Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical d...Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.展开更多
Crohn’s disease(CD)is a chronic inflammatory bowel disease.Research has identified genetic predisposition and environmental factors as key elements in the development of the disease.However,the precise mechanism that...Crohn’s disease(CD)is a chronic inflammatory bowel disease.Research has identified genetic predisposition and environmental factors as key elements in the development of the disease.However,the precise mechanism that initiates immune activation remains undefined.One pathway for luminal antigenic molecules to enter the sterile lamina propria and activate an immune response is via transcytosis.Transcytosis,although tightly regulated by the cell,has the potential for transepithelial transport of bacteria and highly antigenic luminal molecules whose uncontrolled translocation into the lamina propria can be the source of immune activation.Viewed as a whole,the evidence suggests that unregulated intestinal epithelial transcytosis is involved in the inappropriate presentation of immunogenic luminal macromolecules to the intestinal lamina propria.Thus fulfilling the role of an early pre-morbid mechanism that can result in antigenic overload of the lamina propria and initiate an immune response culminating in chronic inflammation characteristic of this disease.It is the aim of this paper to present evidence implicating enterocyte transcytosis in the early etio-pathogenesis of CD.展开更多
文摘Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
文摘Crohn’s disease(CD)is a chronic inflammatory bowel disease.Research has identified genetic predisposition and environmental factors as key elements in the development of the disease.However,the precise mechanism that initiates immune activation remains undefined.One pathway for luminal antigenic molecules to enter the sterile lamina propria and activate an immune response is via transcytosis.Transcytosis,although tightly regulated by the cell,has the potential for transepithelial transport of bacteria and highly antigenic luminal molecules whose uncontrolled translocation into the lamina propria can be the source of immune activation.Viewed as a whole,the evidence suggests that unregulated intestinal epithelial transcytosis is involved in the inappropriate presentation of immunogenic luminal macromolecules to the intestinal lamina propria.Thus fulfilling the role of an early pre-morbid mechanism that can result in antigenic overload of the lamina propria and initiate an immune response culminating in chronic inflammation characteristic of this disease.It is the aim of this paper to present evidence implicating enterocyte transcytosis in the early etio-pathogenesis of CD.
