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Inflammation and Fibrosis |
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
Correspondence to: Y. Tomino, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421 Japan. yasu{at}med.juntendo.ac.jp
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ABSTRACT |
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 TOP ABSTRACT DISCUSSIONCONCLUSIONSREFERENCES |
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Peritoneal fibrosis (PF) is invariably observed in patients undergoing
long-term peritoneal dialysis (PD). The condition is thought to occur in
response to a variety of insults, including bioincompatible dialysates (acidic
solution, high glucose, glucose degradation products, or a combination),
peritonitis, uremia, and chronic inflammation. Recently, the pathophysiologic
mechanisms that contribute to the fibrosing process have been intensively
studied. Transforming growth factor-β has been shown to be a key mediator
of PF. Loss of the mesothelial cell layer has been identified in several
studies and shown to correlate with submesothelial thickening and
vasculopathy. An association has also been identified between increased
submesothelial thickness in the peritoneal membrane and increased solute
transport, suggesting a relationship between PF and loss of ultrafiltration
capacity. Thus, to maintain long-term PD and improve quality of life for
patients, it is important to develop interventions for prevention and
treatment of PF.
Several strategies for peritoneal fibrosis intervention have been
reported, including developing biocompatible dialysate, targeting mediators
responsible for inflammation and fibrosis, and reconstituting the peritoneum
using mesothelial or bone marrow–derived cells. Recent experimental
trials in animal models and clinical studies are presented in this
review.
KEY WORDS: Peritoneal fibrosis; tranilast; intervention.
Pathologic changes in the peritoneal membrane with long-term peritoneal dialysis (PD) are characterized by reduction or loss of mesothelial cells and enlargement of the submesothelial compact zone because of interstitial fibrosis, accompanied by changes in the structure and number of blood vessels (1). The healthy peritoneum consists of a single-cell layer of mesothelial cells that sit atop the basement membrane and maintain a smooth surface that prevents adhesion within the peritoneal cavity.
During PD, peritoneal mesothelial cells are exposed to a variety of insults, including bioincompatible solutions, peritonitis, uremia, and chronic inflammation. Williams et al. analyzed parietal peritoneal samples and observed an increase in the submesothelial compact zone with increased time on PD (1). Loss of the mesothelial cell layer has been identified in several studies and has been shown to correlate with submesothelial thickening and vasculopathy (1). An association also has been identified between increased submesothelial thickness and increased solute transport (2). These pathologic changes are closely associated with the main clinical characteristics observed in long-term PD patients, namely an increased peritoneal transport rate and loss of ultrafiltration capacity.
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DISCUSSION |
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TOPABSTRACTDISCUSSIONCONCLUSIONSREFERENCES |
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These stimuli enhance the production of fibrogenic and angiogenic mediators in mesothelial cells and cause mesothelial damage, leading to loss of cell–cell and cell–matrix interaction, apoptosis, and epithelial-to-mesenchymal transition. As a result, the mesothelial cells disappear from the peritoneal surface. Progressive extracellular matrix (ECM) production and angiogenesis occur in the submesothelial tissues.
MEDIATORS OF PF
Transforming growth factor β1 (TGF-β1) is considered to play a
central role in PF. High glucose solution stimulates the synthesis of
TGF-β1 through activation of protein kinase C (PKC) in the peritoneal
cells. It has been demonstrated that high glucose concentrations induce an
increase in TGF-β receptor types I and II, as measured by flow cytometry
of peritoneal mesothelial cells
(4). The chronic induction of
TGF-β1 is further exacerbated in the presence of peritonitis, with
interleukin-1β and tumor necrosis factor 
promoting PF
(5) through increased
expression of smooth-muscle antibody–positive myofibroblasts in
the interstitium (6).
Other cytokines, such as TGF-β2, TGF-β3, plateletderived growth factor, fibroblast growth factor-2, and connective tissue growth factor (7) are involved in the initiation of the fibrogenic process. Glucose degradation products have been shown to alter mesothelial cell function and proliferation (8) and to induce collagen and TGF-β expression (9). Honda et al. showed that the deposition of AGEs in the interstitium and vessel walls was correlated with fibrosis (10). In rats made uremic with subtotal nephrectomy, increased AGE deposition and increased vascularization with increased expression of fibroblast growth factor-2 were noted (11).
