Altered Prostaglandin Metabolism Research Articles

Smoking alters hydroxyprostaglandin dehydrogenase expression in fetal membranes

IntroductionThe way in which tobacco smoking increases the risk of preterm labor remains uncertain. Altered prostaglandin metabolism is one potential mechanism. MethodsProteins in fetal membrane samples (amniochoriodecidua) from 20 women were relatively quantified using Tandem Mass Tagging nano-liquid chromatography mass spectrometry. ResultsProstaglandin synthases and two enzymes involved in prostaglandin degradation, hydroxyprostaglandin dehydrogenase (HPGD) and CBR1, were detected by the mass spectrometer. The expression of HPGD was significantly lower in smokers relative to non-smokers (0.43 fold, p = 0.016). There was no effect of labor, inflammatory status or gestational age on the HPGD levels. DiscussionWe describe for the first time an association between maternal smoking and HPGD expression. We propose that reduced expression of HPGD is one mechanism through which smoking may contribute to preterm labor. Lower levels of this enzyme, key to metabolising prostaglandins, may result in higher levels of prostaglandins and therefore precipitate labor prematurely.

Alteration of prostaglandin metabolism in alcoholic liver disease: its association with platelet dysfunction after chronic alcohol ingestion

Recently, hepatic microcirculation has been focused on as an important pathogenic factor in progression of alcoholic liver disease (ALD). Therefore, blood levels of several prostaglandins, which are associated with organ microcirculation, were determined in various liver diseases, including ALD. Blood thromboxane B2 (TXB2) level was significantly increased in ALD, when compared to other types of liver diseases, whereas both 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and prostaglandin E were not changed. These consequences resulted in the imbalance of 6-keto PGF1 alpha to TXB2, which might promote platelet aggregation and blood vessel contraction. Indeed, the increase of beta-thromboglobulin and platelet factor 4 in blood was observed in ALD. Furthermore, in ALD, the rate of arachidonate-induced platelet aggregation was prominently enhanced, and malondialdehyde production in platelet, which was well correlated with blood TXB2 levels, significantly increased. Thus, the present study may indicate that, in ALD, hyper-aggregability of platelet is produced, because of the derangement of prostaglandin metabolism and platelet dysfunction.

Fibroblast growth factor-23 increases mouse PGE2production in vivo and in vitro

Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE2 production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE2 production, an effect that was inhibited by 50 microM PD-98059 and 10 microM SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a approximately 10-fold increase in PGE2 excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE2. In conclusion, FGF-23 increases urinary and renal tubular PGE2 production via the MAP kinase pathway and PGE2 inhibits proximal tubule phosphate transport.

Probing antiphospholipid-mediated thrombosis: the interplay between anticardiolipin antibodies and endothelial cells.

