RESUMEN
Monocrotaline (MCT) is bioactivated in liver cytochrome P-450s to MCT pyrrole (MCTP), which primarily injures the lung endothelium to result in the development of pulmonary hypertension (PH) in rats. However, whether there is a relation between the degree of PH and the activity of liver cytochrome P-450 to convert MCT to MCTP remains unclear. To examine the relation between these physiological and biochemical changes, we first measured the severity of MCT-induced (20 mg/kg) PH in male, female, castrated male, and phenobarbital (PB, liver P-450s inducer)-pretreated male rats. The degree of right ventricular hypertrophy was more severe in PB-pretreated male than in control male rats. It was also more severe in male than in either female or castrated male rats, suggesting that sex-specific P-450s could be involved in the metabolic pathways of MCT in the liver. Further to explore which of the isozymes (2A2, 2C11, and 3A) of P-450s in the liver is responsible for the bioactivation of MCT, we measured the rate of MCTP production in hepatic microsomes by a modified Mattock's method. Treatment of male rats with PB and pregnenolone 16alpha-carbonitrile (PCN), which is the specific inducer of P-450 3A, increased the rate of MCTP production, suggesting that P-450 3A may contribute to the conversion to pyrrole. Therefore we measured the amount of P-450 3A protein by immunoblotting and attempted to inhibit MCT metabolism by using antibodies to P-450 3A. P-450 3A was significantly induced by PCN (6.5-fold) and PB (4.6-fold) treatment and reduced by castration (0.38-fold). The amount of P-450 3A was closely correlated with the production of MCTP, and the conversion of MCT to MCTP was strongly inhibited by antibodies against P-450 3A. These results indicated that P-450 3A was predominantly responsible for the metabolism of MCT to MCTP in rat liver and suggested a tight linkage between the degree of PH and the activity of liver P-450 3A.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/enzimología , Monocrotalina/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Animales , Biotransformación , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/inmunología , Femenino , Corazón/efectos de los fármacos , Ventrículos Cardíacos/patología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia , Inmunoglobulina G/inmunología , Hígado/inmunología , Masculino , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/inmunología , Monocrotalina/análogos & derivados , Monocrotalina/toxicidad , Orquiectomía , Tamaño de los Órganos , Oxidorreductasas N-Desmetilantes/inmunología , Ratas , Ratas Sprague-Dawley , Factores Sexuales , Presión Ventricular/efectos de los fármacosRESUMEN
A 64-year-old woman was admitted to our hospital with a hemothorax after one year of therapy for angiosarcoma that had arisen from the skin of the head. The hemothorax was believed to have resulted from metastasis of the angiosarcoma. Interleukin-2 (IL-2) at a dose of 20 x 10(4) U once daily was administered intrapleurally. Clinical improvement was first observed on the second day after the first dose of IL-2. Increases in natural and in lymphokine-activated killer activity of lymphocytes in pleural effusion were found on the eighth day. Starting on the 16th day of IL-2 therapy, no more fluid was drained, so administration of IL-2 was stopped. The clinical course indicated that the pleural effusion disappeared not because of pleurodesis but because of the anti-cancer effects of IL-2. There were no marked side effects, and intrapleural administration of IL-2 may be useful in patients with hemothorax due to metastasis of angiosarcoma.
Asunto(s)
Hemangiosarcoma/secundario , Hemangiosarcoma/terapia , Hemotórax/terapia , Interleucina-2/administración & dosificación , Neoplasias Pulmonares/secundario , Femenino , Hemotórax/etiología , Humanos , Inyecciones , Neoplasias Pulmonares/complicaciones , Persona de Mediana Edad , Pleura , Cuero Cabelludo , Neoplasias Cutáneas/patologíaRESUMEN
To study the relationship between cytokines and the development of monocrotaline-induced pulmonary hypertension, monocrotaline was given and interleukin-2 was measured. The amount of interleukin-2 produced by pulmonary cells obtained by bronchoalveolar lavage was high only on the 14th day after monocrotaline injection (p < 0.01). This suggests that many kinds of cells in the monocrotaline-treated rat lung were activated by cytokines, and that these interactions play an important role in the development of monocrotaline-induced pulmonary hypertension in rats.
