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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two murine models of lupus were employed to challenge an hypothesized mechanism by which antiphospholipid antibodies (APLA) might promote thrombosis: altering prostacyclin (PGI2) and thromboxane (TX) production. PGI2 levels in mouse blood and the ex vivo release of PGI2 and TX from mouse kidney were measured. Since APLA have been reported to alter synthesis or activation of several molecules mediating fibrinolysis, murine plasma levels of the fibrin degradation product, D-dimer were also determined. Two murine strains, one prone to spontaneous "lupus-like" illness (MRL-lpr) and related strain (MRL-(+2)), were compared. The assays confirm that MRL-lpr mice have increased anticardiolipin antibody (ACA) and two-fold increased release of TX from renal tissues compared to MRL-(+2) mice. However, these mice have low levels of plasma D-dimer. NIH Swiss mice injected with IgG (containing APLA) from thrombosis-prone lupus patients had high blood ACA titers and D-dimer levels, but both ACA and D-dimer were low or non-detectable in Swiss mice injected with saline or normal IgG. Unlike mice with spontaneous lupus-like illness, healthy mice injected with APLA did not differ from controls with respect to plasma or tissue PGI2 or TX levels. The two murine models of lupus differ, because an altered PGI2-TX ratio is a finding in the chronic murine lupus strain MRL-lpr, but is not seen when APLA are injected into normal mice. It is unlikely that APLA alone has a direct effect on cellular production of eicosanoids in vivo.
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PMID:Discordant effects on eicosanoids and fibrin degradation products in two murine models of antiphospholipid antibody. 906 53

In conclusion, a revised view of the contact system has been presented. This system has little to do with the initiation of hemostasis. Like lupus anticoagulants, deficiencies of contact proteins give prolonged APTTs but may be risk factors for thrombosis. BK from kininogens is a potent modulator of vascular biology inducing vasodilation, tissue plasminogen activator release, and prostacyclin liberation. Kininogens, themselves, are selective inhibitors of alpha-thrombin-induced platelet activation preventing alpha-thrombin from cleaving the cloned thrombin receptor after arginine41. Kininogens' alpha-thrombin inhibitory activity exists in intact kininogens, BK, and all of BK's breakdown products. HK also is the pivotal protein for contact protein assembly on endothelium. It is the receptor for prekallikrein which when bound to HK becomes activated to kallikrein by an endothelial cell enzyme system independent of activated forms of plasma factor XII. Prekallikrein activation on endothelial cells results in kinetically favorable single chain urokinase and plasminogen activation. Thus the "physiologic, negatively charged surface" for contact system activation is really the assembly of these proteins on cell membranes and activation by membrane-associated enzymes.
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PMID:Contact activation: a revision. 919 36

The antiphospholipid antibodies (APA) are acquired antibodies against a phospholipid which has been associated with slow progressive thrombosis and infarction in the placenta. Clinical features (venous or arterial thrombosis, recurrent fetal loss, thrombocytopenia) in conjunction with positive laboratory findings (positive IgG or IgM anticardiolipin antibodies, or positive lupus anticoagulant tests) will satisfy criteria for diagnosis of the antiphospholipid antibody syndrome (APS). A number of studies report the incidence of antiphospholipid antibodies in different patient populations: normal obstetrical patients (5.3% of 7278 women), women with recurrent pregnancy loss (20% of 2226 women), women with systemic lupus erythematosus (37% of 1579 women) and, more recently, women undergoing in vitro fertilization (24% of 3343 women). As in all autoimmune syndromes it is possible that APA are secondary to some underlying disease or that they are instrumental in the pathogenesis of the various manifestations. The most commonly proposed mechanisms of antiphospholipid antibody induced thrombosis include decreased prostacycline production by endothelial cells, increased thromboxane production by platelets, and decreased protein C activation. More recently it has been demonstrated that certain phospholipids are exposed on the endothelial surface and may alter implantation during in vitro fertilization. Treatment with subcutaneous heparin and aspirin has been shown to benefit women with recurrent pregnancy loss and APA resulting in successfully deliveries of approximately 75%. Several trials of treatment with heparin and aspirin in women with positive APA undergoing IVF have been completed. Although none of the studies were randomized, prospective, blinded trials there does not appear to be a significant difference in implantation rate, pregnancy rate, or ongoing pregnancy rate. This subject remains, however, an area of active investigation as antiphospholipid antibodies have been shown to interact with syncytiotrophoblast and cytotrophoblast layers and could theoretically affect implantation.
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PMID:Antiphospholipid antibodies and reproduction. 942 98

