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NDT Advance Access published online on September 25, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp502
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© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Cyclooxygenase-2 inhibitor: a potential therapeutic strategy for ultrafiltration failure in peritoneal dialysis*

Yong-Lim Kim1,2,3, Sun-Hee Park1,3, Ji-Young Choi1,3 and Chan-Duck Kim1,3

1 Division of Nephrology, Department of Internal Medicine 2 Cell and Matrix Research Institute, Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine 3 Clinical Research Center for End Stage Renal Disease, Daegu, Korea

Correspondence and offprint requests to: Yong-Lim Kim; E-mail: ylkim{at}knu.ac.kr

Keywords: angiogenesis; cyclooxygenase 2 inhibitors; fibrosis; peritoneal dialysis; ultrafiltration

Cyclooxygenase (COX) is a rate-limiting enzyme in the biosynthesis of prostaglandins from arachidonic acid. So far, three isoforms have been identified: COX-1, which can be induced in some systems but is constitutively expressed in most cells and has a role in tissue homeostasis; COX-2, which is an inducible isoform whose expression is stimulated by cytokines, growth factors and tumour promoters [1]; COX-3, which was very recently discovered in dog brain, and is a splice variant of COX-1 that is inhibited by acetaminophen [2].

In contrast to classic nonsteroidal anti-inflammatory drugs, which inhibit both COX-1 and COX-2, selective COX-2 inhibitors such as celecoxib or rofecoxib specifically inhibit COX-2 with similar anti-inflammatory effects and fewer gastrointestinal adverse effects. Furthermore, recent data show that selective COX-2 inhibitors have pro- or anti-fibrotic effects in the liver, lung or kidney [3–8]; inhibit angiogenesis and tumourigenesis [9]; and reduce neurologic injuries in neurologic diseases [10]. However, there is still controversy about whether inhibition of COX-2 is protective or deleterious in tissue fibrosis.

In earlier reports in the field of peritoneal dialysis (PD), human peritoneal mesothelial cells (HPMCs) were shown to actively control inflammation by producing prostaglandin (PG) in response to inflammatory cytokines [11] and the PG release was influenced by bioincompatible PD solutions [12]. In addition, intraperitoneal cyclooxygenase inhibition during peritonitis decreases vascular permeability, although it does not affect the effective peritoneal surface area [13]. However, during stable PD, cyclooxygenase inhibition with indomethacin does not affect permeability or peritoneal surface area [14].

More recently, however, COX-2 was reported to be a mediator of dialysate-induced peritoneal membrane changes [15] and selective COX-2 inhibition could be a potential therapy to alleviate it [16,17]. The role of COX-2 in the peritoneal membrane is summarized in Table 1.


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  		Table 1 The role of COX-2 in peritoneal membrane

 
In this issue of the Nephrol Dial Transplant, Fabbrini et al. [17] show that treatment with celecoxib, a first generation selective COX-2 inhibitor, improves ultrafiltration capacity in an animal model of PD. The reported mechanisms for improving ultrafiltration capacity are that celecoxib treatment reduces (1) submesothelial fibrosis, (2) angiogenesis and (3) lymphangiogenesis after exposure to a PD solution, but it is not related to the change of aquaporin-1 or prevention of epithelial-to-mesenchymal transition (EMT). The possible mechanisms of COX-2 inhibitors as a potential treatment for ultrafiltration failure in PD are represented in Figure 1.


Figure 1
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  		Fig. 1 The possible mechanisms for improving ultrafiltration capacity in PD after COX-2 inhibitor treatment. Mesothelial cell, peritoneal macrophage and T cell exposed to bioincompatible PD solution or episode of peritonitis induce inflammatory cytokines and growth factors and subsequently increase expression of COX-2 in mesothelial cells. COX-2 inhibitor treatment reduces submesothelial fibrosis, angiogenesis and lymphangiogenesis via reducing COX-2 effect. GDPs denote glucose degradation products, AGEs advanced glycation end products, IL-1 interleukin 1, IL-6 interleukin 6, FGF2 fibroblast growth factor 2, COX-2 cyclooxygenase-2, EMT epithelial-mesenchymal transition, PGE2 prostaglandin E2, TXA2 thromboxane A2, MAPK mitogen-activated protein kinase, PDK-1 3-phosphoinositide-dependent kinase-1, SERCA sarcoplasmic endoreticulum Ca2+ ATPase.

 
The effect of COX-2 inhibitors in peritoneal fibrosis is consistent with previous reports. HPMCs exposed to high glucose induce COX-2 expression, and selective COX-2 inhibitors decrease TGF-β synthesis and extracellular matrix production [16]. In addition, higher COX-2 expression is observed in the EMT of mesothelium ex vivo, and is related to peritoneal transport characteristics [15], although a direct role for COX-2 as an inducer of EMT is uncertain.

Fabbrini et al. suggest that the anti-fibrotic effects of COX-2 inhibitors in PD are independent of the anti-inflammatory effects. Inflammatory parameters such as influx of inflammatory cells into the peritoneal cavity and MCP-1, or hyaluronic acid levels in PD effluent, were not different between celecoxib-treated and the control group. However, milky spot and mast cell numbers in the omentum were significantly reduced in celecoxib-treated animals, suggesting that the beneficial effect of COX-2 inhibition is partially dependent on its anti-inflammatory effects. Under similar conditions, celecoxib reduces peritoneal inflammation assessed by the drained cell number and cell population in flow cytometry with mouse cells [15]. Therefore, in order to better understand the contribution of COX-2 inhibitors in peritoneal fibrosis and whether or not it depends on an anti-inflammatory pathway in the peritoneum, a further systematic approach is needed.