The association of antiphospholipid (aPL) antibodies with thrombosis in patients with antiphospholipid syndrome (APS) is well documented in humans and in animal studies. However, the mechanisms by which aPL antibodies induce thrombosis are the subject of much current study. It has been suggested that aPL may activate endothelial cells (ECs), thus creating a hypercoagulable state that precedes and contributes to thrombosis in patients with APS. Several studies have shown that aPL upregulate ECs' adhesion molecules (CAMs): intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (E-sel) or induce tissue factor (TF) in monocytes in vitro. Similarly, the incubation of EC with antibodies reacting with beta2glycoprotein I (beta2GPI) has been shown to induce EC activation with concomitant upregulation of CAMs, IL-6 production and alteration of prostaglandin metabolism. Our group has shown that aPL-mediated upregulation of adhesion molecules on ECs correlates with an increased adhesion of leukocytes to endothelium in the microcirculation of mouse cremaster muscle, a n indication of EC activation in vivo, andwith enhanced thrombosis in vivo. In another series of studies, investigators have shown that upregulation of expression of adhesion molecules by some murine monoclonal anti-beta2glycoprotein I (anti-beta2GPI) antibodies correlated with fetal resorption in mice in vivo. More recently, one study showed that the anti-hypercholesterolaemic drug fluvastatin inhibited the aPL-mediated enhanced adhesion of monocytes to ECs in vitro. Data from our laboratories indicate that fluvastatin also reverses thrombus formation and activation of EC induced by aPL in an in vivo mouse model. As additional support for the hypothesis that aPL antibodies activate ECs and may create an hypercoagulable state in APS patients, two recent studies indicated that levels of soluble ICAM-1 and VCAM-1 were significantly increased in the plasma of patients with APS and recurrent thrombosis. Furthermore, studies utilizing knockout mice and specific monoclonal anti-VCAM-1 antibodies have demonstrated that expression of ICAM-1, P-selectin, E-selectin and VCAM-1 are important in in vivo aPL-mediated thrombosis and EC activation in mice. Recent data suggests that aPL antibodies also induce expression of TF not only in monocytes but in ECs. Hence, the interference of aPL with the TF mechanism may be another important mechanism by which these antibodies create a hypercoagulable state and prone patients to thrombosis. Specifically, how aPL alters EC activation state and the molecular and intracellular mechanisms involved have not yet been defined. APL may interact with specific cell surface receptors (proteins and/or lipids) induce signals that have consequences downstream, and that ultimately will result in upregulation of cell surface proteins (i.e., CAMs and TF) and subsequently induce EC activation. In that regard, our group recently showed that aPL-mediated upregulation of adhesion molecules in ECs is preceded by activation of the nuclear factor kappa B (NFkappaB). Other intracellular mechanisms triggered by aPL are not completely understood and are the subject of current investigation. In conclusion, studies suggest that activation of ECs by aPL is an important mechanism that may precede thrombus formation in patients with APS. Hence, the interplay between aPL antibodies and ECs is important inthe pathogenesis of thrombosis in APS.

Atopic dermatitis: molecular mechanisms, clinical aspects and new therapeutical approaches.

Atopic dermatitis (AD) is a genetically determinated, chronic inflammatory skin disorder associated with cutaneous erythema and severe pruritus, affecting 10-15% of children with increasing incidence and socio-economical relevance. Frequently, AD is associated with development of allergic rhinitis and/or asthma later in childhood. In most of patients AD is associated with a sensitization to food and/or environmental allergens and increased serum-IgE, while only a fewer percentage missed links to the classical atopic diathesis. Currently investigated pathogenetic aspects of AD include imbalanced Th1/Th2 responses, altered prostaglandin metabolism, intrinsic defects in the keratinocyte function, delayed eosinophil apoptosis, and IgE-mediated facilitated antigen presentation by epidermal dendritic cells. An inflammatory response of the two-phase-type and the effects of staphylococcal superantigens (SAgs) are also reported. At present a standardized cure of AD and a consensus on therapeutical approach of the severe form of the disease have not been established. Current management of AD is directed to the reduction of cutaneous inflammation and infection, mainly by S. aureus, and to the elimination of exacerbating factors (irritants, allergens, emotional stresses). Since patient with AD show abnormalities in immunoregulation, therapy directed to adjustment of their immune function could represent an alternative approach, particularly in the severe form of the disease. In this review, we analyse the clinical and genetic aspects of AD, the related molecular mechanisms, and the immunobiology of the disease, focusing our attention on current treatments and future perspectives on this topic.

Effect of fish oil supplementation on aortic compliance in rats: role of the endothelium

Arterial compliance improves with dietary fish oils in patients with high cardiovascular risk. Since fish oils alter prostaglandin metabolism and the L-arginine-nitric oxide pathway, and since compliance may be modified by vasoactive substances, the effect of the endothelium and some of its derivatives on aortic complaince were examined. Rats were randomly allocated to four groups, the first of which fed only the regular chow. The remaining three groups were fed the chow supplemented by daily gavage with either coconut, fish or safflower oil for 8 weeks. The thoracic aorta was removed and six 2 mm rings obtained. Rings were paired and one from each pair treated with either N W-nitro-L-arginine, indomethacin or de-endothelialized. A diameter-tension curve was initiated from wire touch position using incremental increases in wire distance until no further response observed. The data was transformed to a diameter-pressure relationship and fitted with a linear equation, the slope of which related directly to compliance. De-endothelialization (slopes: control vs de-endothelialized: 9.05±0.15 vs 8.31±0.24; P < 0.05) and indomethacin (slopes: control vs indomethacin: 9.11±0.15 vs 7.76±0.37; P < 0.05) significantly decreased arterial compliance as did dietary fish oils (slopes: control vs n-3: 9.16±0.11 vs 7.84±0.39; P < 0.05). No further effect was seen with indomethacin in the fish oil treated group. It is concluded that the endothelium and in particular, endothelium derived prostanoids, contribute to vessel compliance. We also conclude that fish oils have a similar action to indomethacin, leading to the increase in aortic stiffness observed.

