Selective Blocking of TNF Receptor 1 Attenuates Peritoneal Dialysis Fluid Induced Inflammation of the Peritoneum in Mice

• Published in: PloS one 2016-10, Vol.11 (10), p.e0163314-e0163314
• Main Authors: Kälble, Florian, Damaske, Janine, Heide, Danijela, Arnold, Iris, Richter, Fabian, Maier, Olaf, Eisel, Ulrich, Scheurich, Peter, Pfizenmaier, Klaus, Zeier, Martin, Schwenger, Vedat, Ranzinger, Julia
• Format: Article
• Language: English
• Subjects: Acids; Analysis; Animals; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - immunology; Arthritis; Autoimmune diseases; Binding sites; Biology; Biology and Life Sciences; CA-125 Antigen - blood; Cancer; Collagen; Collagen - metabolism; Dialysis; Disease; Disease Models, Animal; Engineering and Technology; Enzyme-Linked Immunosorbent Assay; Genetic engineering; Glucose; Granulocytes - cytology; Granulocytes - metabolism; Health aspects; Hyaluronic acid; Hyaluronic Acid - metabolism; Immunology; Inflammation; Inflammation - prevention & control; Leukocytes (granulocytic); Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monoclonal antibodies; Nephrology; Neurosciences; Peritoneal Dialysis; Peritoneum; Peritoneum - metabolism; Peritoneum - pathology; Receptors; Receptors, Tumor Necrosis Factor, Type I - immunology; Receptors, Tumor Necrosis Factor, Type I - metabolism; Receptors, Tumor Necrosis Factor, Type II - immunology; Receptors, Tumor Necrosis Factor, Type II - metabolism; Research and Analysis Methods; Side effects; Signaling; Structure-function relationships; Transgenic mice; Tumor necrosis factor; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Tumors; Ultrafiltration
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0163314

Chronic inflammatory conditions during peritoneal dialysis (PD)-treatment lead to the impairment of peritoneal tissue integrity. The resulting structural and functional reorganization of the peritoneal membrane diminishes ultrafiltration rate and thereby enhances mortality by limiting dialysis effectiveness over time. Tumour necrosis factor (TNF) and its receptors TNFR1 and TNFR2 are key players during inflammatory processes. To date, the role of TNFR1 in peritoneal tissue damage during PD-treatment is completely undefined. In this study, we used an acute PD-mouse model to investigate the role of TNFR1 on structural and morphological changes of the peritoneal membrane. TNFR1-mediated TNF signalling in transgenic mice expressing human TNFR1 was specifically blocked by applying a monoclonal antibody (H398) highly selective for human TNFR1 prior to PD-treatment. Cancer antigen-125 (CA125) plasma concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Western blot analyses were applied to determine TNFR2 protein concentrations. Histological staining of peritoneal tissue sections was performed to assess granulocytes within the peritoneal membrane as well as the content of hyaluronic acid and collagen. We show for the first time that the number of granulocytes within the peritoneal membrane is significantly reduced in mice pre-treated with H398. Moreover, we demonstrate that blocking of TNFR1 not only influences CA125 values but also hyaluronic acid and collagen contents of the peritoneal tissue in these mice. These results strongly suggest that TNFR1 inhibition attenuates peritoneal damage caused by peritoneal dialysis fluid (PDF) and therefore may represent a new therapeutic approach in the treatment of PD-related side effects.