Smad3 deficiency ameliorates experimental obliterative bronchiolitis in a heterotopic tracheal transplantation model

Allan M. Ramirez, Shinsuke Takagawa, Marin Sekosan, H. Ari Jaffe, John Varga, Jesse Roman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Chronic allograft rejection manifested as obliterative broncfaiolitis (OB) remains the single greatest impediment to long-term survival after lung transplantation. Transforming growth factor-β (TGF-β1) 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-β1, through Smad3, in the development of OB using heterotopic tracheal transplantation in wild-type and Smad3-null mice. TGF-β1 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 Smad3 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-deflcient flbroblasts expressed reduced fibronectin in response to TGF-β1 compared to wild-type cells. Together, these studies suggest that the TGF-β signal transducer, Smad3, is required for the development of experimental OB in transplanted tracheas.

Original languageEnglish (US)
Pages (from-to)1223-1232
Number of pages10
JournalAmerican Journal of Pathology
Volume165
Issue number4
DOIs
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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