Altered Prostaglandin Metabolism Induced by Angiotensin-Converting Enzyme Inhibitors in Broncho-Alveolar Lavage Fluid of the Guinea Pig

The aim of this study was to investigate if prostaglandin (PG) metabolism is altered by angiotensin-converting enzyme (ACE) inhibitors as determined in the broncho-alveolar lavage fluid (BALF) of the guinea pig. Enalapril or imidapril was orally administered once a day for 2 weeks to Hartley male guinea pigs. Twenty-four hours after the last treatment, BALF was collected and the concentrations of PGI2, thromboxane A2 (TXA2) and PGE2 were measured by enzyme immunoassay. Enalapril significantly (P<0.05) increased the TXA2 content, which was inhibited by indomethacin treatment and significantly (P<0.05) decreased the PGI2 content. Imidapril, however, did not affect TXA2 or PGI2 generation. These findings suggest that altered PG metabolism may be associated with coughing as a side effect of enalapril.

Renal blood flow, fibrinolysis, and platelet aggregation following tacrolimus (FK 506) treatment in rats

The search for better immunosuppressive agents is still continuing. Immunosuppression with cyclosporine A (CyA), however successful, has been associated with various side effects an increased incidence of thrombotic events (1,2). The enhanced response of platelets to aggregating agents (3,4), altered prostaglandin metabolism combined with endothelial injury (5), and impaired fibrinolysis (6) in patients treated with this drug are related with the thromboembolic complications. Tacrolimus (FK 506), is a new immunosuppressive drug developed in Japan and introduced for clinical use in transplanted patients, which does not produce such side effects (7). FK 506 is a novel 23-membered macrolide lactone (8). It undergoes hepatic metabolism by cytochrom P450 3A4 and biliary excretion. Its elimination is biphasic with a half-life of about 12 hours in a-phase and calculated approximately to be greater than 30 hours in the j3phase (8,9). Like CyA, FK 506 administration resulted in a decrease in renal blood flow in mice when given acutely or chronically (10,l l), and it was recently reported that FK 506 inhibited the aggregation of human platelets in vitro (12). These findings prompted us to investigate the influence of FK 506 on platelet function and fibrinolysis as well as renal blood flow, because a few data have been reported.

P-570 - Altered prostaglandin metabolism induced by angiotensin converting enzyme inhibitors.

P-570 - Altered prostaglandin metabolism induced by angiotensin converting enzyme inhibitors.

Alterations in prostaglandin metabolism of cultured human umbilical vein endothelial cells affected by smoking during pregnancy

Many endothelial cell functions that exert a regulatory influence on fetal hemodynamics and placental perfusion are modulated by metabolites of arachidonic acid, in particular prostaglandins. We used an in vitro model system to study the possible role of the vascular endothelium in the pathogenesis of chronic placental insufficiency. We examined cell growth behavior and prostaglandin metabolism in cultured umbilical vein endothelial cells from mothers exposed to the risk factor smoking during pregnancy (n=18) and compared them with healthy non-smoking control mothers (n=20). Endothelial cells from smoking mothers grew less readily than control cells. The synthesis of the prostaglandins PGI 2 and PGE 2 , both potent vasodilators and platelet aggregation inhibitors, was reduced significantly in endothelial cells from smoking mothers. Thus, if this change also occurs in the placenta, reduced prostaglandin synthesis could contribute to impaired placental perfusion. Our results suggest that prostaglandins may play an important role in the etiology and pathogenesis of chronic placental insufficiency.

