Cigarette smoke exposure alters [14C]arachidonic acid metabolism in aortas and platelets of rats fed various levels of selenium and vitamin E

Rats were placed on a basal diet supplemented with 0, 0.03, or 3 ppm selenium and 0 or 20 ppm vitamin E for 41-43 wk. Selenium deficiency decreased hepatic glutathione peroxidase activity and lowered both aortic prostacyclin (PGI2) and platelet thromboxane (TXA2) production compared to selenium- and vitamin E-supplemented animals. Vitamin E deficiency increased hepatic lipid peroxidation and decreased aortic PGI2 synthesis. Rats exposed daily for 31-32 wk to fresh smoke from a UK 2R1 reference cigarette had carboxyhemoglobin levels of 0.75 +/- 0.12 and 4.73 +/- 0.12% in sham- and smoke-exposed groups, respectively. Animals chronically exposed to cigarette smoke displayed a nearly twofold increase in pulmonary arylhydrocarbon hydroxylase activity. Smoke exposure produced a 26-33% decrease in aortic PGI2 synthesis compared to shams in the Se3E20, Se0.03E20, and Se3E0 groups. Smoking also increased platelet thromboxane 91% and 98% in the Se3E20 and Se3E0 groups compared to shams. It is concluded that cigarette-smoke exposure and selenium or vitamin E deficiency alter aortic PGI2 and platelet TXA2 production.     

Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure

The pharmacokinetics of nicotine and its major metabolites was evaluated in male rats after multiple-cigarette smoke exposure. A smoke-exposure apparatus was used to deliver cigarette smoke to the exposure chamber. The rats were exposed to smoke from a single cigarette every 8 hr for 14 days and to the smoke of a cigarette spiked with radiolabeled nicotine on the 15th day. Blood and urine samples were collected at timed intervals during the 10-min smoke-exposure period of the last cigarette and up to 48 hr thereafter. Nicotine, cotinine, and other polar metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. The data were analyzed by computer fitting, and the derived pharmacokinetic parameters were compared to those observed after a single iv injection of nicotine and after a single-cigarette smoke exposure. The results indicated that the amount of nicotine absorbed from multiple-cigarette smoke was approximately 10-fold greater than that absorbed from a single cigarette. Also, unlike the single-cigarette smoke exposure experiment, nicotine plasma levels did not decay monotonically but increased after the 5th hr, and high plasma concentrations persisted for 30 hr. The rate and extent of the formation of cotinine, the major metabolite of nicotine, were decreased as compared with their values following a single-cigarette smoke exposure. It was concluded that nicotine or a constituent of tobacco smoke inhibits the formation of cotinine and may affect the biotransformation of other metabolites. Urinary excretion tended to support the conclusions that the pharmacokinetic parameters of nicotine and its metabolites were altered upon multiple as compared to single dose exposure.     

Sequential changes in the structure of the rat respiratory system during and after exposure to cigarette smoke

The effect of twice daily exposure to diluted cigarette smoke on the structure of the respiratory system was examined in rats exposed for up to 84 days. Changes in respiratory tract structure were also determined in animals which were exposed for 42 days and then left untreated for an equal length of time. Daily food consumption and growth rate were reduced in sham-smoked and in smoke-exposed rats compared with cage controls. When both these treatments were stopped, food consumption and growth rate increased. Goblet cell hyperplasia of tracheal and bronchial epithelia, increased numbers of alveolar macrophages, squamous metaplasia, and hyperplasia of the larynx were seen in rats after 2 weeks of exposure to smoke. Except for tracheal goblet cell hyperplasia, within 14 to 42 days of exposure commencing all these changes showed a maximal observed response which was subsequently maintained as exposures continued up to 84 days. Tracheal goblet cell hyperplasia and alveolar metaplasia increased progressively during this extended exposure period. When exposure to smoke was discontinued after 42 days, larynx, trachea, and bronchus all reverted to normal at varying rates. The incidence, but not the severity, of the alveolar metaplasia induced during the smoke-exposure period continued to increase when animals were not being exposed to smoke.     

