The Effects of Matriptase Inhibition on the Inflammatory and Redox Homeostasis of Chicken Hepatic Cell Culture Models

Abstract

The function of the transmembrane serine protease matriptase is well described in mammals, but it has not been elucidated in avian species yet. Hence, the aim of the present study was to assess the effects of the 3-amidinophenylalanine (3-AphA)-type matriptase inhibitors MI432 and MI460 on the inflammatory and oxidative state of chicken primary hepatocyte mono-cultures and hepatocyte–nonparenchymal cell co-cultures, the latter serving as a proper model of hepatic inflammation in birds. Cell cultures were exposed to MI432 and MI460 for 4 and 24 h at 10, 25, and 50 µM concentrations, and thereafter the cellular metabolic activity, extracellular interleukin (IL-)6, IL-8, H2O2 and malondialdehyde concentrations were monitored. Both inhibitors caused a transient moderate reduction in the metabolic activity following 4 h exposure, which was restored after 24 h, reflecting the fast hepatic adaptation potential to matriptase inhibitor administration. Furthermore, MI432 triggered an intense elevation in the cellular proinflammatory IL-6 and IL-8 production after both incubation times in all concentrations, which was not coupled to enhanced oxidative stress and lipid peroxidation based on unchanged H2O2 production, malondialdehyde levels and glutathione peroxidase activity. These data suggest that physiological matriptase activities might have a key function in retaining the metabolic and inflammatory homeostasis of the liver in chicken, without being a major modulator of the hepatocellular redox state.

Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 Isoenzyme

“…In our previous studies using intestinal epithelial cells (HIEC and IPEC-J2) and primary human hepatocytes (PHH), it was proven that administration of two 3-amidinophenylalanine analogues, such as inhibitors MI-1900 and MI-1907, up to a concentration 50 µM did not cause significant cell death, and also did not result in elevation in extracellular hydrogen peroxide levels in intestinal epithelial cells [23,24]. Similarly, redox homeostasis of a chicken hepatic cell model exposed to MI-460 and MI-432 was only transiently disturbed, and then was almost completely compensated after 24 h [25].…”

Comparative cryopreservation of bovine and porcine primary hepatocytes

“…Moreover, they are utilized in medical, pharmaceutical and toxicological applications thereby replacing or, at least, reducing in vivo studies (1,2). Basic and applicationrelated research is also performed by use of hepatocytes isolated from farm animals, especially pig and chicken (2)(3)(4). As hepatocytes derived from cattle are seldomly used in research studies, our group established a model of primary bovine hepatocytes in monoculture and in coculture with other hepatic cells to reduce this gap (5)(6)(7).…”