Dermatitis as a Presenting Sign of Cystic Fibrosis

Three percent to 13% of patients with cystic fibrosis present with protein-energy malnutrition that is characterized by hypoproteinemia, edema, and anemia and is associated with high morbidity and mortality. Cutaneous manifestations of malnutrition are rare in patients with cystic fibrosis and have been attributed to deficiencies of protein, zinc, and essential fatty acids. We describe five patients who presented with failure to thrive, hypoproteinemia, edema, and a cutaneous eruption before the onset of pulmonary symptoms and before the diagnosis of cystic fibrosis was made. The rash had a predilection for the extremities (lower > upper), perineum, and periorificial surfaces. In most cases, erythematous, scaling papules developed by 4 months of age and progressed within 1 to 3 months to extensive, desquamating plaques. Alopecia was variable, and mucous membrane or nail involvement was not observed. The rash was associated with malnutrition and resolved in all survivors within 10 days of providing pancreatic enzyme and nutritional supplementation. The pathogenesis of the rash is unclear, but it appears to stem from deficiencies of zinc, protein, and essential fatty acids and may be mediated by alterations in prostaglandin metabolism. Cystic fibrosis should be included in the differential diagnosis of the red, scaly infant, particularly when failure to thrive, hypoproteinemia, and edema are also present. Recognition of rash as a sign of cystic fibrosis complicated by protein-energy malnutrition will allow earlier diagnosis and treatment of these patients and may improve their outcome.

Peroxisomal Abnormality in Fibroblasts From Involved Skin of CHILD Syndrome

Peroxisomal deficiency has been described in a number of syndromes characterized by chondrodysplasia punctata, including the Conradi-Hünermann (C-H) syndrome. Because of overlapping clinical features of X-chromosome inheritance, ichthyosis, and limb-reduction defects in C-H and CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndromes, we examined peroxisomal content using diaminobenzidine cytochemistry and peroxisomal functions in fibroblasts from involved vs uninvolved skin of CHILD syndrome. Fibroblasts from involved skin of a patient with CHILD syndrome accumulated cytoplasmic lipid, visualized with the fluorescent probe, nile-red. Ultrastructurally, fibroblasts of involved skin of CHILD syndrome accumulated lamellated membrane and vacuolar structures. By diaminobenzidine ultracytochemistry, fewer peroxisomes were present. Moreover, the activities of two peroxisomal enzymes, catalase and dihydroxyacetone phosphate acyltransferase, were decreased (approximately 30% of normal). However, peroxisomal oxidation of very-long-chain and branched-chain fatty acids was preserved. Moreover, plasma very-long-chain fatty acids, plasma phytanic acid, and erythrocyte plasmalogen content were normal. The CHILD, C-H, and rhizomelic chondrodysplasia punctata syndromes are all characterized by ichthyosis, chondrodysplasia punctata, and limb defects, as well as peroxisomal deficiency. Thus, these syndromes may be related pathogenically. Because peroxisomes are involved in prostaglandin metabolism, peroxisomal deficiency may directly contribute to the previously reported alterations in prostaglandin metabolism in fibroblasts of involved skin of fibroblasts.

Interferon-gamma production in atopic dermatitis: a role for prostaglandins?

Peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis (AD) have a reduced capacity to produce interferon-gamma (IFN-gamma) in vitro, in response to phytohaemagglutinin (PHA) when compared to healthy non-atopic controls. This defect appears to correlate closely with the severity of AD at the time of sampling, with less IFN-gamma being produced by cells from patients with more severe disease. Enhanced production of IFN-gamma was observed as the patients clinical symptoms improved. In addition, IFN-gamma production could be increased by either pre-culturing the cells for 3 days prior to PHA stimulation or by addition of indomethacin to the culture medium. These observations suggest that the mechanism of reduced IFN-gamma production in AD is unlikely to be due to an intrinsic cellular defect. The possibility that prostaglandins mediate the suppressed production of IFN-gamma in AD was supported by demonstrating that exogenous prostaglandin E2 (PGE2) inhibited IFN-gamma production in PHA-stimulated PBMC. PGE2 at a physiological concentration (10(-9) M) was also shown to enhance interleukin 4 induction of IgE synthesis by PBMC cultures. Our data suggest that alterations in prostaglandin metabolism play a crucial role in the pathogenesis of AD by inhibiting the production of IFN-gamma.

