Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary hypertension may be associated with multiple thrombi in the pulmonary arteries or with diffuse microembolization from a cryptic source. A 27-year-old man without any of the recognized clinical risk factors for venous thrombo-embolic disease presented with repeated attacks of chest pain and dyspnoea. Haemodynamic studies were compatible with the diagnosis of primary pulmonary hypertension. Despite intensive study there was no evidence of peripheral venous thrombosis. A survey of the plasma fibrinolytic profile showed unequivocal evidence of low spontaneous plasma fibrinolytic activity. The plasminogen activator activity of the venous wall was also markedly reduced. From these findings it would seem that a defective fibrinolytic defence mechanism may be an important predisposing factor in the pathogenesis of 'primary' pulmonary hypertension.
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PMID:A possible causal relationship between defective fibrinolysis and pulmonary hypertension. 42 66

The purpose of the present work was to measure prostaglandin (PG)-like activity in arterial blood during acute pulmonary hypertension. Anesthetized cats with the chest opened and given positive pressure ventilation were used. A balloon in the left atrium was inflated to elevate hydrostatic vascular pressure in the lungs. Blood was pumped (10 ml/min) from a carotid artery to superfuse 3 smooth muscle tissues: rat stomach strip, rat colon and chick rectum: the blood was then returned to the jugular vein by gravity. The assay tissues were pretreated with antagonists against catecholamines, histamine, serotonin and acetylcholine during the experiments. They were sensitive to calibrating doses of 2 ng/ml of PGF2 alpha and 1 ng/ml of PGE2. 18 periods with elevated left atrial pressure (P LA) (21--49 mmHg), lasting 2--26 min, were applied in 9 cats. This manoevre usually also caused systemic hypotension. 14 of these PLA elevations were accompanied by increased arterial PG-like activity, which rapidly subsided when the pressure was released or when indomethacin (2 mg/kg, n = 4) was given i.v. In 3 additional experiments it was found that pulmonary degradation of PGs was unaffected during P LA elevation. I.v. infusion of angiotensin II contracted the tissues in a pattern different from that caused by pressure elevations and the PG calibrations, and these contractions were not affected by indomethacin. This indicates that the assay tissue contractions cannot be caused by angiotensin II which alone does not increase PG-like activity in arterial blood. Consequently, acute pulmonary vascular hypertension appears to stimulate PG synthesis and release in lungs of intact cats.
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PMID:Release of prostaglandin-like substances during elevations of left atrial pressure in the cat. 52 82

Tumor necrosis factor-alpha (TNF alpha) has been proposed as a mediator of endotoxin-induced lung injury. When given to sheep, TNF alpha mimics endotoxin (LPS) causing hypoxemia, pulmonary hypertension, leukopenia, reduced dynamic compliance (Cdyn), increased resistance to airflow (RL), exudation of lung lymph, and enhanced airway reactivity. TNF alpha also induces rapid release of thromboxane A2 (TxA2), prostaglandin E2 (PGE2), and prostacyclin (PGI2). We hypothesized that the inflammatory effects of TNF alpha are due at least in part to cyclooxygenase products, and therefore cyclooxygenase inhibition would have similar effects on TNF alpha-induced lung injury as has previously been demonstrated for LPS-induced lung damage. Using awake sheep with chronic lung lymph fistulas, we measured Cdyn, RL, and FRC using a whole-body plethysmograph. Pulmonary artery (Ppa), left atrial (PLA), and systemic arterial (Psa) pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples (for prostanoid levels) were collected every 30 min. Eleven animals underwent paired random-order experiments receiving ibuprofen (14 mg/kg) 1 h before human recombinant TNF alpha (10 micrograms/kg), or an identical dose of TNF alpha alone. Within 15 min of initiating TNF alpha, Ppa doubled and remained elevated for 4 h. Ibuprofen prevented the early rise in Ppa after TNF alpha. In the group receiving TNF alpha alone, increases in Ppa were accompanied by a 60% decline in leukocyte count and a 50% increase in AaPo2 within 30 min. Ibuprofen prevented increases in AaPo2, but it had no effect on leukopenia or late increases in lymph flow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of cyclooxygenase products in lung injury induced by tumor necrosis factor in sheep. 154 45

More than 10 years ago, thrombolytic therapy with urokinase and streptokinase for pulmonary embolism was found to have considerable advantages over standard heparin therapy. After the introduction of alteplase, a recombinant tissue plasminogen activator, further studies confirmed this benefit. However, thrombolytic therapy for pulmonary embolism has not gained universal acceptance, even though it now has U.S. Food and Drug Administration approval. Clear advantages of thrombolytic therapy over conventional heparin therapy are improved pulmonary capillary blood volume, accelerated clot lysis and accelerated pulmonary perfusion. Earlier reversal of right-sided heart failure, a lower incidence of recurrent pulmonary embolism, a reduced risk of chronic pulmonary hypertension and reduced mortality have been claimed as advantages, but these have not been adequately proved. A recent survey suggests that about half of all patients with pulmonary embolism are potential candidates for thrombolytic therapy. In a subset of patients with hemodynamic compromise, thrombolysis has definite advantages over heparin therapy.
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PMID:Thrombolysis for pulmonary embolism. 192 47

