Absence of prostacyclin greatly relieves cyclophosphamide-induced cystitis and bladder pain in mice.

Cyclophosphamide (CP) has been widely used in the treatment of various malignancies and autoimmune diseases, but acrolein, a byproduct of CP, causes severe hemorrhagic cystitis as the major side effect of CP. On the other hand, a large amount of prostacyclin (PGI2 ) is produced in bladder tissues, and PGI2 has been shown to play a critical role in bladder homeostasis. PGI2 is biosynthesized from prostaglandin (PG) H2 , the common precursor of PGs, by PGI2 synthase (PTGIS) and is known to also be involved in inflammatory responses. However, little is known about the roles of PTGIS-derived PGI2 in bladder inflammation including CP-induced hemorrhagic cystitis. Using both genetic and pharmacological approaches, we here revealed that PTGIS-derived PGI2 -IP (PGI2 receptor) signaling exacerbated CP-induced bladder inflammatory reactions. Ptgis deficiency attenuated CP-induced vascular permeability and chemokine-mediated neutrophil migration into bladder tissues and then suppressed hemorrhagic cystitis. Treatment with RO1138452, an IP selective antagonist, also suppressed CP-induced cystitis. We further found that cystitis-related nociceptive behavior was also relieved in both Ptgis-/- mice and RO1138452-treated mice. Our findings may provide new drug targets for bladder inflammation and inflammatory pain in CP-induced hemorrhagic cystitis.

Prostaglandin I2 analogs inhibit proinflammatory cytokine production and T cell stimulatory function of dendritic cells.

Signaling through the PGI(2) receptor (IP) has been shown to inhibit inflammatory responses in mouse models of respiratory syncytial viral infection and OVA-induced allergic responses. However, little is known about the cell types that mediate the anti-inflammatory function of PGI(2.) In this study, we determined that PGI(2) analogs modulate dendritic cell (DC) cytokine production, maturation, and function. We report that PGI(2) analogs (iloprost, cicaprost, treprostinil) differentially modulate the response of murine bone marrow-derived DC (BMDC) to LPS in an IP-dependent manner. The PGI(2) analogs decreased BMDC production of proinflammatory cytokines (IL-12, TNF-alpha, IL-1alpha, IL-6) and chemokines (MIP-1alpha, MCP-1) and increased the production of the anti-inflammatory cytokine IL-10 by BMDCs. The modulatory effect was associated with IP-dependent up-regulation of intracellular cAMP and down-regulation of NF-kappaB activity. Iloprost and cicaprost also suppressed LPS-induced expression of CD86, CD40, and MHC class II molecules by BMDCs and inhibited the ability of BMDCs to stimulate Ag-specific CD4 T cell proliferation and production of IL-5 and IL-13. These findings suggest that PGI(2) signaling through the IP may exert anti-inflammatory effects by acting on DC.

Disturbance of vision by COX-2 inhibitors.

In this review, 35 cases of acute, reversible, sometimes severe, disturbances of vision closely associated with the use of celecoxib or rofecoxib are described. These were identified from three different databases using strict selection criteria. The events included temporary blindness, visual field defect, scotoma, teichopsia, blurred vision, decreased vision and abnormal vision. The reactions had a mean onset time of 9.5 days and recovery occurred within 3 days following withdrawal of the drug. The reactions do not appear to be related to age, gender, dose, or indication for use. The incidence of reported cases is estimated to be not less than 5 per 10,000 patients. Possible mechanisms for this type of reaction are described. The most likely appears to be the result of interference with the retinal blood supply through reduced production of prostanoids. Genetic polymorphisms that affect drug metabolism or uptake could be risk factors and are discussed along with suggestions for research.

Prostacyclin-deficient mice develop ischemic renal disorders, including nephrosclerosis and renal infarction.