Synthesis of prostacyclin and thromboxane A2 by rat gastric mucosa. Comparison of 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido (1,1-a)-pyrimidine-3-carboxamide and cimetidine

The production of prostacyclin (PGI2) and thromboxane A2 (TXA2) was studied in an indometacin-induced ulcer model in rats. The specific activities of prostacyclin synthetase and thromboxane synthetase as well as the tissue content of these prostaglandins were determined. The anti-ulcer effect of cimetidine and a novel agent, i.e. 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,1-a)-pyrimidine-3- carboxamide (Chinoin-127) was compared in this respect. The indometacin treatment shifted the balance of TXA2/PGI2 to the formation of TXA2, and the anti-ulcer agents repaired it. The role of this balance in cytoprotection is discussed.     

New trends in thromboxane and prostacyclin modulators

Thromboxane A2 (TXA2) and prostacyclin (PGI2) are two labile products formed from arachidonic acid by the way of cyclooxygenase. An overproduction of thromboxane A2 has been detected in a series of diseases whereby this prostanoid is assumed to contribute to the underlying pathomechanisms by its potent stimulation of platelet aggregation and smooth muscle contraction. This increased TXA2 biosynthesis is frequently accompanied by a stimulation of prostacyclin formation which is one of the most potent inhibitors of platelet aggregation and smooth muscle contraction. Therefore, TXA2 / prostaglandin endoperoxide H2 receptor antagonists, thromboxane synthase inhibitors and drugs which combine both activities have been developed with the aim to suppress the formation and/or the action of thromboxane A2. Since prostacyclin has been demonstrated to counterbalance the pathological effects of TXA2, several PGI2 agonists have also been developed. This review will highlight the evolution and some of the latest findings in the field of prostacyclin and thromboxane A2 modulators mainly those which are under clinical evaluation or marketed.     

Augmented thromboxane generation by mesenteric arteries from pancreatectomized diabetic dogs is coincident with the vascular tone enhancement evoked by Na arachidonate and prostacyclin

We studied the relationships between arachidonic acid (AA) metabolism and contractile responses to Na arachidonate (NaA) and the prostaglandins (PGs) in mesenteric arteries isolated from sham-operated and totally pancreatectomized dogs. PGE2 and PGF2 alpha produced a similar dose-dependent relaxation of mesenteric arteries from normal and diabetic dogs. On the contrary, NaA and prostacyclin (PGI2) enhanced the resting basal tone of arteries from pancreatectomized animals but depressed it in arteries from intact normal control or from sham-operated groups. Inhibitors of thromboxane A2 (TXA2) biosynthesis abolished in vitro the vasoconstricting effect of NaA and PGI2 in diabetics whereas inhibitors of PGI2 biosynthesis blocked the vasodilating influence of NaA in normal mesenteric vessels. Additionally, antagonists of cyclooxygenase activity prevented both the vasoconstricting and the vasodilating actions of NaA in normal and in diabetic arteries, respectively, as well as the PGI2 tone enhancement in vessels from diabetics. In arteries from pancreatectomized animals treated with insulin, PGI2 induced a biphasic (constriction and relaxation) effect of a magnitude between that of effects seen in normal controls or sham-operated and those in untreated diabetic animals. The basal radioconversion of exogenous [1-14C]AA, showed that mesenteric arteries from diabetic dogs generated more TXB2 than did vessels from intact normal control or sham-operated dogs. Moreover, in the presence of exogenous PGI2, the vascular production of TXB2 from AA in the diabetic group was significantly greater than that of preparations not exposed to PGI2. The % conversion of AA into PGI2 (assessed as 6-oxo-PGF1 alpha) was similar in normal controls, in sham-operated and in diabetic vessels. Insulin given in vivo abolished the greater basal conversion of AA into TBX2 by mesenteric arteries from diabetic dogs and significantly attenuated the enhanced prostacyclin-evoked generation of thromboxane. The present results strongly suggest that the abnormal constricting response evoked by NaA and PGI2 in mesenteric arteries from diabetic dogs could be related to the generation of TXA2 by vessel walls.     