Asunto(s)
Hipertensión Pulmonar/inmunología , Interleucina-2/metabolismo , Pulmón/metabolismo , Monocrotalina , Animales , Hipertensión Pulmonar/etiología , Pulmón/citología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
To study the relationship between proliferation of smooth muscle cells and structural changes in arteries of rats given monocrotaline, light microscopy with immunohistochemistry for bromodeoxyuridine (BrdU) was done after a single subcutaneous injection of monocrotaline. In increase in DNA synthesis in smooth muscle cells was seen from 3 days until 14 days after administration. Since this increase was seen before pulmonary hypertension and medial thickness developed some mechanisms that induce proliferation of pulmonary atrial smooth muscle may have been triggered soon after monocrotaline injection.
Asunto(s)
Monocrotalina/farmacología , Músculo Liso Vascular/citología , Animales , División Celular/efectos de los fármacos , Replicación del ADN , Hipertensión Pulmonar/etiología , Inyecciones Subcutáneas , Masculino , Monocrotalina/administración & dosificación , Músculo Liso Vascular/metabolismo , Arteria Pulmonar , Ratas , Ratas Sprague-DawleyRESUMEN
It is well known that the initial reaction of monocrotaline-induced pulmonary hypertension in rats (MPH) is injury to the endothelial cells of pulmonary vascular bed by monocrotaline-pyrrole (MP), which is converted from monocrotaline (M) by cytochrome P450 monooxygenase in hepatic microsomes. It is also known that the degree of MPH differs between sexes. The mechanisms of MPH remain, however, to be elucidated. The purpose of this study is to clarify the relationship between the converting ability of hepatic microsomes and the sexual difference in MPH using castrated male rats. A 40 mg/kg dose of M was given to fifteen 6 week-old male, twelve 6 week-old female and fifteen 6 week-old castrated male, Sprague-Dawley, rats. The castration was done at three weeks of age. Four weeks after M administration, the right ventricular systolic pressure (RVSP) and the right ventricular to total ventricular weight ratio (RV/T) were measured as indices of pulmonary hypertension. Livers were taken from six 6 week-old male, six, 6 week-old female and six 6 week-old castrated male, Sprague-Dawley, rats and then homogenized and centrifuged to extract hepatic microsomes. M, at 3.3 mM, was added to concentrated hepatic microsomes (0.25 to 1.5 mg/ml) in order to produce MP. The concentration of the MP was measured using a modification of Mattock's method. The mean value of RVSP was 86.5 mmHg in males, 59.6 mmHg in females and 73.9 mmHg in castrated males. The mean value of RV/T was 0.453 in males, 0.358 in females and 0.403 in castrated males.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hipertensión Pulmonar/inducido químicamente , Microsomas Hepáticos/metabolismo , Monocrotalina/metabolismo , Animales , Castración , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
A 39-year-old male was admitted with persistent cough, palpitations and dyspnea on exertion. Chest X-ray showed cardiomegaly, left pleural effusion and left hilar mass shadow. Echocardiogram revealed dilatation and hypertrophy of the right atrium and ventricle. Perfusion lung scintigram disclosed a complete defect of the left lung and a partial defect of the right upper lobe. CT scan showed an intravascular tumor mass in the bilateral main pulmonary arteries. Digital subtraction angiography of the pulmonary artery revealed complete obstruction of the left pulmonary artery and stenosis of the right pulmonary artery. MR image showed intravascular tumor infiltrating the mediastinum and surrounding tissue. Sarcoma was highly suspected, but a histopathological diagnosis could not be made. The patient died of heart failure two months after admission to our hospital. Postmortem examination showed that the pulmonary trunk and left main pulmonary artery were markedly dilated and completely occluded by the tumor. Tumor infiltrated into the left upper lobe and mediastinal lymph nodes. The tumor was histologically diagnosed as undifferentiated sarcoma.