We used a canine model of embolic pulmonary hypertension, induced by injection of autologous radioactive blood clots, to investigate effects of recombinant tissue-type plasminogen activator (rt-PA) on dynamics of thrombolysis and on pulmonary pressure-flow (PQ) characteristics. Over 5 (rt-PA5) or 15 (rt-PA15) minutes, 1 mg/kg rt-PA was infused. Rate and extent of thrombolysis were assessed by counting over both lung fields with a gamma camera. Emboli increased mean pulmonary artery pressure from 14 to 36 mm Hg (p less than 0.005). This change was predominantly due to an increase in the effective outflow pressure (PI) (from 9 to 29 mm Hg, p less than 0.001), obtained by extrapolation from the linear PQ relation. While pulmonary hemodynamics improved with rt-PA5 and rt-PA15, the change was greatest with rt-PA15. For example, the increase in PI that occurred with embolization was abolished with rt-PA15. Also, the decrease in pulmonary artery pressure was greatest with rt-PA15. While not significantly different, extent of total clot lysis tended to be greatest with rt-PA15 (p less than 0.07). Also, while during infusion, the concentration of rt-PA5 was threefold that of rt-PA15, the corresponding rate of thrombolysis was similar with rt-PA5 and rt-PA15. These results indicate that the improvement in pulmonary hemodynamics with rt-PA is primarily explained by a decrease in PI. Furthermore, they suggest an upper limit to the dose-thrombolytic rate relation with rt-PA.
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PMID:Recombinant tissue-type plasminogen activator in canine embolic pulmonary hypertension. Effects of bolus versus short-term administration on dynamics of thrombolysis and on pulmonary vascular pressure-flow characteristics. 249 7

Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.
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PMID:Monocrotaline pneumotoxicity in mice. 257 Apr 81

Clinical experience with thrombolytics in non-coronary disorders is limited to the plasminogen activators streptokinase, urokinase and alteplase; therapeutic trials with anistreplase (APSAC) are almost, and with saruplase completely, limited to acute myocardial infarction. In terms of thrombus clearance, thrombolytic drugs are superior to heparin in patients with recent deep vein thrombosis in the pelvis or lower limbs. In aggregate, thrombi younger than 8 days are lysed in approximately 60% of patients treated with streptokinase, urokinase or alteplase. The results of studies assessing the subsequent development of the postphlebitic syndrome are conflicting, but most suggest that thrombolytic therapy can reduce symptoms of chronic venous insufficiency. Currently, the combination of systemic thrombolytic drugs followed by heparin is recommended for patients with acute major pulmonary embolism who are haemodynamically unstable. Streptokinase, urokinase and alteplase have all been shown to accelerate the lysis of pulmonary emboli and to decrease pulmonary vascular obstruction and pulmonary hypertension. Systemic venous or intrapulmonary infusions of alteplase offers the same benefit in terms of angiographic and haemodynamic improvement. A short infusion of 100 mg alteplase over 2 hours seems to be superior to a 24-hour infusion of urokinase. None of the thrombolytic trials in pulmonary embolism have been large enough to demonstrate a reduction in mortality. It is now generally accepted that, unless contraindicated, thrombolytic therapy is the front-line treatment for patients with massive pulmonary embolism and major haemodynamic disturbance. The local treatment of acute arterial occlusion in limb arteries results in rapid clearing of the artery in 67% of patients treated with streptokinase; the corresponding success rates for urokinase and alteplase are 81% and 88 to 94%, respectively. The main question appears to be the identification of patients in whom local thrombolysis is the treatment of choice, as opposed to established therapeutic modalities. Thrombolytic treatment following a major ischaemic stroke is hazardous, although clinical improvement has been noted in a minority of patients with recanalised cerebral arteries. The safety and efficacy of thrombolytic treatment remains unproven for this indication, and its use must be restricted to experimental protocols. Thrombolytic treatment in retinal artery or vein occlusion has, in practice, been abandoned.
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PMID:Use of thrombolytic drugs in non-coronary disorders. 268 38

