Molecular ablation of transforming growth factor β signaling pathways by tyrosine kinase inhibition: The coming of a promising new era in the treatment of tissue fibrosis

Fibrotic diseases. A therapeutic challenge There are numerous human diseases including systemic sclerosis; pulmonary, liver, and kidney fibrosis; and the newly recognized nephrogenic systemic fibrosis, which are characterized by abnormal and exaggerated deposition of collagen in the affected organs (reviewed in refs. 1-6). Tissue fibrosis causes disruption of normal organ architecture, and ultimately leads to their dysfunction and failure. The extent and rate of progression of the fibrotic process largely determine the course, response to therapy, and prognosis of these diseases. Although their etiology and pathogenesis are diverse and have not been completely elucidated despite intensive investigations, it is apparent that a common feature is the accumulation of abundant fibrous tissue and the presence of large numbers of fibroblasts displaying an activated phenotype. This phenotype is characterized by a notable elevation in the expression of the genes encoding type l and type lll collagens and fibronectin, the initiation of expression of αsmooth muscle actin, and the reduction in expression of genes encoding extracellular matrixdegradative enzymes. Regardless of the etiologic event, the resulting alterations in the biosynthetic activity of extracellular matrix producing cells are crucial in the pathogenesis of fibrotic diseases. Indeed, it is the persistent activation of the genes encoding various collagens in these cells which distinguishes controlled repair, such as that occurring during normal wound healing, from the uncontrolled fibrosis which is the hallmark of the fibrotic diseases. However, despite numerous recent advances in the molecular biology of the events responsible for the regulation of genes encoding collagens and other extracellular matrix proteins, there is limited knowledge regarding the intimate mechanisms responsible for the pathologic increase in their expression in fibrotic diseases. The wide spectrum of organs affected by the fibrotic diseases and the large number of individuals suffering their devastating effects pose one of the most serious health problems in current medicine and represent an enormous burden on health services and resources causing severe economic consequences. Despite the high frequency and the diversity of organs affected by the fibrotic diseases, there is currently no effective treatment. The recent elucidation of