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Inflammation and Fibrosis |
Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, PR China
Correspondence to: K.N. Lai, Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, PR China. knlai{at}hkucc.hku.hk
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ABSTRACT |
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 TOP ABSTRACT EXTRINSIC FACTORSINTRINSIC FACTORSREFERENCES |
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During peritoneal dialysis, peritoneal cells are repeatedly exposed to a
non-physiologic hypertonic environment with high glucose content and low pH.
Current sterile dialysis solutions cause inflammation in the submesothelial
compact zone, leading to fibrosis, angiogenesis, and, eventually,
ultrafiltration failure. Although the normal interstitium separates the
peritoneal microvasculature from the dialysis fluid and makes transperitoneal
transport less efficient, changes in the submesothelial compact zone can
result in progressive increases in solute transfer and ultrafiltration
diminution. This peritoneal dysfunction will further be amplified with the
development of an epithelial-to-mesenchymal transition of mesothelial cells
and dissipation of the osmotic driving force through the increased area and
solute transport that accompany neoangiogenesis of the submesothelial
microvasculature. The alteration of the peritoneal membrane can be further
aggravated by peritonitis, advanced glycation end-products, and glucose
degradation products. Furthermore, new data are emerging to support a
proinflammatory role for peritoneal adipocytes.
KEY WORDS: Mesothelium; adipocytes; inflammation; fibrosis.
The peritoneum is covered by a mesothelial monolayer beneath which is a basement membrane and submesothelial layer that contain collagen, fibroblasts, adipose tissue, blood vessels, and lymphatics (1). During peritoneal dialysis (PD), peritoneal cells are repeatedly exposed to a non-physiologic hypertonic environment with high glucose content and low pH. Mesothelial cells (MCs) play an important role in regulating the inflammatory response in the peritoneal cavity by producing proinflammatory cytokines and chemoattractants. By secreting these chemokines and cytokines, MCs contribute to the recruitment of leukocytes following the expression of adhesion molecules (2).
After years of PD, chronic changes, with fibrosis, develop in the peritoneum. The most marked changes occur when PD patients have experienced severe and recurrent peritonitis. Other authors have made similar observations that long-term exposure to PD solutions appears to increase fibrosis and the probability of ultrafiltration failure (3).
Conventional PD fluids (PDFs) make use of the osmotic gradient generated by glucose. Years of exposure to PDFs result in the formation of an avascular layer of interstitial matrix and plasma proteins in the submesothelial compact zone, and in an epithelial-to-mesenchymal transition (EMT) of mesothelial cells. The fibrotic process in the peritoneal membrane is developed following PD-related acute and chronic release of inflammatory mediators. The present review aims to provide an overall picture of extrinsic and intrinsic events leading to fibrosis of the peritoneal membrane (Figure 1).
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EXTRINSIC FACTORS |
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TOPABSTRACTEXTRINSIC FACTORSINTRINSIC FACTORSREFERENCES |
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PDFs: The reactive compound D-glucose exerts an effect on mesothelial cells either directly or through its degradation pathway. Glucose, but not mannitol, upregulates synthesis by MCs of transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) in a doseand time-dependent manner. The two pathways of glucose degradation—degradation into glucose degradation products (GDPs) and formation of advanced glycation end-products (AGEs)—also play an important role in peritoneal mesothelial biology (5).
Accumulation of AGEs in the peritoneal tissue promotes expression of various growth factors and subsequently results in deterioration of ultrafiltration capacity in PD (6). Exposure to GDPs leads to enhanced cytotoxic damage and proinflammatory response in MCs (7). In addition, GDPs stimulate the production by MCs of vascular endothelial growth factor (VEGF), which enhances vascular permeability and angiogenesis (8). In addition, GDPs downregulate the expression of intercellular tightjunction proteins such as ZO-1, occludin, and claudin-1 in MCs, again via VEGF. In addition to direct cytotoxic effects, GDPs may contribute to cytotoxicity by inducing AGE formation (7).
Several studies have investigated the biocompatibility of various PDFs with
various peritoneal cell types
(9,10).
