Targeting naproxen coupled to human serum albumin to nonparenchymal cells reduces endotoxin-induced mortality in rats with biliary cirrhosis

✍ Scribed by C Albrecht; D K Meijer; C Lebbe; H Sagesser; B N Melgert; K Poelstra; J Reichen

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 250 KB
• Volume: 26
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510260624

✦ Synopsis

targeting NAP to EC/KC results in improved survival, higher SEE EDITORIAL ON PAGE 1680 efficacy, and sparing of renal function in cirrhotic rats. (HEPA-TOLOGY 1997;26:1553-1559.) Endotoxin is thought to play a major role in cirrhotic liver disease. Cyclo-oxygenase inhibitors were shown to be par-Endotoxin is thought to play a significant role in the pathotially protective against endotoxin but cannot be used in cirgenesis of both acute and chronic liver disease. 1,2 Various rhotic patients because of renal side-effects. We argued that studies have shown systemic endotoxinemia in individuals administration of naproxen (NAP) linked to human serum with chronic liver disease, [3][4][5][6] suggesting an interrelation bealbumin (HSA), which results in specific delivery of NAP to tween intestinal lipopolysaccharide (LPS) and the manifestaendothelial cells (EC) and Kupffer cells (KC) and exhibited tion of liver injury. Several lines of evidence indicate that hepatoprotective effects against lipopolysaccharide (LPS) in the function of the sinusoidal lining cells of the liver is critical vitro, could protect cirrhotic rats from LPS toxicity while preto the viability of the hepatocytes. 2 First, Kupffer cells (KC) serving renal function. The studies were performed in rats appear to play a prominent role in the clearance of endorendered cirrhotic by bile duct ligation (BDL); animals retoxin. 7,8 Damage to KC by a variety of toxic or metabolic ceived LPS (Escherichia coli, 800 mg/kg) intravenously. Five injuries could lead to an impairment of the ability to take groups were studied: LPS alone, rats pretreated with a convenup and detoxify endotoxin. This primary injury to sinusoidal tional dose of NAP (50 mg/kg), NAP-HSA (22 mg/kg), NAP cells may render the liver more sensitive to normally innocuequimolar to NAP-HSA (1.5 mg/kg), or the HSA carrier. LPS ous amounts of gut-derived endotoxin, resulting in further induced significant mortality (55%); this was not affected by impairment of LPS detoxification, and finally in endotoxin equimolar NAP (57%) but accentuated by conventional NAP passage into the systemic circulation. 9 In cirrhotic patients (88%). In contrast, NAP-HSA provided significant protection with portal hypertension, the presence of portosystemic (9%; P õ .05). After conventional NAP treatment, significant shunts may also contribute to a spill-over of intestinal endorenal toxicity was observed as evidenced by a marked reductoxin into the systemic circulation. 2 tion in sodium excretion (LPS vs. NAP-HSA vs. NAP [50 mg/ KC and endothelial cells (EC) are considered to be the kg] 33 { 22 vs. 50 { 39 vs. 4 { 3 mmol/h; P õ .05). Renal most important cell types of the liver involved in the initiaprostaglandin E 2 (PGE 2 ) excretion was reduced by NAP in tion of inflammatory reactions through the release of a casall groups, but most markedly at the conventional dosage cade of inflammatory mediators. [10][11][12][13] Complex interactions of (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 132 { 115 vs. 39 { these mediators upon LPS stimulation were reported, ascrib-19 vs. 9 { 8 ng/mL; P õ .05). Successful targeting was eviing a key role in the early inflammatory response to tumor denced by a significant hepatic enrichment of NAP in the necrosis factor a (TNF-a). It was shown that TNF-a is in-NAP-HSA group compared with the equimolar untargeted volved in the stimulatory action of LPS 14 and apparently group (30.16 { 9.33 vs. 1.13 { 1.95 nmol/g liver). Thus, contributes to the pathogenesis of LPS-induced liver injury. 15 Upon stimulation with LPS, KC synthesize and liberate TNFa, whereas hepatocytes and sinusoidal EC do not produce Abbreviations: LPS, lipopolysaccharide; KC, Kupffer cells; EC, endothelial cells; detectable amounts of this protein, 16 emphasizing the central TNF-a, tumor necrosis factor a; NSAID, nonsteroidal anti-inflammatory drug; NAP, role of KC in LPS-associated liver damage. naproxen; HSA, human serum albumin; NAP-HSA, naproxen covalently coupled to These findings indicate that, in chronic liver disease, it is a human serum albumin; PGE2, prostaglandin E2; BDL, bile duct ligation; MECC, micellar electrokinetic capillary chromatography; MSOF, multisystem organ failure.