As a second mechanism for improving ultrafiltration, Fabbrini et al. suggest an anti-angiogenic effect of COX-2 inhibitors. The anti-angiogenic effects of COX-2 inhibitors are well documented [9]. The anti-angiogenesis effects caused the utilization of COX-2 inhibitors as chemopreventive agents against gastrointestinal cancers and colorectal adenomatous polyps [21,22]. As proposed mediators of angiogenesis, thromboxane A2 stimulates endothelial cell migration and angiogenesis [23]. Also, COX-2-induced PGE2 stimulates vascular endothelial growth factor (VEGF). VEGF induces prostacyclins by increasing phopholipase-A2-mediated arachidonic acid release [24,25] and up-regulates expression of COX-2 [26]. The effect of PG would be amplified via positive feedback mechanism (Figure 1). Consistently, the VEGF/VEGF-2 receptor pathway is proposed to be a COX-2-independent target of COX-2 inhibitors in cancer cells [27]. However, because COX-2-derived isomerase or receptors are expressed in a tissue-specific manner, the anti-angiogenesis effects in the peritoneal membrane should be confirmed. Furthermore, the molecular mechanisms of the prevention of peritoneal neoangiogenesis by COX-2 inhibitors and whether or not there are tissue-specific differences needs to be explored. In addition to its angiogenic effects, PG (prostacyclin and PGE2) itself increases both vascular permeability and vascular surface area for solute transport in PD [28,29]. Therefore, COX-2 inhibition improves ultrafiltration by reducing vascular permeability and vascular surface area.

A third effect of COX-2 inhibitors on peritoneal lymphangiogenesis has been suggested as a mechanism to improve ultrafiltration. Previous reports suggested that COX-2 is related to lymph node metastasis through lymphangiogenesis in breast or gastric cancers [30,31], but there is no information with regard to the effect of COX-2 inhibitors on lymphangiogenesis in PD. Therefore, considering the contribution that lymphatic absorption has on ultrafiltration failure in PD [32], the approach used by Fabbrini et al., demonstrating inhibition of lymphangiogenesis and its relationship with ultrafiltration capacity, appears to be novel in PD.

It is also of interest to evaluate the effect of COX-2 inhibitors on EMT in PD. According to previous reports showing that COX-2 enhances TGF-β-induced EMT through a PGE2-dependent mechanism and that inhibition of COX-2 with shRNA inhibits EMT in mammary epithelial cell lines [33], COX-2 inhibitors in PD are hypothesized to contribute to the prevention of EMT. However, celecoxib treatment does not result in the prevention of peritoneal EMT [15,17], although COX-2 expression is increased in TGF-β-induced EMT in HPMC [15]. Currently, it is not clear whether COX-2 expression is essential to induce EMT or if COX-2 is induced when EMT occurs. Further analysis with regard to COX-2 and EMT is needed in peritoneal fibrosis.

Nevertheless, despite the beneficial effect of COX-2 inhibitors in ultrafiltration failure in experimental PD, the clinical application of COX-2 inhibitors to treat ultrafiltration failure in PD patients should be used cautiously because of the potential harmful effects that include possible deleterious effect of COX-2 inhibitors on the glomerular filtration rate, which could further compromise residual renal function in PD patients [34]. In addition, for PD patients with cardiovascular risk factors higher than the general population, COX-2 inhibitors may lead to an increased risk of cardiovascular mortality [35]. Finally, the experimental dosage of COX-2 inhibitors was about 5-fold higher than the usual dosage in humans; therefore, it is impractical to administer the same dosage to PD patients.

In addition, regarding the different effects of celecoxib and rofecoxib on angiogenesis [36], additional questions about whether all coxibs have the same effects on fibrosis, angiogenesis or lymphangiogenesis in PD should be answered in future trials. Also, the dual inhibition of lipoxygenase and cyclooxgenase or celecoxib derivatives, such as OSU-03012 that target protein kinase 1 (PDK1), may represent a new therapeutic pathway to prevent peritoneal membrane damage in the future [37,38].

In conclusion, celecoxib ameliorated PD-induced peritoneal fibrosis, angiogenesis and lymphangiogenesis, and recovered the ultrafiltration capacity in an animal model of PD. These beneficial effects could represent a new therapeutic strategy in ultrafiltration failure, but the underlying mechanisms of celecoxib treatment in peritoneal membrane damage should be confirmed in cell- or tissue-specific studies.



   Acknowledgments
 
This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A084001). And we would like to thank Seungwoo Han M.D. for his expertise in the preparation of the figure.

Conflict of interest statement. None declared.



   Notes
 
* Editorial comment on Fabbrini P et al. Celecoxib treatment reduces peritoneal fibrosis and angiogenesis and prevents ultrafiltration failure in experimental peritoneal dialysis (NDT 1003–2008). Back



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Received for publication: 27. 8.09
Accepted in revised form: 28. 8.09


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