Plasminogen activator inhibitor-1, which is upregulated by TGF-β1, has multiple effects as an inhibitor of fibrinolysis in collagen matrix metabolism (12). It is likely involved at an early stage in PF with the inhibition of fibrinolytic activity on the surface of peritoneal tissues and the subsequent accumulation of fibrin tissue, which forms the initial scaffold for subsequent PF (13).
The renin–angiotensin system is also believed to have a role in the fibrotic process. Human peritoneal mesothelial cells express all the components of that system (14). Angiotensin II induces fibronectin expression in human peritoneal mesothelial cells (HPMCs) via extracellular signal-activated kinases 1 and 2 (ERK1, ERK2) and p38 mitogen-activated protein kinase (MAPK) (15).
INTERVENTION IN PF
Attempts have been made to prevent and inhibit PF. To avoid chronic
production of inflammatory mediators in the peritoneal cavity, development of
a more biocompatible PD solution is naturally important. The use of Balance
(Fresenius Medical Care, Bad Homburg, Germany)—a neutral-pH, low-GDP
fluid—was accompanied by a significant improvement in effluent markers
of peritoneal membrane integrity and decreased circulating AGE levels
(16). Mesothelial cells taken
from the effluent of icodextrin solution, a non-glucose–based dialysate,
showed greater proliferation ex vivo than did those taken from
glucose effluent (17). Amino
acid–based dialysis solution also showed better preservation of
mesothelial cell mass (18).
These new dialysis solutions suggest potentially beneficial effects on
peritoneal membrane preservation.
The main target of therapeutic intervention is TGF-β. In studies of mesothelial cells, emodin (3-methyl-1,6, 8-trihydroxyanthraquinone) has been shown to ameliorate glucose-induced synthesis of TGF-β1 (19) and extracellular matrix (20). Emodin, which is a natural tyrosine kinase inhibitor, inhibits TGF-β1 synthesis by suppressing activation of PKC and phosphorylation of cyclic adenosine monophosphate (cAMP)–responsive element binding protein (20).
Pentoxyphilline is a methylxanthine derivative that inhibits collagen synthesis and arrests HPMCs in G1 phase (21). It was demonstrated to inhibit p38 MAPK, ERK1, and ERK2 in the TGF-β signaling pathway.
Diltiazem, a calcium channel blocker, was recently reported to inhibit interleukin-1β–induced TGF-β production on HPMCs (22). Diltiazem has been shown to suppress activation of p38 MAPK and the stress-activated C-Jun N-terminal kinase pathway, resulting in inhibition of TGF-β production and types I and III collagen synthesis. The inhibition by diltiazem was independent of intracellular calcium.
Dipyridamole is a widely used antiplatelet agent that acts on a phosphodiesterase inhibitor that increases cAMP. The increase of cAMP suppresses ERK1 and ERK2 activation and collagen gene expression induced by TGF-β (23).
Adenovirus-mediated gene transfer of decorin, a TGF-β–inhibiting proteoglycan, has been shown to reduce collagen content in a daily infusion model of PD (24).
Tranilast was initially used as an anti-allergy agent, but later also in disorders associated with excessive fibrotic response, such as scleroderma and keloid formation. Previous studies have shown that tranilast inhibits the release of TGF-β and other inflammatory cytokines from macrophages and fibroblasts. Tranilast inhibited proliferation, migration, and collagen synthesis in human vascular smooth-muscle cells (25) and suppressed vascular intimal hyperplasia after balloon injury in rabbits (26). Tranilast is also postulated to possibly have some effects on peritoneal mesothelial cells, with therapeutic potential for treatment of PF.
In culture medium, TGF-β1 levels increased after stimulation of rat peritoneal mesothelial cells with high concentrations of D-glucose (Figure 1). The treatment of mesothelial cells with tranilast significantly inhibited TGF-β1 release induced by D-glucose (Figure 1). Because TGF-β1 exhibits autocrine self-stimulation, we also examined TGF-β1 mRNA expression. The increase of TGF-β1 mRNA expression by D-glucose was also significantly reduced by addition of tranilast (data not shown).
