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Ocular surface as mucosal immune site
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Rachel R. Caspi, Anthony St. Leger
Data from conjunctival biopsies reveal an increase in CD4+ T cells and DCs in the epithelium and activated IL-2R-bearing T cells (CD4+ and CD8+), macrophages, and B cells in the stroma. An increase in IL-17-producing cells has also been reported. TH2 cells are present and may amplify the fibrotic process through production of cytokines, such as IL-13, that stimulate resident fibroblasts to produce profibrotic cytokines, such as TGF-β, platelet-derived growth factor, basic fibroblast growth factor, and connective tissue growth factor, all of which are increased in the conjunctiva. All of these contribute to indirect fibrogenesis, which can then lead to fibrosis and disease.
Liver Function Tests in the Differential Diagnosis of Hepatotoxicity
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
A new noninvasive RIA test has recently been developed for use in humans to detect the fibrotic activity present in cirrhotic liver. The presence and amount of liver fibrosis is easily established through biopsy of the liver, but proves to detect the level of fibrogenesis have been previously lacking in our diagnostic armamentarium.
Sclerotherapy Of Esophageal Varices
Published in John P. Papp, Endoscopie Control of Gastrointestinal Hemorrhage, 2019
Recurrent hemorrhage is one of the parameters that help to estimate the efficacy of therapeutic procedures for variceal bleeding. Minor rebleeds occurred in 23.8% within the primary admission period, and 80% occurred after the first treatment and were easily controlled by repeated sclerotherapy. As one procedure is not sufficient to induce adequate fibrogenesis, this is to be expected when primary treatment is not complete. About 6% of patients rebled within the next four months, 18.8% at some time later in their follow-up, therefore, examinations are crucial in detecting recurrent varices; 40% of all patients were subjected to repeated injections after four months, 40% after one year, while in the remaining 20%, primary sclerotherapy had efficiently covered the portal-systemic collaterals for 2 to 5 years.
Drug development of nonalcoholic fatty liver disease: challenges in research, regulatory pathways, and study endpoints
Published in Expert Opinion on Drug Discovery, 2021
Albert Do, Ysabel C. Ilagan-Ying, Wajahat Z. Mehal, Joseph K. Lim
Our current knowledge of NASH pathogenesis stems from an understanding that it results from multifactorial disease mechanisms, rather than from a single disease pathway. This complexity has led to a wide range of drugs in development with various disease targets. Specific molecular treatment targets are beyond the scope of this review, but in brief, some treatment pathways being targeted include excess fatty acid delivery to the hepatocyte, excess hepatic triglyceride production through de novo lipogenesis, insulin resistance as promoter of hepatic steatosis, the inflammatory response from lipotoxic lipids, an altered intestinal microbiome, and extracellular matrix deposition resulting in fibrosis [15,16]. Of these, fibrosis has been identified as the most important indicator of disease progression and predictor of liver-associated outcomes including cirrhosis, liver cancer, and mortality [17–19]. However, fibrogenesis is the result of multiple processes, each of which could represent a therapeutic target [15].
Advances in the clinical use of collagen as biomarker of liver fibrosis
Published in Expert Review of Molecular Diagnostics, 2020
Steffen K. Meurer, Morten A. Karsdal, Ralf Weiskirchen
The hallmark of liver fibrosis is the formation and deposition of excess fibrous connective tissue, leading to progressive architectural tissue remodeling [14,15]. Although the triggering factors of hepatic fibrosis are manifold (genetic disorders, viral infection, alcohol abuse, autoimmune attacks, metabolic disorders, cholestasis, venous obstruction, parasite infections, and others), the principal mechanisms leading to the onset of fibrogenesis are the same. The pathological sequence of fibrosis is initiated by parenchymal cell destruction that induces an inflammatory response, in which non-parenchymal cells and resident immune cells are triggered to release a large variety of inflammatory and pro-fibrogenic mediators within the liver tissue [16]. This in turn provokes the activation of hepatic stellate cells (HSC) that transit to matrix-producing myofibroblasts (MFB) [14,15]. At the same time, it comes to proliferation of the bile ducts and elevated production and deposition of different collagen types in the space of Disse, liver parenchyma, and the portal tracts Figure 1.
Current and emerging pharmacotherapeutic interventions for the treatment of liver fibrosis
Published in Expert Opinion on Pharmacotherapy, 2020
Joeri Lambrecht, Leo A. van Grunsven, Frank Tacke
Although its important contribution to the current burden of health, no clinically approved direct anti-NAFLD pharmacological treatment is available. When patients with NAFLD/NASH undergo significant lifestyle changes or bariatric surgery, fibrosis resolution, and overall improvement of the patient outcome is regularly observed [9,10]. However, only a small fraction of patients is able to achieve relevant and durable lifestyle modifications (such as weight loss ≥ 10%) [9]. Moreover, the beneficial effects of these etiology-specific interventions strongly decline in the advanced stages of liver fibrosis and are often too slow to prevent important complications. Additionally, they cannot prevent disease progression during the end-stages of liver disease [1]. Therefore, several novel pharmacotherapeutic approaches are being evaluated, which have an inherent anti-fibrotic mechanism. As fibrogenesis is a general phenomenon during chronic liver disease, such anti-fibrotic therapeutics would thus rely on etiology-independent mechanisms of action. Additionally, anti-fibrotic drugs may obtain efficacy by targeting fibrosis-perpetuating and initiating mechanisms such as inflammation, injury-induced signaling cascades, and the gut-liver axis. This review provides an update of the recent advances in the pharmacological therapy of liver fibrosis.