Targeting lysyl oxidase reduces peritoneal fibrosis

• Published in: PloS one 2017-08, Vol.12 (8), p.e0183013
• Main Authors: Harlow, Christopher R, Wu, Xuan, van Deemter, Marielle, Gardiner, Fiona, Poland, Craig, Green, Rebecca, Sarvi, Sana, Brown, Pamela, Kadler, Karl E, Lu, Yinhui, Mason, J Ian, Critchley, Hilary O D, Hillier, Stephen G
• Format: Article
• Language: English
• Subjects: Abdomen; Abdominal Cavity - surgery; Abdominal wall; Aminopropionitrile - pharmacology; Animals; Biology and Life Sciences; Bone morphogenetic protein 1; Collagen; Collagen (type I); Collagen - antagonists & inhibitors; Collagen - genetics; Collagen - metabolism; Crosslinking; Deposition; Dexamethasone; Dexamethasone - pharmacology; Diaphragm; Diaphragm (anatomy); Epithelium - drug effects; Epithelium - metabolism; Epithelium - pathology; Extracellular Matrix Proteins - antagonists & inhibitors; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Fibrosis; Gene Expression; Granulomas; Humans; In vitro methods and tests; Infertility; Inflammation; Inhibition; Interleukin; Interleukin 1; Interleukin-1alpha - pharmacology; Intestine; Laparoscopy; Lesions; Life sciences; Liquid oxygen; Lysine; Lysyl oxidase; Medical research; Medical schools; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular Targeted Therapy; mRNA; Multi wall carbon nanotubes; Nanotechnology; Nanotubes; Nanotubes, Carbon - toxicity; Oxidase; Pain; Peritoneal Fibrosis - chemically induced; Peritoneal Fibrosis - genetics; Peritoneal Fibrosis - pathology; Peritoneal Fibrosis - prevention & control; Peritoneum; Physical Sciences; Prevention; Primary Cell Culture; Progesterone; Progesterone - pharmacology; Protein-Lysine 6-Oxidase - antagonists & inhibitors; Protein-Lysine 6-Oxidase - genetics; Protein-Lysine 6-Oxidase - metabolism; Reproductive health; Research and Analysis Methods; RNA, Messenger - genetics; RNA, Messenger - metabolism; Steroid hormones; Steroids; Surgery; Tissue Adhesions - chemically induced; Tissue Adhesions - genetics; Tissue Adhesions - pathology; Tissue Adhesions - prevention & control
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0183013

Abdominal surgery and disease cause persistent abdominal adhesions, pelvic pain, infertility and occasionally, 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, so we investigated whether targeting Lox might be an approach to reduce abdominal adhesions. Female C57Bl/6 mice were treated intraperitoneally with multiwalled carbon nanotubes (NT) to induce fibrosis, together with chemical (ß-aminoproprionitrile-BAPN) or miRNA Lox inhibitors, progesterone or dexamethasone. Fibrotic lesions on the diaphragm, and expression of fibrosis-related genes in abdominal wall peritoneal mesothelial cells (PMC) were measured. Effects of BAPN and dexamethasone on collagen fibre alignment were observed by TEM. Isolated PMC were cultured with interleukin-1 alpha (IL-1α) and progesterone to determine effects on Lox mRNA in vitro. NT-induced fibrosis and collagen deposition on the diaphragm was ameliorated by BAPN, Lox miRNA, or steroids. BAPN and dexamethasone disrupted collagen fibres. NT increased PMC Lox, Col1a1, Col3a1 and Bmp1 mRNA, which was inhibited by steroids. Progesterone significantly inhibited IL-1α induced Lox expression by PMC in vitro. Our results provide proof-of-concept that targeting peritoneal Lox could be an effective approach in ameliorating fibrosis and adhesion development.