Factors such as buffer, glucose, or the GDPs formed during heat sterilization
have been shown to be critical. Exposure of MCs to GDPs resulted in
dose-dependent inhibition of cell growth, viability, and release of
interleukin-6 (IL-6) and tumor necrosis factor-
(TNF-).
Synthesis of TGF-β and VEGF also increased after MCs were exposed to
various GDPs (11).
Mesothelial cell repair (remesothelialization) after exposure to GDPs was
impaired independent of D-glucose concentration
(12), with EMT being
responsible for part of this effect. The intracellular adhesion molecule
E-cadherin appears to have a central role in the control of EMT. After
exposure of mesenchymal cells to PDFs, the expression of cytokeratin-18 and
E-cadherin was reduced, and the expression of -SMA and vimentin (a sign
of EMT) was increased (13).
Immunofluorescence studies demonstrated that tight junctions such as ZO-1,
occludin, and claudin-1 became weak and were downregulated after incubation
with dialysis solution
(14,15).
Infection: Bacterial peritonitis has been associated with a sharp increase (by a multiple of 400) in total cell and neutrophil counts in PD effluent up to 3 weeks after peritonitis despite clinical remission. A progressive increase was observed in the percentage of mesothelial cells or dead cells in the total cell population in effluent over a 6-week period. Dialysate levels of interleukin-1 (IL-1), IL-6, and TGF-β increased markedly on day 1 before their levels decreased gradually. Active release of proinflammatory cytokines and sclerogenic growth factors was observed through at least 6 weeks despite apparent clinical remission of peritonitis. After peritonitis, the peritoneal cytokine networks may potentially affect the physiologic properties of the peritoneal membrane (16).
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INTRINSIC FACTORS |
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TOPABSTRACTEXTRINSIC FACTORSINTRINSIC FACTORSREFERENCES |
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. Molecules of complementary DNA (cDNA) for TGF-β were
significantly more numerous per macrophage throughout the peritonitis period
than per macrophage in noninfected effluent
(16). No significant
correlations were observed between PDF levels of TGF-β and TGF-β
cDNA molecules per macrophage, suggesting that peritoneal macrophages are not
the only source of TGF-β in PDFs. Mesothelium: Mesothelial cells are biologically active and play roles beyond local host defense. Table 1 summarizes those distinctive biologic roles.
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Exposure of cultured MCs to 4.25% dextrose PDF results in increased hydrogen peroxide production at levels similar to those resulting from stimulation of MCs with phorbol myristate acetate (18). The MCs are sensitive to the effect of pH even though clinical studies have shown that PDFs are usually buffered (to a pH of 7.4 from the initial 5.2 within 15 – 30 minutes of instillation) (19). Bicarbonate-buffered solutions stimulate less production of TGF-β by cultured MCs than conventional PDFs do (20). A 6-month controlled trial showed an increase in cancer antigen 125 and a decrease in hyaluronan levels in overnight effluent with the use of bicarbonate-buffered PDF (21).
Glucose in the PDF can bring about major changes in the environment of the mesothelial cells and the cells underlying the mesothelium, increasing the production of various cytokines as a result. It is noteworthy that glucose may exert little effect on the synthesis of specific mediators, for example, VEGF, and yet GDPs or AGEs greatly enhance such synthesis (22).
Submesothelial Compact Zone: After 6 years of continuous PD, a good percentage of patients show a marked increase in the thickness of the submesothelial compact zone (4). The layer resembles scar tissue with a relatively amorphous, avascular appearance (23).
Animal studies reveal that, in the early stages of PD, the thickness of the fibrotic submesothelial compact zone is not uniform (24). In the first few weeks of exposure, a spotty inflammation is detected at various places in the peritoneum. With time, these areas of inflammation and sclerosis gradually coalesce and become more uniform, covering much of the peritoneum that is in contact with the PDF.