Post-obstruction diuresis: influence of renal prostaglandins.

The possible role of altered renal prostaglandin metabolism in the generation of post-obstruction diuresis (POD) was examined in 16 adult male Sprague-Dawley rats. Inhibition of cyclooxygenase by the administration of a combination of two nonsteroidal anti-inflammatory drugs (NSAID), meclofenamate and indomethacin in 8 of these rats exaggerated, rather than lowered the degree of natriuresis and diuresis that followed the release 24 h after bilateral ureteral ligation. Urine osmolarity was similar in the two groups of rats treated with the NSAID and vehicle. The results suggest an enhanced synthesis of renal vasoconstrictor and antidiuretic prostaglandins (thromboxane A2 or PGF2 alpha) during bilateral ureteral ligation. NSAIDs such as aspirin, indomethacin, meclofenamate and others may promote POD by blocking this prostaglandin pathway while promoting the cytochrome P450 monooxygenase pathway which may produce vasodilator, diuretic and natriuretic paracrine hormones. Additionally, inhibition of prostaglandin synthesis may have enhanced post-obstruction diuresis in the present studies by allowing a greater volume expansion during obstruction, as indicated by a reduced hematocrit in the rats that were pretreated with NSAID.

Avarol restores the altered prostaglandin and leukotriene metabolism in monocytes infected with human immunodeficiency virus type 1.

Infection of monocytes with human immunodeficiency virus type 1 (HIV-1) (strain Ada-M) caused increased levels of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in vitro. These two products result from the activities of the two enzymes cyclooxygenase and 5-lipoxygenase. The addition of the sesquiterpenoid hydroquinone Avarol, an HIV inhibitor, strongly reduced the levels of LTB4 and PGE2 via inhibition of both cyclooxygenase and lipoxygenase in monocytes. The 50% inhibition concentrations (IC50) for the enzymes were determined to be 2.26 microM (cyclooxygenase) and 1.97 microM (lipoxygenase). A 50% reduction of the extent of PGE2 and LTB4 production in HIV-infected monocytes was measured at a concentration of 0.9 microM Avarol, a dose which caused an 80% anti-HIV effect in vitro (50% inhibition of virus release from infected cells: 0.3 microM). We conclude that Avarol inhibits the enzymes cyclooxygenase and lipoxygenase and suggest that, in general, inhibitors of these enzymes are promising anti-HIV compounds.

Lipoprotein abnormalities in the progression of renal disease

Chronic renal disease is a progressive process. Implicated factors include abnormalities of the clotting cascade, altered prostaglandin metabolism, increased dietary protein intake, and abnormalities of lipoprotein metabolism. Several animal models have associated increased serum concentrations of cholesterol and triglycerides with progressive decline in renal function. The mechanism(s) of lipid-associated renal injury are unknown but may relate to lipid uptake by glomerular mesangial cells, hyperviscosity secondary to the hyperlipidemia, and a direct effect of the lipids on the glomerular basement membrane. Patients with chronic renal disease have well recognized increases in serum lipid concentrations. Whether lowering these concentrations will delay or prevent progressive renal failure or renal histologic abnormalities is unknown, but studies are underway to evaluate the effect of lipid-lowering agents in patients at risk for chronic progressive renal disease.

Short-term TPN containing n-3 fatty acids ameliorate lactic acidosis induced by endotoxin in guinea pigs

We evaluated the effect of total parenteral nutrition (TPN) enriched with n-3 fatty acids on the physiologic response to endotoxin in guinea pigs. Animals were randomly assigned to receive TPN differing only in lipid source for 3.5 d. Group 1 received soybean fat emulsion (Intralipid) whereas group 2 received fish (menhaden) oil. During the last 7 h of TPN, animals were further randomized to have either saline or E coli endotoxin added to the infusate. Acid-base status and serum lactate concentrations were determined. Animals infused with soybean fat emulsions and endotoxin developed a significant metabolic acidosis, lactic acidemia, and decrease in mixed venous O2 compared with controls and fish-oil-treated animals (p less than 0.05). The significantly reduced serum lactate and higher mixed venous O2 in fish-oil-infused animals suggests that the underlying mechanism involves improvement in endotoxin-induced tissue hypoperfusion, presumably through alterations in prostaglandin metabolism.

