Expression of airway remodeling proteins in mast cell activated by TGF-β released in OVA-induced allergic responses and their inhibition by low-dose irradiation or 8-oxo-dG.
Allergic asthma is characterized by chronic airway remodeling, which is associated with the expression of extracellular matrix proteins (ECM) by TGF-β. However, to date there are no reports demonstrating that structural proteins are directly expressed in mast cells. This study aimed to investigate whether ECM proteins are expressed in mast cells activated with antigen/antibody reaction, and whether the resolution effects of irradiation or 8-oxo-dG may contribute to allergic asthma prevention. Bone marrow-derived mast cells (BMMCs) were activated with DNP-HSA/anti-DNP IgE antibody (act-BMMCs). C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) to induce allergic asthma. Mice were treated orally with 8-oxo-dG or exposed to whole body irradiation (using (137)Cs gamma ray at a dose of 0.5 Gy) for three consecutive days 24 h after OVA challenge. Expression of extracellular matrix (ECM) proteins, TGF-β signaling molecules and NF-κB/AP-1 was determined in the BMMCs, bronchoalveolar lavage (BAL) cells or lung tissues using Western blot, polymerase chain reaction (PCR) and electrophoretic mobility shift assay (EMSA), respectively. Act-BMMCs increased expression of ECM proteins, TGF-β/TGF-β receptor I, TGF-β signaling molecules and cytokines; and increased both NF-κB and AP-1 activity. In addition, the population of mast cells; expression of mast cell markers, TGF-β signaling molecules, ECM proteins/amounts; OVA-specific serum IgE level; numbers of goblet cells; airway hyperresponsiveness; cytokines/chemokines were increased in BAL cells and lung tissues of OVA-challenged mice. All of the above end points were reduced by irradiation or 8-oxo-dG in vitro and in vivo, respectively. The data suggest that mast cells induce expression of ECM proteins through TGF-β produced in inflammatory cells of OVA mice and that post treatment of irradiation or 8-oxo-dG after OVA-challenge may reduce airway remodeling through down-regulating mast cell re-activation by TGF-β/Smad signals.
Department of Pharmacology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
Gwan Ui
GU
Hong
Nam Goo
NG
Kim
Jai Youl
JY
Ro
D000080242:8-Hydroxy-2'-Deoxyguanosine; D056151:Airway Remodeling / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D001992:Bronchoalveolar Lavage Fluid; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D024202:Electrophoretic Mobility Shift Assay; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D006967:Hypersensitivity / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000080242:8-Hydroxy-2'-Deoxyguanosine; D010047:Ovalbumin; D003849:Deoxyguanosine