We investigated an effect of ureteral obstruction on a progressive immune complex glomerulonephritis in murine lupus erythematosus. Unilateral ureteral obstruction for 8 days significantly decreased the expanded glomerular mesangial area, as measured by computer-assisted morphometry (4.44 +/- 0.33 x 10(-4) mm2 to 3.60 +/- 0.34 x 10(-4) mm2, P < .05), and reduced the staining for IgG, C3, and extracellular matrix components, whereas the nephritis was exacerbated in the contralateral non-obstructed kidney. The renal concentration of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) in the obstructed kidneys 8 days after obstruction significantly exceeded that of kidneys in sham-operated controls (344.2 +/- 83.9 pg/mg tissue protein vs 50.0 +/- 27.5 pg/mg tissue protein, P < .01; 71.9 +/- 11.4 pg/mg tissue protein vs 9.5 +/- 2.3 pg/mg tissue protein, P < .01), whereas thromboxane B2 (TxB2) levels were similar in the two groups (33.9 +/- 4.5 pg/mg tissue protein vs 31.3 +/- 2.6 pg/mg tissue protein). Next, an experiment was performed to evaluate the role of renal eicosanoids in the amelioration in the immune complex glomerulonephritis after ureteral obstruction. Treatment with the cyclooxygenase inhibitor indomethacin abolished the decrease in mesangial area induced by ureteral obstruction (7.7% +/- 6.9%). CV-4151, a thromboxane synthetase inhibitor, had no effect on the decrease in mesangial area (-25.8% +/- 6.8%, P < .05). We conclude that unilateral ureteral obstruction quickly decreased the mesangial expansion in immune complex glomerulonephritis, and vasodilatory eicosanoids such as PGE2 and PGI2 at least partly contribute to the amelioration of glomerular histology.
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PMID:Ureteral obstruction reverses glomerular proliferation in immune complex glomerulonephritis. 1007 61

Pulmonary hypertension (PHT) associated with systemic lupus erythematosus (SLE) has a dismal prognosis. Vasodilators and immunosuppressive therapy have been tried over the years with discouraging results. Prostacyclin (PGI2) which has potent vasodilatatory and anti-platelet effects has been demonstrated to significantly decrease pulmonary arterial pressure and pulmonary vascular resistance during acute infusion. Satisfactory response has been reported in SLE patients with PHT treated with short-term intravenous continuous PGI2 infusion. We report here a 48-month experience of the use of monthly low dose infusion of a PGI2 analogue, iloprost, in a SLE patient with pulmonary hypertension in New York Heart Association functional Class III. There was an initial haemodynamic response to an acute infusion of iloprost. Repeated infusions were followed by marked improvement in her functional status and her mean pulmonary arterial pressure dropped from 80 mmHg in the first few months and remained static at around 55 mmHg for the subsequent years.
Lupus 1999
PMID:Pulmonary hypertension secondary to systemic lupus erythematosus: prolonged survival following treatment with intermittent low dose iloprost. 1041 14

The thromboxane A2/prostacyclin (TX/PGI) ratios were measured in patients with renal diseases to elucidate the relationship between the ratios and the pathological changes of the diseases. Urinary stable metabolites of thromboxane A2 and prostacyclin, 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1alpha, respectively, were converted to 1-methyl ester-propylamide-9,12,15-tris-dimethylisopropylsilyl ether derivative and 1-methyl ester-6-methoxime-9,12,15-tris-dimethylisopropylsilyl ether derivative, respectively, and applied to a gas chromatography/selected ion monitoring. The TX/PGI ratios of 10 outpatients and 6 inpatients with chronic glomerulonephritis were higher than those of 13 healthy volunteers. In an inpatient with systemic lupus erythematoides, the TX/PGI ratios were gradually lowered to the normal level with the therapies. Furthermore, the ratios seemed to change in advance of the changes of the levels of urinary protein and hematuria. These observations suggested that the TX/PGI ratio was a useful index to assess the pathological condition of renal diseases and the effects of treatment.
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PMID:Changes of the thromboxane A2/prostacyclin balance in the urine of patients with renal diseases analyzed by gas chromatography/selected ion monitoring. 1068 Jul 70