Effects of phospholipases A2 from Vipera russelli snake venom on blood pressure, plasma prostacyclin level and renin activity in rats

Vipera russelli venom contains several isoenzymes of phospholipase A2 (PLA2) which were isolated by column chromatography. The effects of PLA2 fractions on blood pressure, plasma prostacyclin level and renin activity were studied in normotensive and renal hypertensive rats. PLA2 fractions II-5, II-7, III-3 and III-6 (0.1 mg/kg) injected i.v. into rats decreased the arterial blood pressure. The hypotensive action of PLA2 fractions was not affected by heat treatment (70-80 degrees C, 30 min, pH 6.8). After indomethacin (30 mg/kg, i.v.), the hypotensive response to PLA2 was markedly reduced. Plasma prostacyclin (PGI2) and thromboxane A2 (TXA2) levels were measured by radioimmunoassays of their degradation products, 6-keto-PGF1 alpha and TXB2, respectively. PLA2 fractions (0.1 mg/kg) induced an increase in plasma PGI2 and TXA2 levels. There was a positive linear correlation between the PLA2-induced hypotensive effect and the ratio of increased 6-keto-PGF1 alpha to TXB2 (r = 0.83) in normotensive rats. In renal hypertensive rats, the increase in PGI2 level was larger than in normotensive rats. Plasma renin activity was also measured by the radioimmunoassay. Plasma renin activity was reduced by PLA2 fractions in renal hypertensive rats, but not in normotensive rats. These results suggest that the hypotensive effect of PLA2 fractions in normotensive rats may be partly due to the increase in plasma prostacyclin and thromboxane A2 levels. In addition to the larger increase in plasma PGI2 level, the reduction in plasma renin activity may also contribute to the greater hypotensive effect of PLA2 fractions in renal hypertensive rats.     

Effects of chronic smoke exposure on the cardiovascular responses to acute nicotine infusion in the rat

Rats were exposed daily to cigarette smoke for 17-22 weeks in order to characterize mean arterial pressure and regional hemodynamic effects of chronic smoke exposure and to determine if cardiovascular reactivity to acute nicotine infusions is altered by chronic smoke exposure. Urethane-anesthetized animals were instrumented with miniaturized pulsed-Doppler flow probes on the iliac and mesenteric vascular beds. Under resting conditions sham-smoked and smoke-exposed animals had similar levels of mean arterial pressure and mesenteric blood flow; however, resting heart rate was lower in the smoke-exposed group, while iliac blood flow was elevated in the smoke-exposed group. Acute nicotine infusion (6.25, 12.5 and 25 micrograms/kg per min) produced equivalent, dose-dependent pressor effects as well as increases in iliac and mesenteric resistance in sham and smoke-exposed groups. Thus, chronic cigarette smoke-exposure in rats may exert significant cardiovascular effects other than on arterial pressure such as lowered heart rate and elevated blood flow to skeletal muscle beds, while cardiovascular responses to nicotine are not altered by chronic smoke-exposure.     

The effect of cigarette smoke on gastroduodenal mucosal endogenous prostacyclin level (experimental and clinical observations)

In our opinion the endogenous prostacyclin (PGI2) is one of the most important natural protective substances in the gastric mucosa. We have, therefore checked in experimental circumstances in rats, as well as in clinical observations in humans, the possible effect of smoking on endogenous gastroduodenal mucosal PGI2 level. The animal experiments seem to verify that cigarette smoke really has an unwanted effect on the gastric mucosa. The target of this action is the endogenous PGI2 content of the mucosa. According to our observations in humans there is a definite tendency toward decreased endogenous PGI2 production in the gastroduodenal mucosa of smokers too.     

阿司匹林预处理对大鼠脑缺血再灌注损伤的神经保护作用

目的:观察阿司匹林(ASA)预处理对大鼠局灶性脑缺血再灌注损伤(I/R)的神经保护作用,并对其作用机制进行探讨。方法:复制大鼠大脑中动脉缺血再灌注模型,分别采用TTC染色法、神经功能缺损评分法观察ASA预处理对大鼠脑梗死体积和神经功能评分的影响,以及对脑组织中超氧化物歧化酶(SOD)、丙二醛(MDA)和血前列环素I2(PGI2)/血栓素A2(TXA2)的影响。结果:ASA能够降低I/R大鼠脑梗死体积和神经功能评分,增加脑组织中SOD的活性,降低MDA的含量,升高血PGI/TXA2的比值。结论:ASA对大鼠脑缺血再灌注损伤有一定保护作用,其作用机制与增加脑组织中SOD的活性、降低MDA的含量、提高血PGI2/TXA2的比值有关。     

Inhalation of tobacco smoke induces increased proliferation of urinary bladder epithelium and endothelium in female C57BL/6 mice