BACKGROUND: Prostacyclin (PGI2) is a short-lived endogenous inhibitor of platelet aggregation and a potent vasodilator and regulator of the growth of vascular smooth muscle cells. To study the role of PGI2 in the vascular system in vivo, PGI2-deficient (PGID) mice were established by genetic disruption of the PGI2 synthase gene. METHODS AND RESULTS: PGI2 synthase-null mice were generated by replacing the exons of PGI2 synthase gene that encodes for the catalytic site of the enzyme with a neomycin resistance gene. In these mice, PGI2 levels in the plasma, kidneys, and lungs were reduced, whereas thromboxane and prostaglandin E2 levels became elevated. Blood pressure and the amounts of urea nitrogen and creatinine in plasma of the PGID mice were significantly higher than those of wild-type mice (P<0.05). They developed progressive morphological abnormalities in the kidneys, accompanied by atrophy, surface irregularity, fibrosis, cyst, arterial sclerosis, and hypertrophy of vessel walls. Thickening of the thoracic aortic media and adventitia were observed in aged PGID mice. Importantly, these phenotypes have not been reported in PGI2 receptor-deficient mice. CONCLUSIONS: PGI2 deficiency resulted in the development of vascular disorders with the thickening of vascular walls and interstitial fibrosis, especially in mouse kidneys. The findings demonstrated in vivo that PGI2 is important in the homeostasis of blood vessels. Our established PGID mice are useful for studies on the initiation and development of vascular diseases, such as ischemic renal disorders with arterial sclerosis and infarction, and also for studies on the novel signaling pathway of PGI2.

Prostacyclin deficiency and reduced fetoplacental blood flow in pregnancy-induced hypertension and preeclampsia.

BACKGROUND: Low endothelial generation of prostacyclin (PGI(2)) is a typical feature of pregnancy-induced hypertensive disorders. The aim of the current study was to establish whether changes in PGI(2) are accompanied by alterations in fetoplacental blood flow and to test the hypothesis that PGI(2) deficiency contributes to reduced fetoplacental perfusion in pregnancy-induced hypertension (PIH) and preeclampsia. METHODS: The study included 11 women with normal pregnancies, 12 with PIH/preeclampsia, and 7 with otherwise complicated pregnancies. Fetoplacental blood flow was assessed both by umbilical artery Doppler sonography measuring the resistance index (RI) and by means of neonatal birth weight. PGI(2) formation was measured in umbilical arteries prepared immediately after birth. PGI(2), RI and birth weight were correlated with and without correction for gestational age. Furthermore, data from patients with PIH/preeclampsia were compared with normal pregnancies as controls. RESULTS: A significant inverse correlation was found between umbilical PGI(2) formation and umbilical RI and between birth weight and RI, whereas PGI(2) and birth weight were directly related. Patients with PIH/preeclampsia showed reduced PGI(2) formation, markedly increased gestational age-corrected RI and significantly reduced percentile birth weight. CONCLUSIONS: These results provide evidence showing that PGI(2) is a relevant mediator of fetoplacental blood flow and suggest an important role of PGI(2) deficiency in PIH/preeclampsia.

Síndrome de Hellp como manifestación de descompensación de la preeclampsia durante el puerperio: presentación de dos casos / Hellp syndrome as a decompensation of pre-eclampsia during puerperium. two cases presentation

Se presentan dos casos clínicos extremos de enfermedad hipertensiva inducida por el embarazo y síndrome de Hellp puerperal, así como la revisión de la literatura. Hellp es un acrónimo en inglés, utilizado para describir a la paciente con preclampsia severa o eclampsia, quien también presenta hemólisis, enzimas hepáticas elevadas y plaquetas disminuidas. No ha sido dilucida por completo su etiología pero se ha aceptado la teoría de un desequilibrio en el metabolismo prostanoide. Su incidencia oscila de 5 a 15 por ciento entre las pacientes con enfermedad hipertensiva inducida por el embarazo. La mortalidad materna entre 10 y 28 por ciento y la neonatal al rededor de 40 por ciento. Debido a las complicaciones fatales que puede presentar, la base del tratamiento es la interrupción del embarazo. Se señala la importancia de la detección temprana de esta entidad clínica, lo cual mejora el pronóstico materno-fetal

Complete cerebral ischemia, prostacyclin deficiency, and therapeutic possibilities.

This report summarizes the results of our studies on the effects of prostacyclin (PGI2) on the outcome of global cerebral ischemia (GCI). GCI was produced for 15 and 20 min. In vivo dialysis of the hippocampus was used to determine the changes in extracellular concentrations of calcium (Ca/2e) and blood-brain barrier (BBB) permeability. Moreover, EEG and general physiological parameters were recorded. This was combined with morphological observations. PGI2 was infused continuously i.v. at a rate of 2 micrograms/kg/min. Rabbits with untreated GCI served as reference. Treatment with PGI2 significantly enhanced EEG recovery and normalization during recirculation, and reduced both the decrease in Ca+2e, and the BBB leakage. The number of ischemic neurons in the PGI2-treated rabbits was significantly lower than in the non-treated ones. PGI2 reduced brain edema. These data suggest that PGI2 may protect against postischemic brain damage, in part by inhibiting excessive calcium influx to neurons and in part by tightening of BBB.