Alterations in Prostaglandin Metabolism in Cultured Human Umbilical Vein Endothelial Cells Affected by Atherogenic Risk Factors during Pregnancy

Alterations in Prostaglandin Metabolism in Cultured Human Umbilical Vein Endothelial Cells Affected by Atherogenic Risk Factors during Pregnancy

Elevated levels of prostaglandin E 2 in the liver of rats fed a choline deficient diet: possible involvement in liver tumor promotion

The effect of feeding a choline deficient (CD) diet, an efficient liver tumor promoting regimen, on the prostaglandin metabolism in the liver of male Sprague-Dawley rats was investigated. The possible biological significance of the alteration was examined using hypolipidemic peroxisome proliferators and modifiers of prostaglandin metabolism such as indomethacin and menhaden oil in the short term assay of the induction of enzyme altered foci in the liver. A CD diet, when fed for 10–30 days, induced 2–2.5· times increases in the levels of prostaglandin E 2 (PGE 2) in the liver, while the hypolipidemic peroxisome proliferators, 4-chloro-6(2,3-xylidino) pyrimidinylthio(N-hydroxyethyl)-acetamide (BR93l) and di(2-ethylhexyl)-phthalate (DEHP), markedly reduced the levels of this metabolite. The addition of BR93l or indomethacin to a CD diet suppressed the diet-induced elevations of PGE 2 and a substitution of fats in a CD diet with menhaden oil had the same effect. Furthermore, both indomethacin and menhaden oil added to a CD diet suppressed the induction of γ-glutamyltranspeptidase positive hepatocyte foci in the liver of rats initiated with a single dose of diethylnitrosamine after 8 weeks of the dietary promotion. The results suggest that altered prostaglandin metabolism may be involved in the liver tumor promoting effect of a CD diet.

Epidemiology and mechanistic basis of analgesic-associated nephropathy

End-stage renal failure (ESRF) due to analgesic nephropathy is still a common clinical condition in several countries, but the prevalence in dialysis patients shows large geographical differences. The frequency of ESRF of unknown aetiology is the inverse of that linked to analgesic abuse, and data suggest that the occurrence of analgesic nephropathy may be underestimated. The study of analgesic nephropathy is difficult because the earliest damage to the kidney is a renal papillary necrosis (RPN), which cannot easily be diagnosed. Continued analgesic abuse generally leads to a progressive secondary cortical degeneration which is easier to diagnose. If analgesic abuse is stopped at an early enough stage in nephropathy, clinical symptoms stabilize or improve, and ESRF may be averted. A high incidence of upper urothelial carcinoma (UUC) is also observed in individuals with a history of analgesic abuse, but it is still not clear if the two have a related pathogenesis. Study of the mechanism of RPN in animals administered analgesics and nonsteroidal anti-inflammatory drugs (NSAID) has been difficult owing to their extrarenal toxicity. Several model compounds cause identical clinical changes and have as their selective target the renal medullary interstitial cells; subsequently, other changes (including cortical and glomerular degeneration) develop as a secondary cascade. A number of mechanisms have been proposed to explain RPN (e.g., counter-current concentrating mechanism, ischaemic injury, altered prostaglandin metabolism, immunological changes), but peroxidative metabolism of papillotoxic chemicals within the interstitial cells seems to be the most likely cause. Analgesic abuse is a costly socioeconomic condition for which there is currently no clinical treatment. If it is diagnosed early enough, severe renal degeneration can be prevented. Additional epidemiological information is needed to establish the causative role of analgesics and other chemicals, in order to determine the relative risk of each. Additional animal experiments are needed in order to clarify the molecular pathogenesis of RPN and UUC, to differentiate the stages in progression to ESRF and to develop more sensitive and selective diagnostic criteria.