Endothelial cell functions, primarily involving regulated mediator secretion or altered surface protein expression, are vital for normal homeostasis. Endothelial cells secrete the potent vasodilator and anti-platelet agent prostacyclin and nitric oxide, and also the potent vasoconstrictor peptide endothelin-1; they control the selective adhesion and emigration of leukocytes from the bloodstream; and they are the source of circulating von Willebrand factor, tissue plasminogen activator and type 1 plasminogen activator inhibitor. The properties of healthy endothelium ensure that an antithrombotic and anticoagulant balance is maintained in the bloodstream, and provide a tonic vasodilator action that controls blood flow and pressure on a minute-to-minute basis. Disturbances of normal endothelial function are strongly implicated in the pathogenesis of atherosclerosis and autoimmune vasculitic diseases including lupus.
Lupus 2000
PMID:Normal endothelial cell function. 1080 85

Specific inhibitors of cyclooxygenase 2 (COX-2) have been approved for the treatment of osteoarthritis and rheumatoid arthritis. Unlike nonsteroidal anti-inflammatory drugs, specific COX-2 inhibitors do not inhibit platelet activation. However, these agents significantly reduce systemic production of prostacyclin. As a result, theoretical concerns have been raised that specific COX-2 inhibitors could shift the hemostatic balance toward a prothrombotic state. Patients with connective tissue diseases (CTD), who may be predisposed to vasculopathy and thrombosis, often have arthritis or pain syndromes requiring treatment with antiinflammatory agents. Herein we describe 4 patients with CTD who developed ischemic complications after receiving celecoxib. All patients had a history of Raynaud's phenomenon, as well as elevated anticardiolipin antibodies, lupus anticoagulant, or a history compatible with antiphospholipid syndrome. It was possible to measure a urinary metabolite of thromboxane A2 in 2 of the patients as an indicator of in vivo platelet activation, and this was markedly elevated in both. In addition, the patients had evidence of ongoing inflammation as indicated by elevated erythrocyte sedimentation rate, hypocomplementemia, and/or elevated levels of anti-DNA antibodies. The findings in these 4 patients suggest that COX-2 inhibitor-treated patients with diseases that predispose to thrombosis should be monitored carefully for this complication.
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PMID:Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors. A report of four cases. 1135 60

Subcutaneous prostacyclin (treprostinil) is an effective short-term treatment for pulmonary hypertension. The most frequently described adverse effect-pain in the area of injection-rarely requires that treatment be withdrawn. Sildenafil is a selective fosfodiesterase-5 inhibitor with pulmonary vasodilating effects. We describe the use of sildenafil as a substitute for treprostinil in a patient with pulmonary hypertension associated with lupus erythematosus. Treatment with treprostinil was discontinued due to uncontrollable abdominal pain.
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PMID:[Sildenafil as a substitute for subcutaneous prostacyclin in pulmonary hypertension]. 1453 98

Pulmonary hypertension (PH) is a rare but potentially life-threatening complication of systemic lupus erythematosus (SLE). We reviewed the literature on this complication, its pathogenesis and clinical presentation, and treatment options. PH is reported in 0.5% to 14% of patients with SLE. The literature describes the cases of 105 patients, 90% of whom were female. Average age was 33 years, and overall mortality was 25 to 50% two years after PH diagnosis. As in patients with primary pulmonary hypertension, dyspnea is the most common presenting symptom of PH in patients with SLE. Up to 58% of patients with both PH and SLE have Raynaud's phenomenon. Echocardiography can show right ventricular hypertrophy and dilation, even before symptom onset. Right-heart catheterization, with an assessment of vasoreactivity, is a necessary part of the work-up and is also needed for treatment decision-making. PH in patients with SLE is associated with intimal hyperplasia, smooth-muscle hypertrophy and medial thickening, similar to the changes seen in primary PH. Several pathological mechanisms have been proposed for PH associated with SLE. They include vasoconstriction, vasculitis, thrombosis, anticardiolipin antibody and lupus anticoagulant. Endothelial dysfunction may be an important factor in the onset of PH, possibly by contributing to vasospasm. Higher serum endothelin levels are found in patients with SLE and pulmonary hypertension than in other SLE patients. Several specific antibody patterns have been reported in patients with PH and SLE. Oral calcium channel blockers are indicated for patients who respond to acute NO challenge. Continuous intravenous prostacyclin represents a therapeutic advance, although it appears less effective than in primary PH. Some patients have been improved by new oral endothelin receptor antagonists, usually combined with intensive immunosuppressive therapy. Patients with SLE have an increased risk of PH. Vigilance is therefore required to detect early signs of PH. Early diagnosis allows treatment to start before irreversible vascular lesions occur.
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PMID:[Pulmonary hypertension associated with systemic lupus erythematosus]. 1565 27


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