Deficiency of prostacyclin production in meningococcal shock.

A deficiency of prostacyclin (PGI2) production by the vascular endothelium might underline the severe vasoconstriction and intravascular thrombosis that characterise meningococcal shock. The effect on PGI2 synthesis by human umbilical vein endothelial cells (HUVEC) in culture was examined in sera from children with meningococcal shock, healthy adults, and children with other febrile illnesses. In comparison with adult controls, PGI2 synthesis was reduced when HUVEC were incubated with the sera from 10 of 13 patients with meningococcal shock. A similar defect was observed with only four of 20 sera from children with other febrile illnesses. The effect of sera from patients with meningococcal shock on HUVEC was reversible with normal serum, and seems to be due to the absence of a factor necessary for PGI2 production rather than an inhibitor. These findings suggest that a deficiency of PGI2 may have a role in the pathogenesis of meningococcal shock and that exogenous PGI2 may be of therapeutic benefit.

[Hellp syndrome. Presentation of a case and review of the literature]. / Síndrome Hellp. Presentación de un caso y revisión de la literatura.

A severe case of preeclampsia with Hellp Syndrome is reported. Clinical findings, laboratory abnormalities and pathogenesis, were discussed. We concluded that severe preeclampsia and Hellp Syndrome are not different diseases, but the natural course of preeclampsia per se.

[The role of thromboxane A2 and prostacyclin in the pathogenesis of diabetes mellitus in children and adolescents]. / Rol' tromboksana A2 i prostatsiklina v patogeneze sakharnogo diabeta u detei i podrostkov.

The follow-up of children and adolescents (n-41) suffering from insulin-dependent diabetes mellitus has demonstrated that the increase of the thromboxane/prostacyclin ratio pointing to the derangement of microcirculatory regulation occurs during the decompensation phase of the disease and is a risk factor of the development of diabetic complications. The revealed disorders of arachidonic acid metabolism may be one of the causes of the tendency towards decrease of pulse arterial pressure in grave diabetes mellitus.

[The significance of eicosanoids in gestosis]. / Bedeutung der Eikosanoide bei der Gestose.

Eicosanoids, especially prostaglandins and other arachidonic acid metabolites, play an important role in gestosis. Experimental and clinical evidence suggest prostacyclin deficiency, enhanced platelet reactivity and increased production of thromboxane A2 as possible reasons for gestosis. In addition, pathological interactions between cyclooxygenase-derived products and the renin-angiotensin- and kallikrein-kinin systems may exist and contribute to hypertension and reduced fetoplacental blood flow. Moreover, pregnancy-induced hypertension appears to be also related to lipoxygenase products and enhanced lipid peroxidation. In general, little is known about the regulation of arachidonic acid metabolism in gestosis. It is also unknown whether altered activities of mediators and hormones are cause or effect of pregnancy-induced hypertension. This is particularly relevant to the site of eicosanoid formation, i.e. platelets, the trophoblast or endothelial cells. At this time, it is not possible to give therapeutical recommendations, which are specifically designed to correct changes in eicosanoid production in gestosis. Antihypertensive therapy alone is insufficient, particularly with regard to the fetal situation. Preventive treatment with low-dose acetylsalicylic acid may have a protective effect against pregnancy-induced hypertension. Presently, more selective antagonists of thromboxane generation and/or action are being developed and might provide fresh insights both into the pathology of the disease and improved drug treatment.

Thrombotic thrombocytopenic purpura and related disorders.

This article provides us with background information on the disease. Clinical features, variants and classification, laboratory findings, and pathology are discussed. Knowledge of the disease's pathogenesis has increased recently and specific causes discussed are predisposing factors, triggering agents, endothelial damage, defective PGI2 bioavailability, FVIII/vWF multimeric structure abnormalities, platelet activation, and hemolytic anemia. Proposed specific therapies discussed are steroids, heparin, antiplatelet agents, prostacyclin, splenectomy, immunosuppressive agents, plasma infusion, and plasma exchange.