As the fibrosis becomes more uniform, ultrafiltration is gradually lost. An avascular layer in the submesothelial compact zone results in a marked decrease in the concentration of osmotic agent in the vicinity of the filtering vasculature. An avascular matrix of macromolecules is laid down over the abnormal microvasculature, which includes vessels produced by angiogenesis. The glucose in the PDF diffuses down its concentration gradient through the avascular gel matrix to the blood vessels underlying the matrix. Uptake of the glucose by these vessels will be quite rapid as permeability increases because of the abnormal angiogenic vessels and the increased surface area of the microvasculature. Diffusion through the matrix also occurs rapidly because of the low resistance of the abnormal interstitium and the lack of cells. Thus, the glucose or osmotic gradient between the interstitium and the blood vessels can dissipate rapidly.
Osmotic filtration from the abnormal blood vessels into the interstitium will likely occur at a low rate because of the reduced osmotic force adjacent to the microvasculature. The filtered fluid, once it leaves the blood and transports into the tissue, has no means to move from the deeper interstitium into the peritoneal cavity. In addition, fibrosis speeds the absorption of glucose into the gel matrix and ultimately into the blood, effectively lowering the osmotic pressure adjacent to the blood vessels, and hence eliminating the osmotic filtration dramatically.
Submesothelial Blood Vessels: In parallel with fibrosis, the number and vasculopathy of the capillaries in the peritoneum progressively increase, a change that is involved both in the elevation of small-solute transport across the peritoneal membrane and in ultrafiltration failure.
The substances in PDF that are most responsible for peritoneal deterioration are glucose and GDPs. The latter stimulate VEGF production by MCs (25). Local production of VEGF during PD appears to play a central role in the processes leading to peritoneal neoangiogenesis and functional decline. The changes in peritoneal structure over time on PD, as demonstrated in functional tests, has been confirmed in biopsy studies performed on patients. Those studies show neoangiogenesis and fibrosis as the underlying morphology changes that contribute to the functional phenomena.
As mentioned earlier, uptake of glucose by submesothelial blood vessels will be quite rapid after permeability increases because of abnormal angiogenic vessels and the increased surface area of the microvasculature. The result is dissipation of the osmotic driving force. In addition, disruption of intercellular tight junctions in MCs may occur following downregulation of ZO-1 expression, in which VEGF plays an important role (15). Neoangiogenesis was also observed in a rat model of experimental encapsulating peritoneal sclerosis. The VEGF and angiopoietin systems play an important role in the neoangiogenesis seen in that model (26).
EMT: Chronic exposure of the mesothelium to sterile PDFs results in EMT. Yanez–Mo et al. (13) recovered and cultured human MCs from the spent dialysate of 54 stable patients, splitting the cells 2 – 3 times. Of the patients sampled, 85% had had no previous peritonitis. The group also cultured omental mesothelial cells from 39 CAPD patients. Omental fibroblasts were separated from three of those samples. The authors were able to demonstrate a transition from an epithelial type of mesothelial cell to a fibroblast-like cell with progressive and continuous exposure to clinical PDFs. Loss of normal markers of the mesothelium, such as ICAM-1 and cytokeratin, were observed, as was alteration of the mesothelium from an omental cobblestone-like cellular layer to a fibroblastic layer. Among patients exposed to dialysate for more than 12 months, mesothelial cells changed to less than 30% cobblestone phenotype from 75%, the remainder of the cells being fibroblast-like. In some patients, loss of cytokeratin in the mesothelial cell layer was observed within less than 9 months. These findings clearly support the conclusion that chronic exposure of the peritoneum to the current glucose-based PDFs leads to morphology and phenotype changes in the mesothelium with 24 months.
Glucose and GDPs in PDFs stimulate TGF-β and VEGF production by MCs. The potent profibrotic factor TGF-β induces EMT of the MCs. Exposure of human peritoneal MCs and L929 fibroblasts to acetaldehyde, formaldehyde, glyoxal, methylglyoxal, and furaldehyde resulted in a dose-dependent inhibition of cell growth, viability, and IL-1β–stimulated IL-6 release (11). Suppression of MC function was greater than suppression of fibroblast function. Combinations of GDPs at the lowest concentrations had significant effects on cell function, but filtered (low-GDP) solutions had significantly lesser effects.