Cigarette smoking is the major environmental risk factor for bladder cancer in humans. Aromatic amines, potent DNA-reactive bladder carcinogens present in cigarette smoke, contribute significantly. However, increased cell proliferation, caused by direct mitogenesis or in response to cytotoxicity, may also play a role since urothelial hyperplasia has been observed in human cigarette smokers. We examined the urothelial effects of cigarette smoke (whole body inhalation exposure (Teague) system) in female C57BL/6 mice at various times in two studies, including reversibility evaluations. In both studies, no urothelial hyperplasia was observed by light microscopy in any group. However, in study 1, the Ki-67 labeling index (LI) of the urothelium was significantly increased in the smoke exposed group compared to controls through 3 months, but was not present at 6, 9 or 12 months even with continued exposures. In the groups that discontinued smoke exposure, it returned to the same levels as controls or lower. In study 2, the bromodeoxyuridine LI was similar to controls on day 1 but significantly increased at 5 days in the smoke exposed group. In the group that discontinued smoke exposure for 2 days, the LI was increased compared to controls but not significantly. Superficial urothelial cell cytotoxicity and necrosis were detectable by scanning electron microscopy at 5 days. Changes in LI of submucosal endothelial cells generally followed those of the urothelium and effects were reversible upon cessation of exposure. The increased urothelial proliferation appeared to be due to superficial cell cytotoxicity with consequent regeneration.     

Effects of smoking and nicotine on human prostacyclin and thromboxane production in vivo and in vitro

We studied the effects of smoking and nicotine on the production of proaggregatory thromboxane A2 (TxA2), antiaggregatory prostacyclin (epoprostenol, PGI2), and on lipid peroxidation in vivo and in vitro. In the in vivo study, serum concentrations of thromboxane B2 (TxB2), a stable metabolite of TxA2, increased immediately after smoking three cigarettes but not after smoking the equivalent amount of tobacco in a pipe, whereas serum lipid peroxide values did not change in either group. In vitro, nicotine (2 X 10(-3) mol/liter) inhibited pulmonary TxB2 production by 70% and simultaneously stimulated the production of 6-keto-prostaglandin F1 alpha, a stable metabolite of PGI2, by 40%, which suggest that nicotine does not exert its effect at the cyclooxygenase level. During aggregation in platelet-rich plasma, TxB2 production was inhibited by 53% with 2 X 10(-3) mol/liter of nicotine, and during whole blood clotting the inhibition was 34% with 2 X 10(-4) mol/liter of nicotine. Thus the rise in cigarette smokers' serum TxB2 was probably caused by some constituent of cigarette smoke other than nicotine. The increased production of TxA2 following cigarette smoking may provide one explanation for the increased incidence of atherosclerosis and its complications in cigarette smokers.     

Thromboxane A2 analogue (U-46619) stimulates vascular PGI2 synthesis

Since platelet release reaction products (e.g. serotonin, ADP) stimulate prostacyclin (PGI2) release in vitro, we have investigated whether thromboxane A2 (TXA2) also has a similar effect. An analogue, U-46619, was used for the experiments, since TXA2 is extremely unstable. U-46619 stimulated rat aortic PGI2 release; this stimulation was abolished by (a) EDTA and (b) verapamil. We conclude that TXA2 is a calcium-dependent stimulator of PGI2 release; this property may be relevant to the limitation of platelet aggregates in vivo and to vascular injury.     

Transformation of arachidonic acid and prostaglandin endoperoxides by the guinea pig heart. Formation of RCS and prostacyclin.