PIP: Thrombotic thrombocytopenic purpura (TTP) is a syndrome that occurs mainly in adults with multiorgan microvascular thrombosis consisting of thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal involvement, and fever. The female to male ratio is 3:2, and peak incidence occurs in the 3rd decade of life. Clinical signs are the consequence of hyaline thrombosis and occlusion of capillaries and arterioles. Renal ailment manifests itself in hematuria and proteinuria with azotemia and even overt renal failure. In severe disease, azotemia is typical of hemolytic uremic syndrome (HUS). TTP was first described in 1925 by Moschcowitz. The clinical picture of TTP consists of a prodromal phase, a viruslike disease occurring in up to 40% of patients. 60% have neurologic disturbances, 90% have purpura initially, and fever occurs in all. Anemia is often severe with hemoglobin values of 7-9 gm/dl, renal involvement in 90%, and renal failure in 40-80% of patients. Clinical variants include the acute and fulminant variety mortality, the chronic form, and the relapsing form. Predisposing factors and triggering agents are autosomal recessive inherited traits in acute idiopathic TTP, systemic diseases, tumor antigens, pregnancy and puerperium, viruses (endotoxins for HUS), and possibly oral contraceptives and hypertension. Therapy includes corticosteroids (prednisone 100-400 mg/day); heparin for postpartum HUS; and antiplatelet agents (Dextran 70, aspirin, and dipyridamole in high doses). The infusion of PGI2 is controversial; splenectomy is also questionable; and vincristine, azathioprine, and cyclophosphamide have unproven efficacy. Fresh-frozen plasma exchange is the method of choice as it produces survival in 90%. Others are iv immunoglobulins, vitamin E, and dialysis and renal transplant. Platelet transfusions are contraindicated because of sudden death and decreased survival.

Alterations in blood pressure by derangement of the mechanisms that regulate sodium excretion.

Understanding the sequence of events responsible for pressure-related natriuresis and their pathophysiologic alterations may be useful in distinguishing various types of essential hypertension of renal origin. The perturbation of a distal step in the sequence is likely to be reflected in a simple physiologic defect. For instance, pathophysiologic alterations in the medullary production of prostaglandin E2 might directly influence natriuresis and diuresis because of its modulatory effect on tubular reabsorption of sodium and water. Perturbation of more proximal steps in the sequence could influence all the distal events as well. For instance, prostaglandin I2 and endothelium-derived relaxing factor may be produced by the preglomerular vasculature in response to alterations in renal perfusion pressure and may modulate the release of renin from the juxtaglomerular cells. Thus, variations in the production of prostaglandin I2 or endothelium-derived relaxing factor may be reflected by various renal vascular, tubular, and systemic homeostatic events related to the renin-angiotensin system.

[Prostacyclin-thromboxane balance and risk factors of ischemic heart disease]. / Prostatsiklin-tromboksanovyi balans i faktory riska ishemicheskoi bolezni serdtsa.

The paper considers the significance of prostacyclin-thromboxane (PGI2/TxA2) balance for cardiovascular performance in health and in angina pectoris and myocardial infarction. The functional interaction between prostacyclin and thromboxane was examined in terms of a number of risk factors for coronary heart disease (CHD), such as ageing, atherosclerosis, arterial hypertension, diabetes mellitus, obesity, hypokinesia, smoking, alcoholism, sex differences, and predisposition to the disease. A unidirectional pattern of changes in the PGI2/TxA2 balance towards TxA2 was found in CHD and in the presence of all the aforementioned risk factors. The paper discusses possible mechanisms responsible for these changes, as well as their contribution to the pathogenesis and prevention of CHD.

[Prevalence of plasma factor deficiency in the Vienna population. Results of a screening study of 1,300 adults]. / Prävalenz des Plasmafaktormangels in der Wiener Bevölkerung. Ergebnisse einer Screening-Untersuchung an 1300 Erwachsenen.

A screening investigation for the presence of risk factors for the development of atherosclerosis demonstrates a plasma factor deficiency in 0.8% in the Viennese population. These findings are in agreement with the data of a newborn screening performed earlier. All the persons were clinically healthy. In 4 of them at least 1 family member suffered from the same defect. The pathogenetic relevance of the plasma factor defect for thrombophilia at young age is discussed.