Targeting lysyl oxidase reduces peritoneal fibrosis.

Autor: Harlow CR; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Wu X; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., van Deemter M; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Gardiner F; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Poland C; MRC/University of Edinburgh Centre for Inflammation Research, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Green R; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Sarvi S; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Brown P; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Kadler KE; University of Manchester, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, Michael Smith Building, Manchester, United Kingdom., Lu Y; University of Manchester, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, Michael Smith Building, Manchester, United Kingdom., Mason JI; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Critchley HOD; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom., Hillier SG; MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2017 Aug 11; Vol. 12 (8), pp. e0183013. Date of Electronic Publication: 2017 Aug 11 (Print Publication: 2017).
DOI: 10.1371/journal.pone.0183013
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusion: Our results provide proof-of-concept that targeting peritoneal Lox could be an effective approach in ameliorating fibrosis and adhesion development.
Databáze: MEDLINE
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