Pathogenesis of Liver Injury

Acute and chronic liver injuries are everyday occurrences in clinical practice. Indeed, monitoring, surveillance, and screening for liver disease by measuring serum aminotransferase values are standards of care. Despite the widespread recognition of the importance of liver injury in human health, the mechanisms underlying liver injury remain complex and incompletely understood. However, considerable progress has been made recently in understanding the pathogenesis of liver injury. This emerging information has spurred several biotech and large pharmaceutical companies to develop and test hepatoprotective and antifibrogenic agents. Given the rapid expansion of our knowledge on the pathogenesis of liver injury, which is being translated into potential therapeutic approaches, it is both timely and topical to review the pathogenic mechanisms of liver injury. Therefore, this issue of Seminars in Liver Disease is devoted to this topic.

In the first article, Akazawa and Gores review the role of death receptors in mediating liver injury. The liver is uniquely susceptible to death receptor-mediated apoptosis. For example, stimulation of the Fas death receptor in animals leads to acute and massive liver injury followed by death. These authors have nicely highlighted the signaling cascades involved in death receptor-induced apoptosis by distinguishing the pathways for each receptor. More importantly, they have diligently reviewed the literature and highlighted the role of death receptor-mediated cell death in a variety of human liver diseases. The current data suggest death receptor-mediated apoptosis is a critical feature of viral hepatitis, alcohol-induced liver disease, nonalcoholic steatohepatitis, and cholestatic liver diseases. Alternatively, it would also appear that induction of stellate cell apoptosis is a potential antifibrogenic strategy in the treatment of human liver diseases. The authors highlight all these emerging concepts with a focus on translational research in human liver diseases. This contribution helps set the background for the remainder of the issue, which deals with more specific mechanisms of liver injury.

In the second article, Szabo, Mandrekar, and Dolganiuc focus on the innate immune response in hepatic inflammation. There is growing evidence from developmental models that the liver is an integral component of the innate immune system. It is not surprising, therefore, that the innate immune response plays a critical and fundamental mechanism in the pathogenesis of liver injury. Szabo and coworkers review the definition of the innate immune system and its mechanism of activation. In particular, they focus on the role of toll-like receptors in activating and controlling the innate immune system. Our current understanding of these receptors, ligands, and signaling pathways is carefully delineated, especially to the role of toll-like receptor 4. This receptor appears to play a critical role in mediating liver injury and hepatic fibrogenesis. Mechanisms that turn off toll-receptor signaling would appear to be a fruitful area for hepatoprotection.

In addition to a prominent role of the innate immune system of liver injury, the liver is also a target of the adaptive immune response. The adaptive immune response is mediated by T and B cells. In this third article, Eksteen, Afford, Wigmore, Holt, and Adams carefully review the mechanisms for activating the adaptive immune system. The processes of antigen recognition are outlined. The complex interplay between T-cell subsets, regulatory T cells, dendritic cells, and B cells, is nicely emphasized. In addition, these experts provide insight into how the adaptive immune response mediates a variety of human liver diseases, including viral hepatitis. The interplay between the innate and adaptive immune responses is also appraised. A critical role for CD40 in mediating hepatic damage is brought to light as well as the significant role of adhesion molecules.

More recently, the endoplasmic stress pathway and its importance in mediating cellular injury have become recognized. The endoplasmic reticulum (ER) plays an important role in protein folding. Misfolded proteins induce the unfolded protein response pathway. These processes are very sensitive to oxidative stress and cellular concentrations of redox reactive molecules. This is a complex pathway that, when triggered, activates a series of important transcription factors with diverse gene targets. Given the critical role of the liver in protein synthesis, it is not surprising that it is sensitive to damage by the ER stress pathway. Kaplowitz, Than, Shinohara, and Ji review our current understanding of the ER stress pathway. They highlight its likely importance in mediating alcohol-induced liver injury. This is a very timely and topical contribution written by a team of investigators on the cutting edge of this new aspect of pathobiology.

It has long been recognized that oxidative stress plays a critical role in mediating liver injury. Indeed, markers of oxidative stress, such as oxidative DNA damage, are universal in human liver diseases. Nonetheless, the mechanisms by which oxidative stress induces liver injury have remained controversial and incompletely understood. Czaja has been a pioneer in demonstrating that oxidative stress induces activation of stress kinases, which in turn mediate posttranslational responses, activation of transcription factors, and gene expression profiles with adverse consequences for the cell. For example, c-Jun-terminal kinase is now recognized to be a major mediator of cell death and injury when its activation is sustained or prolonged. Oxidative stress is one mechanism by which this kinase is turned on, with detrimental consequences. All of these mechanisms and their potential as therapeutic targets are nicely reviewed by this expert investigator.

Oftentimes, the role of the vascular system in liver pathobiology is neglected. Although heterogeneous disturbances in portal blood flow have profound consequences on organ function and dysfunction, limited information on the hepatic microvascular system exists in hepatic injury syndromes. DeLeve underscores the role of the sinusoidal endothelial cell in maintaining structure and function of the liver. She reviews several instances in which these cells are the primary targets of drugs, pharmacological agents, and other pathophysiological disturbances. The consequence of sinusoidal endothelial cell function on disrupting global hepatic function is emphasized; more importantly, in a provocative manner, she suggests that perhaps alterations in hepatic microvasculature may be the initial stimulus for hepatic fibrogenesis. This is a very interesting contribution with profound implications-an area of investigation that clearly merits further work.

The cholangiopathies are a group of liver disturbances characterized by disturbances in bile duct epithelial cell function and structure. These epithelial cells are referred to as cholangiocytes. Indeed, cholangiocyte pathobiology contributes to diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, polycystic liver diseases, and cholangiocarcinoma. Xia and coworkers review the mechanisms by which cholangiocytes participate in inflammatory disorders, undergo cell death, and lead to syndromes characterized by impairment in bile flow. This is a very important article as diseases targeting cholangiocytes are common in clinical practice, are difficult to treat, and have devastating consequences. Xia and colleagues emphasize multiple cellular and molecular processes in these diverse diseases. This article is a must-read for those interested in the cholangiopathies.

The most nefarious consequence of liver injury is hepatic fibrogenesis. Hepatic fibrogenesis culminates in the syndrome of cirrhosis, portal hypertension, and the sequela of end-stage liver disease. It is now recognized that hepatic stellate cells, when transformed to myofibroblasts, are the primary source of collagens type I and III in the diseased human liver. Guo and Friedman are experts in hepatic stellate cell biology. The controversies regarding the source of these cells and their different subtypes are described. The cellular and molecular mechanisms responsible for the activation of these cells, including cytokines, reactive oxygen species, alterations in the liver matrix, and engulfing of apoptotic bodies, are thoroughly captured by this state-of-the-art article. Appropriate approaches to turn off these cells are evident from an understanding of the mechanisms by which they are “turned on.” This article integrates the multiple mechanisms of liver injury including the innate immune response, the adaptive immune response, reactive oxygen species, and death receptors into this final common pathway of hepatic fibrogenesis. This is an exciting article, and one that will provide an encyclopedic-type foundation for understanding this important area of liver pathobiology.

In summary, this issue of Seminars in Liver Disease addresses a timely and topical area of research. Most importantly, we believe that this issue of Seminars in Liver Disease will stir further investigation. It is anticipated that in the future, a wide variety of therapeutic approaches will be predicated upon our understanding of these mechanisms of liver injury. The advent of such hepatoprotective and antifibrogenic agents will hopefully have a significant impact on public health in the future.