Current Enzyme Inhibition - Volume 6, Issue 2, 2010

This special issue of Current Enzyme Inhibition (CEI) entitled “TGF-β Signaling and its Inhibition: Implication in Fibrosis” is comprised of five informative review articles describing the significance of Transforming growth factor-β (TGF-β) in tissue fibrosis. Fibrosis, a devastating connective tissue disorder, is characterized by vascular injury, inflammation, profibrotic cytokine secretion by infiltrating cells, fibroblast activation, myofibroblast differentiation, excessive collagen and other extracellular matrix protein synthesis and accumulation, loss of tissue homeostasis and ultimately, impaired organ function. As fibrosis is associated with differet diseases in different organs, millions of people are affected by this connective tissue disorder every year. At present, there is no effective treatment for the reversal of fibrosis. In order to develop novel therapeutic approaches for the treatment of fibrosis in different organs, numerous studies have been performed in vitro using cultured cells and in vivo using animal models of fibrosis and patients with tissue fibrosis. Irrespective of fibrotic organs, one common concept emerges from these studies-TGF-β plays a pivotal role in the development of tissue fibrosis. In most fibrotic tissues, TGF-β levels are elevated and neutralization of elevated TGF-β activity ameliorates progression of fibrosis. As TGF-β also plays a significant role in controlling cellular growth and immunity, complete neutralization or depletion of TGF-β will not be an ideal approach to treat fibrosis. Therefore, it is important to understand the downstream events and its major players in TGF-β signal transduction pathway which control fibroblast activation, myofibroblast differentiation from resident fibroblasts or EMT/EndMT-derived fibroblasts and synthesis of ECM proteins. In the last decade, extensive research has been conducted to better understand the molecular basis of tissue fibrosis particularly in light of profibrotic cytokine TGF-β signaling. Understanding the molecular basis of tissue specific fibrosis will be beneficial in designing new therapeutic approaches to treat tissue specific fibrosis. Numerous pharmacological, natural and cellular inhibitors of TGF-β signaling have been tested to block tissue fibrosis in different organs. The primary goal of this special issue of CEI is to give readers a very comprehensive review of the progress of fibrosis research in different organs and possible therapeutic approaches. Although every organ in the human body can be affected by fibrosis, this special issue of CEI specifically covers the pathogenesis of fibrosis and its direct association to the multifaceted nature of TGF-β signaling in liver, lung, heart, kidney and skin. The first article by Matsuzaki has described the clinical features of human liver fibrosis and the role of Smad-dependent TGF-β signaling in the pathogenesis of liver fibrosis. This article elegantly described the significance of site specific phosphorylation of Smad3 [C-terminally phosphorylated form, linker phosphorylated form and both C-terminal and linker phosphorylated form] by TGF-β receptor I kinase, cyclin-dependent kinase 4 and c-Jun N-terminal kinase in cytostatic and fibrogenic TGF-β signals in hepatocytes and mesenchymal cells. The importance of specific blockade of c-Jun N-terminal kinase-dependent Smad linker phosphorylation in the treatment of liver fibrosis has been discussed. In second article, Yue, Shan and Lasky have reviewed the significance of TGF-β signaling in the pathogenesis of pulmonary fibrosis in light of epithelial-to-mesenchymal transition (EMT), myofibroblast differentiation and excessive collagen and other ECM proteins accumulation. Authors discuss the molecular basis of TGF-β activation by a number of mediators and its significance in lung fibrosis. The significance of proteoglycans and histone deacetylases in TGF-β-induced myofibroblast differentiation and fibrosis has also been discussed. In this article, Lasky and colleagues also summarized the present standing of various clinical trials for treatment of pulmonary fibrosis. The third article by Ellmers has reviewed the role of TGF-β signaling in cardiac fibrosis.The significance of Smad and non-Smad pathways as well as Renin-angiotensin system (RAS) in TGF-β signaling and in the development of cardiac fibrosis has been described....

