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Targeting lysyl oxidase reduces peritoneal fibrosis.
- Source :
-
PloS one [PLoS One] 2017 Aug 11; Vol. 12 (8), pp. e0183013. Date of Electronic Publication: 2017 Aug 11 (Print Publication: 2017). - Publication Year :
- 2017
-
Abstract
- 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.<br />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.<br />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.<br />Conclusion: Our results provide proof-of-concept that targeting peritoneal Lox could be an effective approach in ameliorating fibrosis and adhesion development.
- Subjects :
- Abdominal Cavity surgery
Animals
Collagen genetics
Collagen metabolism
Epithelium drug effects
Epithelium metabolism
Epithelium pathology
Extracellular Matrix Proteins genetics
Extracellular Matrix Proteins metabolism
Female
Gene Expression
Humans
Interleukin-1alpha pharmacology
Mice
Mice, Inbred C57BL
MicroRNAs genetics
MicroRNAs metabolism
Nanotubes, Carbon toxicity
Peritoneal Fibrosis chemically induced
Peritoneal Fibrosis genetics
Peritoneal Fibrosis pathology
Primary Cell Culture
Progesterone pharmacology
Protein-Lysine 6-Oxidase genetics
Protein-Lysine 6-Oxidase metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Tissue Adhesions chemically induced
Tissue Adhesions genetics
Tissue Adhesions pathology
Aminopropionitrile pharmacology
Collagen antagonists & inhibitors
Dexamethasone pharmacology
Extracellular Matrix Proteins antagonists & inhibitors
Molecular Targeted Therapy
Peritoneal Fibrosis prevention & control
Protein-Lysine 6-Oxidase antagonists & inhibitors
Tissue Adhesions prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 12
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 28800626
- Full Text :
- https://doi.org/10.1371/journal.pone.0183013