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Endocrine Abstracts (2014) 34 OC3.6 | DOI: 10.1530/endoabs.34.OC3.6

1MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh, UK; 2MRC/University of Edinburgh Centre for Inflammation Research, Edinburgh, UK; 3University of Manchester, Wellcome Trust Centre for Cell-Matrix Research, Manchester, UK.

Abdominal surgery and diseases such as endometriosis cause persistent abdominal adhesions leading to pelvic pain, infertility and in severe cases, bowel obstruction. Current treatments are ineffective and the aetiology is unclear, although excessive collagen deposition is a consistent feature. Lysyl oxidase (LOX) is a key enzyme required for crosslinking and deposition of insoluble collagen.

10–12 weeks old female C57Bl/6 mice (3–10 mice per group) were treated with 25 ng multiwalled carbon nanotubes (NT) as an i.p. insult to induce fibrosis, together with chemical (β-aminoproprionitrile – BAPN) or miRNA LOX inhibitors, progesterone (Prog) or dexamethasone (Dex) for up to 7 days. Fibrotic lesion area and Picrosirius red staining of the diaphragm, and mRNA expression of fibrosis-related genes in abdominal wall peritoneal mesothelial cells (PMC) were measured. Effects of BAPN and DEX on collagen fibre alignment were observed by transmission electron microscopy (TEM). Isolated PMC were cultured with and without interleukin 1α (IL1α) and Prog to determine effects on lox mRNA in vitro.

NT induced extensive fibrosis and collagen deposition on the diaphragm, that was significantly ameliorated by BAPN, LOX miRNA, Prog or Dex. BAPN and Dex disrupted ordered collagen fibre bundles induced by NT as observed by TEM. Expression of lox, col1a1, col3a1 and bmp1 mRNA in abdominal wall PMC were all significantly increased by NT, but this effect was inhibited by treatment for up to 7 days with Prog or Dex. Physiological levels of Prog significantly inhibited IL1α induced lox expression by PMC in vitro.

Our results suggest targeting of LOX in the peritoneum may ameliorate fibrosis and the development of adhesions, and point to simple, naturally occurring or widely used steroids as potential agents to prevent adhesion formation following abdominal surgery.

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