxo-2'-deoxyguanosine suppresses allergy-induced lung tissue remodeling in mice.
We previously reported that 8-oxo-2'-deoxyguanosine (8-oxo-dG) suppressed airway hyperresponsiveness and allergy-associated immune responses in ovalbumin-induced allergic mice by inactivating Rac. In the present study, 8-oxo-dG was investigated for its suppression of inflammation and remodeling in lung tissues induced by allergic reaction in mice. Mice were sensitized and challenged with ovalbumin without or with oral administration of 8-oxo-dG. The mice without 8-oxo-dG administration showed the following inflammatory and airway remodeling signs: infiltration of inflammatory cells into peribronchial area, hyperplasia of mucus-secreting goblet cells in bronchial walls, increase of expressions of Muc5ac and vascular cell adhesion molecule (VCAM)-1, collagen deposition and protein expression, and matrix metalloproteinase (MMP)-2/-9 expressions. We also observed an increase of various inflammation-mediating proteins, namely IL-4, IL-5, IL-8, IL-13, TNF-α and IFN-γ, and activation of STAT1 and NF-κB. Production of reactive oxygen species and nitric oxide (NO(.)) was increased as indicated by a dramatic increase in formation of nitro-tyrosine. Importantly, Rac1 and 2 were also markedly activated. However, 8-oxo-dG suppressed all these inflammatory and tissue remodeling signs as well as activation of Rac1 and 2. These results indicate that 8-oxo-dG can inhibit allergy-induced inflammation and remodeling in airway and lung tissues through Rac inactivation.
Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Jeong-Soon
JS
Kim
Dae-Yong
DY
Kim
Jin-Ku
JK
Lee
Jai-Youl
JY
Ro
Myung-Hee
MH
Chung
D000080242:8-Hydroxy-2'-Deoxyguanosine; D056151:Airway Remodeling / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D020397:Goblet Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006965:Hyperplasia / Q000188:drug therapy; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D016207:Cytokines; D007166:Immunosuppressive Agents; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D019010:Vascular Cell Adhesion Molecule-1; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020744:rac GTP-Binding Proteins; D003849:Deoxyguanosine