Smad3 deficiency ameliorates experimental obliterative bronchiolitis in a heterotopic tracheal transplantation model.
Chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the single greatest impediment to long-term survival after lung transplantation. Transforming growth factor-beta1 (TGF-beta1) has been implicated in the tissue remodeling response associated with OB. Therefore, its intracellular signal transducer, Smad3, is a prime target of investigation. Herein, we examine the role of TGF-beta1, through Smad3, in the development of OB using heterotopic tracheal transplantation in wild-type and Smad3-null mice. TGF-beta1 was detectable within infiltrating mononuclear cells early after transplantation. Later it was detected in fibroblasts and in the connective tissue accumulating within the lumen and the airway wall of the transplanted allografts. Connective tissue growth factor had a similar time and tissue distribution. Nuclear detection of Smad3 and phosphorylated Smads within intraluminal fibroblasts coincided with increased intraluminal deposition of fibronectin and collagen. When transplanted into Smad3-null mice, allografts failed to organize the intraluminal exudates despite fibroblast accumulation and showed reduced fibronectin and collagen deposition. In culture, Smad3-deficient fibroblasts expressed reduced fibronectin in response to TGF-beta1 compared to wild-type cells. Together, these studies suggest that the TGF-beta signal transducer, Smad3, is required for the development of experimental OB in transplanted tracheas.
Ramirez
Allan M
AM
Andrew J. McKelvey Lung Transplantation Center, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Takagawa
Shinsuke
S
Sekosan
Marin
M
Jaffe
H Ari
HA
Varga
John
J
Roman
Jesse
J
D000818:Animals; D015153:Blotting, Western; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D017874:Immediate-Early Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D051900:Smad3 Protein; D014132:Trachea / Q000473:pathology / Q000637:transplantation*; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D016042:Transplantation, Heterotopic / Q000276:immunology*
C526318:CCN2 protein, mouse; D004268:DNA-Binding Proteins; D005353:Fibronectins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D003094:Collagen