To assess abnormalities of right heart function and their reversal with thrombolysis in pulmonary embolism, serial imaging and Doppler echocardiographic studies were performed before and after a 6 hour intravenous infusion of 80 to 90 mg of recombinant tissue-type plasminogen activator (rt-PA) in seven patients with segmental or lobar acute pulmonary embolism. None of the five men and two women had known prior pulmonary hypertension. Substantial clot lysis and improvement in pulmonary blood flow, as determined by serial pulmonary angiography and perfusion lung scanning, were achieved in all. Coincident with clot lysis, pulmonary artery systolic pressure decreased (from 42 +/- 11 to 26 +/- 7 mm Hg, p less than 0.005), right ventricular diameter decreased (from 3.9 +/- 1.0 to 2.0 +/- 0.5 cm, p less than 0.005) and left ventricular diameter increased (from 3.7 +/- 0.9 to 4.4 +/- 0.6 cm, p less than 0.01). Right ventricular wall movement, initially mildly, moderately or severely hypokinetic in one, two and four patients, respectively, normalized in five and improved to mild hypokinesia in two. Tricuspid regurgitation was present before lytic therapy in six patients. In five, flow velocity in the tricuspid regurgitant jets indicated a peak systolic right ventricular minus right atrial pressure gradient of 25 to 52 mm Hg. Tricuspid regurgitation was detected early after lytic therapy in only two patients. Systolic septal flattening was noted before but not after lysis. These findings confirm that pulmonary emboli may result in appreciable right ventricular dysfunction and dilation, resultant tricuspid regurgitation, abnormal septal position and decreased left ventricular size.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early reversal of right ventricular dysfunction in patients with acute pulmonary embolism after treatment with intravenous tissue plasminogen activator. 295 13

The purpose of this study was to determine whether Captopril (an angiotensin converting enzyme inhibitor) or D-penicillamine (an inhibitor of collagen crosslinking) can ameliorate pulmonary fibrosis induced by the plant alkaloid monocrotaline. Rats were randomly assigned to one of six treatment groups: (1) control; (2) Captopril, 60 mg/kg/day, p.o.; (3) D-penicillamine, 30 mg/kg/day, p.o.; (4) monocrotaline, 2.4 mg/kg/day, p.o.; (5) monocrotaline plus Captopril, as above; (6) monocrotaline plus penicillamine, as above; and were killed after 6 weeks of continuous drug administration. Monocrotaline-treated rats exhibited several anatomic correlates of pulmonary hypertension, including cardiomegaly, right heart enlargement, and muscularization of the pulmonary arteries and arterioles. These monocrotaline reactions were accompanied by decreased lung activities of angiotensin converting enzyme (ACE) and plasminogen activator (PLA), indicative of endothelial dysfunction; and by increased lung hydroxyproline concentration, indicative of interstitial fibrosis. The presence of interstitial fibrosis was confirmed by electron microscopy. When given concomitantly with monocrotaline, both Captopril and penicillamine partially prevented the cardiomegaly, right heart enlargement, and vascular muscularization. Both agents also diminished the decreased lung PLA activity and increased hydroxyproline concentration observed in monocrotaline-treated animals. Neither modifying agent influenced the monocrotaline-induced decrease in lung ACE activity. Compared with control rats, the rats receiving Captopril alone exhibited decreased heart weight and increased serum ACE activity, and animals receiving penicillamine alone did not differ significantly from control animals for any of the endpoints studied. These data demonstrate that Captopril and penicillamine ameliorate monocrotaline-induced pulmonary fibrosis in rats. Penicillamine, known to inhibit radiation-induced lung injury, thus is shown to be effective in a second model of pulmonary fibrosis. Perhaps more importantly, the hydroxyproline data demonstrate that the ACE inhibitor Captropril exhibits antifibrotic activity in monocrotaline-treated rat lung.
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PMID:Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine. 299 75

Rats were sacrificed 2 months after a single dose of 10-30 Gy of 60Co gamma rays delivered to either a right unilateral or a bilateral thoracic port. Four indices of lung endothelial function were measured: the activities of angiotensin-converting enzyme (ACE) and plasminogen activator (PLA) and the production of prostacyclin (PGI2) and thromboxane (TXA2). The number of macrophages recovered by bronchoalveolar lavage (BAL) and the degree of right ventricular hypertrophy (an index of pulmonary hypertension) also were determined. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. The response curves for right unilateral and bilateral thoracic irradiation were not significantly different. In contrast, bilateral irradiation was more toxic than unilateral, since rats exposed to the former exhibited decreased body weight, an increased incidence of pleural effusions, an increase in the number of macrophages recovered by BAL, and right ventricular hypertrophy. These data demonstrate that pulmonary endothelial dysfunction induced by hemithorax irradiation represents a direct response of the endothelium to radiation injury and is not secondary to other phenomena such as shunting of function to the shielded lung.
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PMID:Pulmonary endothelial dysfunction induced by unilateral as compared to bilateral thoracic irradiation in rats. 303 87


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