Receptors for GDPs and AGEs: Advanced glycosylation end-products have been
detected immunohistochemically in the peritonea of PD patients
(27). The receptor for AGEs
(RAGE) is the best-characterized signal transduction receptor for AGEs.
Primary binding of AGEs to their receptor was regarded as the action of a
scavenger involved in AGE removal and clearance; however, ligand binding to
RAGE results in activation of key signal-transduction pathways such as nuclear
factor 
B (NF-B) and of multiple cellular signaling cascades such
as mitogenactivated protein kinase
(28).
It is now evident that RAGE is much more than a single receptor for AGEs or a scavenger receptor; it has a broad repertoire of ligands. The key pathophysiologic step seems to be GDP-dependent AGE formation in the uremic milieu, leading to observably enhanced expression of RAGE in the peritoneum. An earlier study showed expression of RAGE in human peritoneal MCs (29). Recently, other AGE receptors, including AGE-R-1 (p60), AGE-R-2 (p90) and AGE-R-3 (gallectin-3) were also found to be expressed by MCs (25). Various GDPs exert differential regulation on the expression of these receptors on human peritoneal MCs (25), but the functional significance of these various receptor forms has not yet been completely delineated.
Local interaction between RAGE and AGEs and GDPs leads to the development
of peritoneal inflammation, neoangiogenesis, and, finally, fibrosis. As
compared with RAGE-deficient (RAGE–/–) mice, otherwise
healthy RAGE-bearing wild-type (WT) mice treated with various GDP-containing
PDFs yielded visceral peritoneal tissue samples that showed increased numbers
of inflammatory cells, CD3+ T cells, and NF-B expression
(30). A central role for
GDP-induced upregulation of peritoneal neoangiogenesis by VEGF via
AGE–RAGE interaction has been proposed in the peritoneal membrane.
Neoangiogenesis—accompanied by upregulation of CD3+ T cells, increased
NF-B binding activity, and increased lectin and VEGF
expression—was augmented in WT mice treated with high-GDP PDF
(30). The findings in WT mice
contrast with those in RAGE-deficient mice, which showed no increased
inflammation (CD3+ T cells and NF-B binding activity) or
neoangiogenesis (by lectin and VEGF) after long-term exposure to
GDP-containing PDFs. After 12 weeks of GDP exposure,
RAGE–/– mice showed no peritoneal fibrosis or
upregulation of TGF-β1
(30). In contrast, fibrosis
and TGF-β expression was increased in RAGE-bearing WT mice after
treatment with high-GDP PDFs.
A separate study showed that AGE–RAGE interaction plays an important role in the induction of extracellular fibrosis in a diabetic animal model of PD (31). In addition, anti-RAGE antibody partially prevents the development of submesothelial and interstitial fibrosis in an animal model of peritoneal fibrosis (32). A role for RAGE in cellular transdifferentiation has also been postulated (33). Anti-RAGE antibody partially alleviates EMT in the development of peritoneal fibrosis (32).
The Inflammatory Role of Peritoneal Adipocytes in PD:Peritoneal adipocytes, previously viewed as less important in peritoneal physiology during PD, are ubiquitous in all peritoneal tissue. Adipose tissue is abundant in omental or mesenteric peritoneum, but less so in parietal, intestinal, and diaphragmatic peritoneum. In parietal peritoneum, adipocytes lie deep under the mesothelium and connective tissue.
During PD fluid dwells, solutes in the PDF move by passive diffusion through the peritoneal barrier and come into contact with the adipocytes. Study of the ultrastructure has revealed that a portion of adipocyte protrudes from the mesothelial surface, and thus, omental adipocytes may come into direct contact with dialysate (1). In addition, dialysate may also reach the parietal adipose tissue when junctional damage or denudation of the mesothelial monolayer has occurred. It is therefore logical to postulate that, with repeated exposure to PDF and continual change in peritoneal physiology during CAPD, peritoneal adipocytes will inevitably be "activated."
