Innate immune system and adipose tissue role and, pharmacological characterization of pentoxifylline in hepatic inflammation

Author(s)

Simone Coghetto Acedo Batista

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2015-06-23

Examining board members

Alessandra Gambero; Dennys Esper Cintra; Patrícia de Oliveira Prada; Lila Missae Oyama; Maria Lucia Cardillo Corrêa Giannella

• Advisor: Alessandra Gambero

Abstract

Nonalcoholic steatohepatitis (NASH) is an inflammatory disease in which excess fat accumulates in the liver and it is usually associated with obesity. Innate immue cells attraction to the liver is an important factor to the beginning and progression of the disease, as well as, unbalanced production of adipokines and also intestinal endotoxins translocation. Pentoxifylline (PTX) shows benefits in alcoholic steatohepatitis patients, suggesting that it could also be useful for NASH. Thus, this project aims to evaluate the hepatic infiltrate of innate immune cells in an obesity model, induced by high fat diet (HFD) and a NASH model, induced by an isocaloric high fructose diet (IHFD), correlating to time/alterations in adipokine production and lipopolysaccharide (LPS) absorption, besides PTX actions as a therapeutic option for the treatment of NASH. C57BL/6 male mice received DH, IHFD and normal diet (ND) during 1, 6, 12 and 24 weeks. Swiss mice received HFD and ND during 12 and 24 weeks and they were treated with PTX 100 mg/kg/day in the last 14 days. Only HFD fed mice were obese. Fasting glucose disturbs were observed since 6 weeks of HFD groups, coinciding with increasing in inflammatory cells infiltrate in the adipose tissue (AT) (macrophages, dendritic cells and natural killer) and proinflammatory adipokines production, with increasing in inflammatory cells infiltration in the liver (neutrophils and macrophages), macrosteatosis and high AST serum levels. In IHFD, only after 24 weeks it was registered glycemic disturb, but microsteatosis, liver inflammatory infiltrate cells (neutrophils and macrophages), high LPS portal levels and increasing in serum AST levels were early observed. In these NASH experimental models there was no fibrosis and the initial hepatic infiltrate of neutrophils and macrophages was substituted later (24 weeks) by dendritic cells (DC) and natural killer (NK). The chemokines, chemokines receptors and cytokines gene expression in the liver is increased right after the diets introduction (1 week), but serum levels of some cytokines were clearly observed in intermediated IHFD group (12 weeks), while in HFD groups these changes had occurred in week 1. PTX use, in NASH models induced by HFD, showed a reduction in steatosis, in TNF-? hepatic production, but not in glycemic control and/or reduction in adiposity and weight of the animals. As a conclusion, in an NASH model associated with obesity, the hepatic infiltrate of immune cells occurs in parallel to the establishment of inflammation in the AT, but in the NASH model induced by IHFD the liver inflammatory cells infiltrated is correlated with high LPS portal levels. Although there is not inflammation in AT, the IHFD was able to set a systemic inflammation, as described in obesity. In both models, the inflammatory cells infiltrate in the liver is initially composed by neutrophils and macrophages and substituted by DC and NK. PTX seems to be a therapeutic option to NASH in obese patients concomitant with other approaches, because there is not any metabolic improvement (AU)

• FAPESP's process: 11/00518-4 - Hepatic inflammation: role of inate immune system and adipose tissue and, pharmacologycal characterization of toll-like receptors and penthoxyphylline.
• Grantee: Simone Coghetto Acedo Batista
• Support Opportunities: Scholarships in Brazil - Doctorate