- Dr. Allan Ramirez, Principal Investigator
- Dr. Jesse Roman, Co-Investigator
- Emory University, Atlanta, USA
- Peroxisome Proliferator-Activated Receptor Gamma in Obliterative Bronchiolitis
The major limitation to long-term survival in lung transplantation is chronic rejection, which manifests as a progressive, fibrotic disorder of small airways called obliterative bronchiolitis(OB). The factors that initiate and perpetuate this process are poorly understood, though it was widely believed that alloimmune mechanisms were solely responsible. However, strategies to further suppress immune responses in OB have been largely unsuccessful, suggesting that other processes belie OB. It appears that the profibrotic cytokine, transforming growth factor-β (TGFβ), may play a critical role in this disease, although its regulation in lung transplantation has not been clearly defined. We have found that the effects of TGFβ in OB are mediated by the second messenger, Smad3. Through Smad3, TGFβ induces a phenotypic change in fibroblasts, enabling them to produce excess amounts of connective tissue matrices that are deposited in the airways of transplanted lungs with OB. In fact, using an animal model of experimental OB, our studies show that mice lacking Smad3 developed far less airway fibrosis than their wild-type littermates. Our search for mediators to counteract the activity of Smad3 has led us to the study of the peroxisome proliferator-activated receptor γ (PPARγ). These nuclear hormone receptors are better known for their effects on insulin sensitivity and adipocyte differentiation, but we have observed in vitro that they can prevent the expression of extracellular matrix genes in cultured fibroblasts, all through the inhibition of Smad3. The focus of this research is twofold: i) study the expression and biology of PPARγ in human lung transplantation and ii) test the effects of PPARγ agonists in the animal model of OB. Of particular interest is the fact that PPARγ activators are already commercially available as treatments for diabetes such that their adaptation into the field of transplantation can rapidly be applied.