Catálogo de publicaciones - libros

Currently, hepatic fibrogenesis is viewed as a dynamic process strictly related to the extent and duration of liver injury. Activated hepatic stellate cells (HSCs) are identified as the major source of extracellular matrix components in the injured liver, and are regarded as a target for antifibrogenic therapy. In addition, transforming growth factor-β (TGF-β) is recognized as a key fibrogenic cytokine produced by Kupffer cells and HSCs. There are several approaches to inhibit TGF-β; use of soluble receptors and gene therapy approaches. Hepatocyte growth factor is a hepatotrophic factor for liver regeneration and appears to suppress hepatic fibrogenesis in animals. HOE 77 and S 4682 are inhibitors of prolyl 4-hydroxylase, which is essential for collagen formation. α-Tocopherol and silybinin reduce lipid peroxidation and attenuate HSC activation in experimental models. Silymarin is extracted from milk thistle, the principle component of which is silybinin. Unfortunately, they have had mixed effects in human liver diseases. A Japanese herbal medicine Sho-saiko-to functions as a potent fibrosuppressant via the inhibition of oxidative stress in hepatocytes and HSCs. Its active components are baicalin and baicalein of flavonids with chemical structures very similar to silybinin.

Understanding the cellular and molecular mechanisms underlying hepatofibrogenesis provides valuable information on the search for effective antifibrogenic therapies.

Reversibility of liver fibrosis has been reported both experimentally and clinically, if the cause of liver damage is removed or adequately treated. We first reported the collagenase activity in the process of experimental liver fibrosis in 1974. The present review discusses the participation of matrix metalloproteinases (MMPs), especially MMP-1/MMP-13, in the spontaneous resolution of liver fibrosis, in association with tissue inhibitor of MMPs (TIMPs). A recent advance in molecular biology has revealed the important role of MMPs and TIMPs in the recovery from liver fibrosis and cirrhosis. In situ hybridization study showed that some stem/progenitor cells expressing MMP-13 mRNA may play an important role in the recovery from liver cirrhosis, and these cells were determined to be neural cells by us to be neural origin. Transfusion of stem cells derived from bone marrow will be applied to patients with liver cirrhosis in near future. Suitable conditions to make stem cells proliferate and differentiate for the expression of MMP-13 should be developed.

Cell death by apoptosis is an active process of cell removal that is initiated and regulated by activation of specific enzymes and signaling molecules. In contrast to necrotic cell death, apoptotic cell death holds the potential for therapeutic manipulation. Recent studies document important roles for apoptosis in both normal and pathological processes, ranging from embryonic development to tissue scarring. Apoptosis is thought to help reduce inflammation by the selective removal of inflammatory cells and to help change fibroproliferative mass into an acellular scar tissue by deleting cellular components. Our understanding of the mechanisms of cell-specific apoptosis during various pathophysiological processes show the opportunity to modulate the rate of apoptosis in a cell type-specific manner, to delay or suppress the progression of such immunoinflammatory diseases as pulmonary fibrosis and formations of pathologic scar tissue. We will briefly present the possible mechanisms of apoptotic cell death and their impact on the formation of fibrotic mass.

Pulmonary fibrosis is a common response to various insults or injuries to the lung. Although there are various initiating factors or causes, the terminal stages are characterized by proliferation and progressive accumulation of connective tissue replacing normal functional parenchyma. Conventional therapy consisting of glucocorticoids or immunosuppressive drugs is usually ineffective in preventing progression of the disease. Further understanding of the molecular mechanisms of endothelial and epithelial cell injury, inflammatory reaction, fibroblast proliferation, collagen deposition and tissue remodeling, should lead to the development of effective treatments against pulmonary fibrosis. An overview is presented regarding each of pathogenic events in pulmonary fibrosis, especially the role of apoptosis and its clinical potentials, which have emerged from the animal models and human tissue studies.

Silicosis continues to be a lung disease with significant morbidity and mortality. Although silica-induced lung injury and cell activation and/or death have been investigated over the past several years, basic research continues to reveal the cell: cell and cell: mediator interactions critical to these events. This chapter will emphasize the production and participation of several inflammatory cytokines, mediators and cell processes in the development of silica-induced lung injury and fibrosis. Mediators to be discussed will include TNFα, IFNγ, IL-1β, IL-12, IL-18, IL-9, TGFβ, MMPs/TIMPs, ROS/RNS, caspases and Fas/FasL in the processes of cell activation, cell proliferation and cell death. The mediator networks and apoptotic pathways elicited by this inorganic particle are complex, driven by many cell types and affect numerous cell functions. Understanding these interactions will help in developing strategies for therapeutic intervention at different stages of the disease.