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

Abstract

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 proor 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 Table 1. The role of COX-2 in peritoneal membrane