The metabolism of arachidonic acid (AA) was studied in perfused isolated hearts from guinea pigs. The coronary effluent was continuously bioassayed for prostaglandin-like substances (PLS) using the cascade technique of Vane. Injections of AA in doses between 1--50 microgram into the perfusion fluid prior to the heart produced vasodilatation of the coronary vascular bed followed by a contraction of the rat stomach strip (RSS), chick rectum (CR) and rat colon (RC) as well as relaxation of the bovine coronary artery (BCA). At the higher doses of AA there was also contraction of the rabbit aorta (RbA). The same pattern of effects on the bioassay tissues was seen when prostaglandin endoperoxide (PGH2) was perfused through the heart. The response of the bank of superfused tissues provided evidence for the formation of prostacyclin (PGX or PGI2), PGE2 and PGF2alpha. Chromatographic studies showed that 6-oxo-PGF1alpha together with other prostaglandins was present in the perfusate after acidification, which suggested that the bovine coronary relaxing substance consists mainly of PGI2. Moreover, the rabbit aorta contracting substance (RCS) released in the perfusate was due to prostaglandin endoperoxides and not to thromboxane (TXA2). The formation of PLS from AA was completely blocked after treatment of the heart with the cyclo-oxygenase inhibitors, indomethacin or meclofenamic acid. Pretreatment of the heart with 15-hydroperoxyarachidonic acid (15-HPAA), a selective inhibitor of prostacyclin synthetase, inhibited the effect of AA on the coronary vasculature and diverted the metabolic transformation of AA towards PGE2 and PGF2alpha.     

Advance in understanding the biosynthesis of prostacyclin and thromboxane A2 in the endoplasmic reticulum membrane via the cyclooxygenase pathway

Recent advances in topological and structural characterization of the prostacyclin (PGI(2)) and thromboxane A(2) (TXA(2)) synthases have led to the understanding of the biosynthesis of PGI(2) and TXA(2) at a structural level. This mini-review focuses on the molecular mechanism of the isomerization of the prostaglandin H(2) to PGI(2)and TXA(2) by their synthases in the endoplasmic reticulum (ER) membrane coordinated with cyclooxygenase-1 or -2. This review summarizes the evidences in which the biosynthesis of PGI(2)and TXA(2) are influenced/modulated by the membrane anchor residues of the synthases and the ER membrane itself, and provides the structural basis for engineering the synthases for the next generation of gene therapy and drug designs targeting the specific synthases.     

Comet assay and air–liquid interface exposure system: A new combination to evaluate genotoxic effects of cigarette whole smoke in human lung cell lines

Over the past three decades, the genotoxic effects of cigarette smoke have generally been evaluated in non-human cell models after exposure to particulate phase, gas phase, or cigarette smoke condensate, rather than the whole smoke aerosol itself. In vitro setups using human cell lines and whole smoke exposure to mimic actual aerosol exposure should more accurately reflect human cigarette smoke exposure. We investigated the VITROCELL® 24 air–liquid interface exposure system in combination with the comet assay to assess DNA damage in two different human lung epithelial cell lines exposed to whole smoke. Results showed a repeatable and reproducible dose–response relationship between DNA damage and increased whole smoke dose in both cell lines. Thus, the combination of the comet assay with the VITROCELL® 24 represents a valuable new in vitro test system to screen and assess DNA damage in human lung cells exposed to whole smoke.     

Effects of cigarette smoke on the metabolism of vasoactive hormones in rat isolated lungs.

1. The effects of exposure of rats to cigarette smoke have been studied on the metabolism of vasoactive hormones in isolated lungs from these animals. 2. Rats were exposed for 1 h per day to cigarette smoke for 1 day or for 10 days. 3. Angiotensin I conversion was increased after 1 day's exposure but after 10 days' exposure conversion returned to normal. 4. Inactivation of prostaglandin E2 was decreased after 1 day's exposure. After 10 days' exposure there was a further decrease which could not be attributed to smoke alone. 5. The inactivation of 5-hydroxytryptamine and bradykinin remained unchanged after both short and longer exposures to smoke. 6. The metabolic activity of the lung towards some vasoactive hormones in the pulmonary circulation is affected by exposure of the animal to cigarette smoke and such changes may be relevant to the initiation of cardiovascular changes consequent upon cigarette smoking.     

Prostacyclins are only weak antagonists of coronary vasospasm induced by authentic thromboxane A2 and serotonin