Asunto(s)
Arteria Pulmonar/patología , Sarcoma/patología , Adulto , Humanos , MasculinoRESUMEN
A case of lymphangiomyomatosis (LAM) in a 35-year-old woman is reported. Because she was already severely dyspneic when she was admitted to our hospital, neither TBLB nor open lung biopsy was performed, and no accurate diagnosis was made. She died of respiratory failure three years after the development of exertional dyspnea, and autopsy revealed LAM. Pneumothorax, a well-known and frequent complication of LAM, did not occur until one month prior to her death. Although pneumothorax frequently complicates LAM, there are a few reports of cases in which pneumothorax did not occur during the course of the disease. We emphasize that LAM should be considered in the differential diagnosis of diffuse interstitial lung disease, even when the patient has no pneumothorax. The retroperitoneal tumor (15 x 10 x 10 cm), which was evident clinically, was later shown to be intra-abdominal involvement of LAM. Although only a few cases of LAM with a large retroperitoneal tumor have been reported, minor intra-abdominal involvement is relatively common. This case also suggested that the finding of a retroperitoneal tumor may be a diagnostic clue in LAM.
Asunto(s)
Linfangiomioma/patología , Neoplasias Retroperitoneales/patología , Adulto , Diagnóstico Diferencial , Femenino , HumanosRESUMEN
We observed the time course of hemodynamic and pathological changes after single injection of various dose of monocrotaline (Mct) to investigate the dose-dependent effects on the induction and regression of pulmonary hypertension in rat: A hundred four-week old male Sprague-Dowley rats were divided into five groups and each group, except the control group, received 10 mg, 20 mg, 30 mg or 40 mg/kg Mct, respectively. The experimental periods were nine weeks after monocrotaline injection. At the third, sixth and ninth week after treatment, the survival rate, cardiac catheterization and pathological changes were evaluated. All rats given 30 mg or 40 mg per kg of Mct died within five weeks. In the third week after the treatment, elevation of the right ventricular systolic pressure (RVSP), the grade of right ventricular hypertrophy (RVH) and histological change showed no significant difference among rats receiving 20, 30 or 40 mg/kg Mct injection. Almost all rats given 10 mg or 20 mg/kg Mct survived through the experimental period of nine weeks. Rats given 10 mg per kg of Mct did not develop pulmonary hypertension or pathological abnormalities in the lungs. Rats receiving 20 mg/kg Mct showed transient elevation of RVSP, RVH and pulmonary histological changes in the early phase, but these findings regressed by the ninth week of the experiment. Namely, rats which received 20 mg pr kg of Mct revealed transient elevation of right ventricular systolic pressure, right ventricular hypertrophy and pulmonary histological changes only in the early phase and these changes regressed gradually thereafter. These results indicate some kind of transient and reversible factor may play a role in the development and regression of Mct-induced pulmonary hypertension in rats.
Asunto(s)
Hipertensión Pulmonar/inducido químicamente , Alcaloides de Pirrolicidina , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipertensión Pulmonar/fisiopatología , Pulmón/patología , Masculino , Monocrotalina , Ratas , Ratas Endogámicas , SístoleRESUMEN
We studied the clinical usefulness of ofloxacin (OFLX) in 13 patients with chronic respiratory tract diseases aggravated by acute infections with identified causative bacteria. 1. Overall clinical efficacies were: highly effective 5, effective 6, slightly effective 2, and ineffective none, showing an efficacy rate of 84.6%. 2. In 6 patients with fever of over 37 degrees C, time lengths in days for symptoms to have been alleviated due to OFLX treatment were; 1 day: 4 cases, 3 days: 1 case and 5 days: 1 case (2.0 days on average). 3. As to bacterial transitions, in 9 of 10 patients Haemophilus influenzae was eliminated and in 1 patient it was substituted by Pseudomonas aeruginosa. In 3 patients Branhamella catarrhalis was eliminated and in 1 patient, the number of P. aeruginosa was reduced. OFLX is expected to have a potent bacteriological effect on H. influenzae and B. catarrhalis. 4. As to side effects, 1 of the 13 patients (7.7%) complained of discomfort in the epigastrium. This discomfort disappeared when a gastric mucosa protective agent was administered. There was no abnormality in laboratory test values. Judging from the above results, we consider OFLX a useful drug for the treatment of patients with chronic respiratory tract diseases aggravated by acute infections.