Affiliation:
1. Department of Experimental Biology, Faculty of Sciences Masaryk University Brno Czech Republic
2. International Clinical Research Center St. Anne's University Hospital Brno Czech Republic
3. Department of Biophysics of Immune System Institute of Biophysics of the Czech Academy of Sciences Brno Czech Republic
4. Contipro a.s. Dolni Dobrouc Czech Republic
Abstract
AbstractPeritoneal adhesions are postsurgical fibrotic complications connected to peritoneal inflammation. The exact mechanism of development is unknown; however, an important role is attributed to activated mesothelial cells (MCs) overproducing macromolecules of extracellular matrix (ECM), including hyaluronic acid (HA). It was suggested that endogenously‐produced HA contributes to the regulation of different fibrosis‐related pathologies. However, little is known about the role of altered HA production in peritoneal fibrosis. We focused on the consequences of the increased turnover of HA in the murine model of peritoneal adhesions. Changes of HA metabolism were observed in early phases of peritoneal adhesion development in vivo. To study the mechanism, human MCs MeT‐5A and murine MCs isolated from the peritoneum of healthy mice were pro‐fibrotically activated by transforming growth factor β (TGFβ), and the production of HA was attenuated by two modulators of carbohydrate metabolism, 4‐methylumbelliferone (4‐MU) and 2‐deoxyglucose (2‐DG). The attenuation of HA production was mediated by upregulation of HAS2 and downregulation of HYAL2 and connected to the lower expression of pro‐fibrotic markers, including fibronectin and α‐smooth muscle actin (αSMA). Moreover, the inclination of MCs to form fibrotic clusters was also downregulated, particularly in 2‐DG‐treated cells. The effects of 2‐DG, but not 4‐MU, were connected to changes in cellular metabolism. Importantly, the inhibition of AKT phosphorylation was observed after the use of both HA production inhibitors. In summary, we identified endogenous HA as an important regulator of peritoneal fibrosis, not just a passive player during this pathological process.
Funder
Institute of Biophysics of the Czech Academy of Sciences
European Regional Development Fund
Subject
Clinical Biochemistry,Molecular Medicine,General Medicine,Biochemistry