Liver fibrosis, representing excessive accumulation of extracellular matrix (ECM) proteins including collagen, occurs in most types of chronic liver disease. Activated hepatic stellate cells (HSC) and portal fibroblasts have been identified as major collagen-producing cells in the injured liver. As a result of chronic liver damage, HSC undergo progressive activation to assume a proliferative and invasive phenotype. In addition to these mesenchymal cells, the liver's epithelial cells, hepatocytes, are involved in hepatic fibrogenesis. Altered transforming growth factor (TGF)-β signaling can promote hepatic fibrogenesis. TGF-β type I receptor and Ras-associated kinases differentially phosphorylate a mediator Smad3 to create distinct phosphorylated forms: C-terminally phosphorylated Smad3 (pSmad3C), linker phosphorylated Smad3 (pSmad3L), and both linker and C-terminally phosphorylated Smad3 (pSmad3L/C). While pSmad3C transmits a cytostatic TGF-β signal in mature hepatocytes, TGF-β signaling enhances growth of activated mesenchymal cells via a cyclin-dependent kinase 4-dependent pSmad3L/C pathway. On the other hand, pro-inflammatory cytokines transmit a fibrogenic signal in both hepatocytes and activated mesenchymal cells through a c-Jun N-terminal kinase-dependent pSmad3L pathway, which participates in deposition of ECM proteins. Linker phosphorylation of Smad3 indirectly prevents Smad3C phosphorylation, pSmad3C-mediated transcription, and the cytostatic effect of TGF-β upon hepatocytes. During progression of human chronic liver diseases, hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic pSmad3L pathway. This review summarizes Smad3 phosphoisoform-mediated signals, showing similarities and differences between hepatocytes and mesenchymal cells and emphasizing the fibrogenic function of hepatocytes in human chronic liver disease.

Pulmonary fibrosis is characterized by epithelial cell injury, accumulation of myofibroblasts, and excessive deposition of collagen and other extracellular matrix elements, leading to loss of pulmonary function. Studies in both humans and animal models strongly suggest that TGF-β1 plays a pivotal role in the pathogenesis of pulmonary fibrosis. This review will first give an overview of TGF-β signaling and the effects of its inhibition on lung fibrogenesis. This overview includes information on TGF-β signal transduction pathways, the importance of TGF-β in the accumulation of myofibroblasts, the role of TGF-β in epithelial injury and apoptosis, the role of TGF-β in extracellular matrix remodeling, and the effects of inhibiting TGF-β signaling in animal models of lung fibrosis. Subsequently this review will highlight recent advances in two areas of particular interest to our research group: (1) TGF-β and proteoglycans; (2) TGF-β and histone deacetylases. Although our understanding of the role of TGF-β and its mechanisms of action in lung fibrogenesis has increased dramatically in recent years, there is still much to be learned about this important molecule, especially how TGF-β function is modulated in vivo, and its complex interactions with other factors expressed during lung injury and repair. Research in these areas will help identify novel therapeutic targets for the treatment of pulmonary fibrosis that will hopefully improve the prognosis of this devastating illness.

Cardiac fibrosis occurs in response to numerous factors including ischemia, myocardial scarring after infarction, pressure overload of the heart, and a complex interplay of multiple hormonal systems. Transforming growth factor-beta (TGF-β) is a locally generated cytokine that participates in healing processes and tissue fibrosis following cardiac injury. TGF-β1 induces the proliferation of cardiac fibroblasts and their phenotypic transformation to myofibroblasts, and the deposition of extracellular matrix (ECM). This review examines current knowledge on TGF-β signal transduction pathways and the effects of TGF-β inhibition on the development of cardiac fibrosis. Improved understanding of the actions and signaling of this cytokine system may lead to the development of new therapeutic strategies that combat the development of myocardial fibrosis in the pathogenesis of heart failure.

Transforming growth factor-β (TGF-β) and its receptors are expressed in the kidney. The effects of TGF-β are mainly through activation of Smad pathways. In different pathophysiological situations such as development, immunomodulation, fibrosis and cell response, TGF-β interacts with other factors including angiotensin II, plasminogen activator inhibitor-1, connective tissue growth factor, integrins, and thymosin β4. Clinical studies have shown that specific polymorphisms of TGF-β genes and increased serum, urine and biopsied specimen levels are associated with human renal diseases. However, the effects of inhibition of TGF-β system are complex, depending on the injury type, disease stage and dosage of the inhibitor. Several animal studies have shown beneficial effects anti-TGF-β especially in chronic renal diseases, while data from clinical studies are still limited. In this review, current knowledge about the role of TGF-β system in the kidney and potential of strategies to modulate TGF-β for renoprotection are discussed.

During repair of connective tissue, resting fibroblasts become ‘activated’; that is, they migrate into the wound where they synthesize and remodel new extracellular matrix. The differentiated fibroblast responsible for this action is termed the myofibroblast, which expresses the highly contractile protein α—smooth muscle actin (α—SMA) and is responsible for the synthesis and remodeling of extracellular matrix (ECM). Persistence of the myofibroblast is a key characteristic of fibrotic diseases including scleroderma. Proteins such as transforming growth factorβ (TGFβ), endothelin-1 (ET- 1), connective tissue growth factor (CCN2/CTGF) and platelet derived growth factor (PDGF) are believed to contribute to myofibroblast differentiation and persistence. Moreover, it is now known that elevated adhesive and contractile signaling is a key feature of fibrotic fibroblasts. This review summarizes recent findings aimed at developing new, rationally-designed therapies for the fibrosis in scleroderma.