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      Targeting lysyl oxidase reduces peritoneal fibrosis

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          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.

          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, C ol1a1, 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.

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          Most cited references 50

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          Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma

          The unique hazard posed to the pleural mesothelium by asbestos has engendered concern in potential for a similar risk from high aspect ratio nanoparticles (HARN) such as carbon nanotubes. In the course of studying the potential impact of HARN on the pleura we have utilised the existing hypothesis regarding the role of the parietal pleura in the response to long fibres. This review seeks to synthesise our new data with multi-walled carbon nanotubes (CNT) with that hypothesis for the behaviour of long fibres in the lung and their retention in the parietal pleura leading to the initiation of inflammation and pleural pathology such as mesothelioma. We describe evidence that a fraction of all deposited particles reach the pleura and that a mechanism of particle clearance from the pleura exits, through stomata in the parietal pleura. We suggest that these stomata are the site of retention of long fibres which cannot negotiate them leading to inflammation and pleural pathology including mesothelioma. We cite thoracoscopic data to support the contention, as would be anticipated from the preceding, that the parietal pleura is the site of origin of pleural mesothelioma. This mechanism, if it finds support, has important implications for future research into the mesothelioma hazard from HARN and also for our current view of the origins of asbestos-initiated pleural mesothelioma and the common use of lung parenchymal asbestos fibre burden as a correlate of this tumour, which actually arises in the parietal pleura.
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            Lysyl oxidase: properties, regulation and multiple functions in biology.

            Lysyl oxidase (LO) is a copper-dependent amine oxidase that plays a critical role in the biogenesis of connective tissue matrices by crosslinking the extracellular matrix proteins, collagen and elastin. Levels of LO increase in many fibrotic diseases, while expression of the enzyme is decreased in certain diseases involving impaired copper metabolism. While the three-dimensional structure of the enzyme is not yet available, many of its physical-chemical properties, its novel carbonyl cofactor, and its catalytic mechanism have been described. Lysyl oxidase is synthesized as a preproprotein, secreted as a 50 kDa, N-glycosylated proenzyme and then proteolytically cleaved to the 32 kDa, catalytically active, mature enzyme. Within the past decade, the gene encoding LO has been cloned, facilitating investigations of the regulation of expression of the enzyme in response to diverse stimuli and in numerous disease states. Transforming growth factor-beta, platelet-derived growth factor, angiotensin II, retinoic acid, fibroblast growth factor, altered serum conditions, and shear stress are among the effectors or conditions that regulate LO expression. New, LO-like genes have also been identified and cloned, suggesting the existence of a multigene family. It has also become increasingly evident that LO may have other important biological functions in addition to its role in the crosslinking of elastin and collagen in the extracellular matrix.
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              Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene.

              Transgenic mice expressing an inducible suicide gene, which allows systemic and reversible elimination of macrophages, were developed. A macrophage-specific c-fms promoter was used to express enhanced green fluorescent protein and a drug-inducible suicide gene that leads to Fas-mediated apoptosis in resting and cycling cells of the macrophage lineage. Transgenic mice were fertile, of normal weight, and showed no abnormal phenotype before drug exposure. The transgene was expressed constitutively in macrophages and dendritic cells (DC) but not significantly in T cells or B cells. Induction of the suicide gene led to depletion of 70-95% of macrophages and DC in nearly all tissues examined. Depletion reduced the ability to clear bacteria from the blood and led to increased bacterial growth in the liver. Depleted mice displayed several abnormalities, including splenomegaly, lymphadenopathy, thymic atrophy, extramedullary hematopoiesis, and development of peritoneal adhesions. This new, transgenic line will be useful in investigating the role of macrophages and DC.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Methodology
                Role: Data curationRole: Investigation
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Methodology
                Role: Methodology
                Role: Data curationRole: Investigation
                Role: Data curationRole: Investigation
                Role: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Methodology
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 August 2017
                2017
                : 12
                : 8
                Affiliations
                [1 ] MRC/University of Edinburgh Centre for Reproductive Health, Edinburgh Medical School, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom
                [2 ] MRC/University of Edinburgh Centre for Inflammation Research, Edinburgh Medical School, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom
                [3 ] University of Manchester, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, Michael Smith Building, Manchester, United Kingdom
                Medical University of South Carolina, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-16-31274
                10.1371/journal.pone.0183013
                5553776
                28800626
                © 2017 Harlow et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 7, Tables: 0, Pages: 19
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: G0900550
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 091840/Z/10/Z
                Award Recipient :
                This study was support by Medical Research Council Project Grant G0900550 (to SGH, JIM, HODC, CRH) and a Wellcome Trust Grant 091840/Z/10/Z (to KEK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Hormones
                Lipid Hormones
                Progesterone
                Biology and Life Sciences
                Biochemistry
                Proteins
                Collagens
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
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                Anatomy
                Respiratory System
                Thoracic Diaphragm
                Medicine and Health Sciences
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                Respiratory System
                Thoracic Diaphragm
                Research and Analysis Methods
                Experimental Organism Systems
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