The actions of prostacyclin and its synthetic analog iloprost on the release and action of platelet-derived serotonin (5-HT) and thromboxane (TX) A2 were studied in vitro. Washed human platelet suspensions (WPS) (4 X 10(8) platelets/ml) were stimulated with arachidonic acid (AA) (30 mumol/L) and the incubate transferred into an organ bath containing bovine coronary arteries (BCA) in Krebs-Henseleit buffer supplemented with a mixture of blocking agents, including indomethacin. This resulted in a biphasic contraction of the coronary arteries, consisting of first, a TXA2-mediated response and second, a 5-HT-mediated response. The 5-HT-mediated reaction was dose-dependently inhibited by methysergide (IC50: 80 nmol/L). Treatment of the WPS with prostacyclin (PGI2) or iloprost prior to stimulation by AA resulted in a dose-dependent inhibition of the 5-HT-mediated contraction, due to inhibition of 5-HT release. The TXA2-mediated component, as well as the concentration of immunoreactive TXB2 in the bath medium, remained unchanged. Addition of PGI2 or iloprost to the BCA prior to transfer of stimulated WPS to the bath medium was followed by a dose-dependent inhibition of both phases. This, however, required concentrations of 100 nmol/L 5-HT and greater than 300 nmol/L TXA2 (IC50), which already produced a nearly complete direct relaxation of the vessel preparations (EC50: 30 nmol/L). It is concluded that a significant spasmolytic action of prostacyclins against platelet-derived vasoconstrictors in vivo might only be obtained at concentrations that already produce considerable direct effects on vessel tone.     

Development of dual-acting benzofurans for thromboxane A2 receptor antagonist and prostacyclin receptor agonist: synthesis, structure-activity relationship, and evaluation of benzofuran derivatives

Prostacyclin (PGI(2)) is an unstable, powerful endogenous inhibitor of platelet aggregation, and thromboxane A(2) (TXA(2)) is an unstable endogenous arachidonic acid metabolite that plays a pivotal role in platelet aggregation and vasoconstriction. The balance between TXA(2) and PGI(2) greatly affects maintenance of the homeostasis of the circulatory system. A novel series of benzofuran-7-yloxyacetic acid derivatives was discovered as potent dual-acting agents to block the thromboxane A(2) receptor and to activate the prostacyclin receptor. Synthesis, structure-activity relationship, and in vitro and ex vivo pharmacology of this series of compounds are described. The most potent in the series was {3-[2-(1,1-diphenylethylsulfanyl)ethyl]-2-hydroxymethylbenzofuran-7-yloxy}acetic acid diethanolamine salt (7) with K(i) of 4.5 nM for thromboxane receptor antagonism and K(i) of 530 nM for prostacyclin receptor agonism. Remarkably, compound 7 is a promising candidate for novel treatment as an antithrombotic agent with other cardiovascular actions to avoid hypotensive side effects.     

Excretion of metabolites of prostacyclin and thromboxane by rats with nephrotoxic nephritis: effects of interleukin-1.

1. To obtain direct evidence of abnormal eicosanoid biosynthesis in rats injected with anti-glomerular-basement-membrane antibodies (a-GBM), products derived from thromboxane A2 (TXA2) and prostacyclin (PGI2) were measured in 24 h urine collections before and after a-GBM. 2. Administration of a-GBM (9.5 mg) caused albuminuria, decreased creatinine clearance, increased numbers of intra-glomerular neutrophils and increased excretion of TXB2, 2,3-dinor-TXB2 (products of TXA2) and 6-oxo-PGF 1 alpha and 2,3-dinor-6-oxo-PGF 1 alpha (products of PGI2) at 24 h. 3. Interleukin-1 (IL-1 beta; 5 micrograms) alone caused an increase in PGI2 metabolite excretion but had no effect on TXA2 metabolites. It had no effect on creatinine clearance but increased numbers of glomerular neutrophils by approximately 4-5 fold compared to a-GBM. 4. Pretreatment of rats with IL-1 beta before a-GBM synergistically increased albumin excretion but only additively increased eicosanoid excretion. Numbers of intra-glomerular neutrophils and creatinine clearance were unchanged compared to IL-1 beta alone. 5. The cyclo-oxygenase inhibitor, ibuprofen (10 mgkg-1 i.p., twice daily for 4 days) inhibited both serum TXB2 production and urinary prostaglandin excretion. It also caused an almost complete attenuation of albumin excretion. Creatinine clearance and glomerular neutrophils remained unchanged after a-GBM/IL-1 beta. 6. We conclude that the 50% inhibition of thromboxane production induced by ibuprofen does not modify the fall in creatinine clearance of accumulation of neutrophils in the glomerulus caused by the a-GBM. This degree of inhibition of eicosanoid production was associated with a striking decrease in proteinuria, but this may reflect a haemodynamic rather than a disease modifying action.