Adipose tissue is a complex organ with functions far beyond those of an
energy storage depot. Compelling evidence has now been found that adipocytes
can mediate various physiologic processes through secretion of an array of
adipokines including leptin, adiponectin, resistin, TNF-, IL-6,
TGF-β, and other growth factors
(34). Moreover, adipocytes
express receptors for leptin, insulin-like growth factor-1, TNF-, IL-6,
and TGF-β, and may form a network of local autocrine, paracrine, and
endocrine signals (35). All of
these adipokines have important endocrine functions in chronic kidney diseases
and may also be important contributors to systemic inflammation in renal
patients.
In PD patients, these functions are of special significance, because the initiation of treatment is often associated with an increase in fat mass that could be associated with a genetic effect on energy metabolism in addition to glucose absorption from the PDF (36). Several studies have suggested that, in contrast to findings in the general population, a high body mass index (BMI) is associated with better outcome in renal-patient populations (37). Critical analysis reveals that a protective effect from a high BMI is present only in patients with a normal or high muscle mass (38). A recent study indicated that, as in other patient groups, increased fat mass in PD may indeed have adverse metabolic consequences, with increased systemic inflammation and worse survival (39).
Interestingly, the release of growth factors differs between visceral and subcutaneous adipose tissue (40). The omental adipose tissue most affected by PD releases 2 – 3 times more IL-6 than subcutaneous fat tissue does (41). Visceral fat mass, but not non-visceral fat mass, correlates significantly with circulating levels of IL-6 (42).
Recently, novel data on leptin synthesis and leptin receptor expression in peritoneal tissue has suggested a potential inflammatory role for peritoneal adipocytes. The mRNA and protein of the full-length leptin receptor are both found to be constitutively expressed in human peritoneal MCs (43). The leptin receptor expression in MCs is upregulated by glucose, but not by leptin. In adipocytes, glucose increases mRNA expression and synthesis of leptin. The JAK–STAT (Janus kinase signal transducers and activation) signal transduction pathway in mesothelial cells is activated by either exogenous or adipocyte-derived leptin. Exogenous leptin induces the release of TGF-β by MCs. The TGF-β synthesis induced by leptin is amplified by glucose through increased expression of the leptin receptor.
These new findings point strongly to the notion that peritoneal adipocytes activated by PDFs exert a proinflammatory effect on MCs through release of adipokines and hence contribute to altered peritoneal physiology and dysfunction during PD.
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ACKNOWLEDGMENTS |
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TOPABSTRACTEXTRINSIC FACTORSINTRINSIC FACTORSREFERENCES |
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B. Diabetes2001; 50:2792
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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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 M. N. Schilte, J. W.A.M Celie, P. M. t. Wee, R. H.J. Beelen, and J. van den Born FACTORS CONTRIBUTING TO PERITONEAL TISSUE REMODELING IN PERITONEAL DIALYSIS Perit. Dial. Int., November 1, 2009; 29(6): 605 - 617. [Abstract] [Full Text] [PDF]
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J. Perl and J. M. Bargman PREDIALYSIS INTERVENTIONS FOR POSTDIALYSIS OUTCOMES Perit. Dial. Int., May 1, 2009; 29(3): 270 - 273. [Full Text] [PDF]
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 L. S. Aroeira, E. Lara-Pezzi, J. Loureiro, A. Aguilera, M. Ramirez-Huesca, G. Gonzalez-Mateo, M. L. Perez-Lozano, P. Albar-Vizcaino, M-A. Bajo, G. del Peso, et al. Cyclooxygenase-2 Mediates Dialysate-Induced Alterations of the Peritoneal Membrane J. Am. Soc. Nephrol., March 1, 2009; 20(3): 582 - 592. [Abstract] [Full Text] [PDF]
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S. Yung and T. M. Chan INTRINSIC CELLS: MESOTHELIAL CELLS -- CENTRAL PLAYERS IN REGULATING INFLAMMATION AND RESOLUTION Perit. Dial. Int., February 1, 2009; 29(Supplement_2): S21 - S27. [Abstract] [Full Text] [PDF]
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