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We also studied the effect of tranilast in the prevention of PF in PD patients. Three patients received tranilast for 20 – 24 weeks (mean: 23 ± 2.7 weeks). We then examined plasma levels of TGF-β1 and PD effluent levels of TGF-β1, hyaluronic acid, and procollagen III peptide. Although the period of treatment was short, we observed a decrease in the levels of TGF-β1, hyaluronic acid, and procollagen III peptide in PD effluent (data not shown). We are now adding more patients to the trial and extending the duration of therapy.
A renin–angiotensin system inhibitor could be a powerful tool in preventing progression of PF. In vitro, losartan, which is an angiotensin receptor blocker (ARB), inhibited angiotensin II–induced increases in cellular reactive oxygen species and high glucose–induced TGF-β1 and fibronectin expression (14). Angiotensin converting-enzyme inhibitors (ACEIs) and ARBs both attenuated the increase in TGF-β1 production and reduced cell proliferation caused by exposure to high glucose (27). In animal models, enalapril (an ACEI) preserved peritoneal function and peritoneal thickness (28). Valsartan (an ARB) and lisinopril (an ACEI) have been demonstrated to reduce levels of TGF-β1 and vascular endothelial growth factor (VEGF) in PD effluent in a rat model (29). The use of ARBs might be able to prevent and treat PF in PD patients.
Because oxidative and carbonyl stress caused by GDPs or AGEs are important mechanisms of peritoneal injury, agents inhibiting these factors are also a possible therapeutic intervention that fit with the attempt to develop biocompatible PD solutions. Aminoguanidine scavenges GDPs and prevents the formation of AGEs. Aminoguanidine also inactivates inducible nitric oxygen synthase, thereby giving it the ability to reduce vascular proliferation by modulating the expression of growth factors (30). Beneficial effects of aminoguanidine on peritoneal microcirculation and tissue remodeling were demonstrated in a rat model of PD (31); however, a clinical trial on aminoguanidine was terminated for safety reasons. Pyridoxamine, a derivative of vitamin B6, is also an inhibitor of AGEs and carbonyl stress. Pyridoxamine significantly improved functional and structural changes in the peritoneal membrane by reduction of AGE accumulation and of angiogenic cytokine expression in uremic rats on PD (32).
Because angiogenesis is also associated with PF, targeting VEGF or other angiogenic factors has been investigated (33,34). In a previous study, we injected anti-VEGF neutralizing antibody intraperitoneally in a rat model of peritoneal sclerosis induced by chlorhexidine gluconate. The VEGF blockade not only inhibited angiogenesis through decrease of VEGF and angiopoietin-1 and -2 expression, but also suppressed progression of PF.
The mesothelial cell layer is important in the maintenance of peritoneal morphology and function. Mesothelial cell transplantation might be another option for promoting repair of the peritoneal membrane and preventing the progression of PF. Recent studies have shown that mesothelial cell transplantation is feasible (35,36) and that genetically modified mesothelial cells can be used to deliver potentially therapeutic recombinant proteins (37). However, Hekking et al. demonstrated prolonged activation of the peritoneum upon mesothelial cell transplantation—a finding that may be related to the cell adherence and culturing conditions of mesothelial cells (38). Further studies are required to find optimal conditions in mesothelial transplantation for controlling peritoneal physiology and function.
A certain fraction of circulating bone marrow–derived cells is thought to contribute to repair of damaged peritoneal membrane in animal models. During the course of peritoneal injury caused by chlorhexidine gluconate in mice, we detected cells stained with c-Kit (a marker of immature bone marrow–derived cells) in the peritoneal membrane (Sekiguchi Y. Roles of bone marrow-derived cells in development of morphological alterations in the peritoneum. Presented at the 11th Congress of the International Society for Peritoneal Dialysis, 25 – 26 August 2006, Hong Kong). Repair of the peritoneal membrane by transplantation of bone marrow cells might be another future intervention.
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CONCLUSIONS |
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TOPABSTRACTDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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  X. Wang, J. Nie, Z. Jia, M. Feng, Z. Zheng, W. Chen, X. Li, W. Peng, S. Zhang, L. Sun, et al. Impaired TGF-{beta} signalling enhances peritoneal inflammation induced by E. Coli in rats Nephrol. Dial. Transplant., February 1, 2010; 25(2): 399 - 412. [Abstract] [Full Text] [PDF]
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