NASH Target Development Service for Inflammation

Both basic and further clinical researches have established that innate immune activation plays an important role in triggering and amplifying hepatic inflammation in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). Indeed, current knowledge opens the possibility of designing new potential therapies to improve current treatments. At present, Creative Biolabs provides novel therapeutic strategies targeting inflammation aimed at modulating related inflammatory signaling pathways based on our drug discovery platform for the treatment of NASH.

Inflammation and NASH

Inflammation, hepatocyte injury, and death are the hallmarks of NASH. Innate immune activation is a critical factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. The pathology of NASH involves a complex network of mechanisms, including increased infiltration of different subsets of immune cells, such as T-lymphocytes, monocytes and neutrophils, to the liver, as well as activation and in situ expansion of liver resident cells such as Kupffer cells or stellate cells. The inducement of liver inflammation may come from outside the liver (such as adipose tissue or intestinal tract) or inside the organs (such as adipose toxicity, innate immune response, cell death pathway, mitochondrial dysfunction, and endoplasmic reticulum stress), both of which contribute to the development of NASH. Regulating these inflammatory signaling pathways may be a potential new therapeutic strategy for NASH.

Fig.1 The role of immune cells in NASH development. (Nati, 2016)

• Inflammasome Inhibitors
  Inflammasomes, critical molecular regulators that play important roles in inflammation, consist of a central protein, an adaptor protein ASC (apoptosis speck-like protein) and a caspase-1 protein. NLRP3 is the most extensively studied inflammasome. The NLRP3 inflammasome is an intracellular multiprotein complex involved in the production of mature interleukin 1-beta (IL-1β) and induces metabolic inflammation. It has been recently demonstrated to play a crucial role in the progression of NASH. NLRP3 inflammasome activation can lead to NAFLD development and progression, including hepatic steatosis, inflammation, liver injury, and fibrogenesis. It was revealed that inhibition of the NLRP3 inflammasome in a mouse model of NASH reduces hepatic inflammation and liver fibrosis. Thus, NLRP3 inflammasome may serve as a novel therapeutic target for the treatment of NASH. Currently, several other inflammasome inhibitors, such as apoptosis signal-regulating kinase-1 (ASK-1) inhibitors, NF-κB inhibitors, ERK inhibitors, and the MAP kinases inhibitors are also under actively assessed for the NASH therapy and showing promising therapeutic effect.

Fig.2 Novel therapeutic strategies targeting ASK1 in NASH. (Schuster, 2017)

• Chemokine Antagonists
  Chemokines are small secretory proteins that regulate inflammation, leukocyte migration, tissue fibrosis, tissue remodeling, and angiogenesis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, hepatic stellate cells, Kupffer cells, endothelial cells, and circulating immune cells. Given that inflammation is a critical factor for the transition from simple steatosis to NASH, and fibrosis, the chemokine system may play a prominent role in the pathogenesis of NAFLD/NASH. Accumulating evidence shows elevated expression of chemokines and their receptors in the livers of obese patients with advanced steatosis and NASH. Actually, using chemokine or its receptor antagonists as anti-inflammatory therapies holds promise as a therapy for the treatment of NASH.
• Targeting Inflammation Resolution
  Inflammation is a key pathogenic feature of NASH. The resolution of steatohepatitis and advanced fibrosis is a clinically relevant therapeutic target for NASH treatment. The mechanism responsible for terminating the inflammatory response is being actively investigated as a potential anti-inflammatory pharmacological target. The regression of acute inflammation is coordinated by many proteins and arachnoid acids, which can down-regulate the recruitment of white blood cells, promote the clearance of white blood cells and DAMP and/or PAMPs, and transform macrophages from M1 to M2 phenotypes, thus facilitating tissue healing. Among these pro-degrading factors, defective annexin A1 (AnxA1), resolvin D1 (RvD1) and pentoxifylline (PTX) activities are involved in the pathogenesis of inflammation and fibrosis in NASH.

Understanding the inflammatory cell mediators and pathways is important for designing therapies to intervene in disease progression. With the increasing prevalence of NASH, the development of effective pharmaceutical approaches becomes very important. Creative Biolabs now provides different strategies targeting inflammation. If you are interested in the development services we provide, please don’t hesitate to contact us for more information.

References

1. Nati, M.; et al. The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH). Reviews in Endocrine and Metabolic Disorders. 2016, 17(1): 29-39.
2. Schuster, S.; Feldstein, A. E. NASH: Novel therapeutic strategies targeting ASK1 in NASH. Nature Reviews Gastroenterology & Hepatology. 2017, 14(6): 329.