Interferon-alpha therapy associated with the development of sarcoidosis.

Interferons (IFNs) have been implicated in the pathogenesis of sarcoidosis. In particular, IFN-gamma has been linked to pulmonary macrophage activation, a characteristic feature of sarcoidosis. IFN-alpha is now being administered therapeutically in a variety of conditions. To date, IFN-alpha has not been implicated in the pathogenesis of sarcoidosis. We report the case of a 50-year-old woman who developed sarcoidosis while being treated with IFN-alpha for chronic myelogenous leukemia. Her disease activity correlated with the dosage of IFN-alpha. We speculate that the immunomodulatory effects of IFN-alpha triggered clinical manifestations of sarcoidosis in this patient.

Influence of chronic lead ingestion on IgG subclass expression of the immune response to bovine serum albumin.

Rats were given free access to drinking water containing 2% lead acetate for 30 days prior to intraperitoneal inoculation with 100 mcg of bovine serum albumin (BSA) in Freund's complete adjuvant. Three weeks later, the animals were boosted with the antigen in Freund's incomplete adjuvant. After an additional three weeks, the animals were bled and the sera assayed for total IgG by radial immunodiffusion and for specific IgM, IgG and IgG subclasses by the enzyme-linked immunosorbent assay (ELISA). BSA-inoculated rats exhibited similar levels of total IgG regardless of exposure to lead, but showed significant increases in IgG compared to nonimmunized controls. However, levels of IgG specific for BSA were significantly lower in the lead exposed group. Analysis of the IgG subclasses specific for BSA revealed that BSA-inoculated rats which were not exposed to lead had greater titers of IgG2b and IgG2c as compared to the lead exposed group. Chronic lead ingestion appears to diminish the overall IgG response to BSA and may alter the normal IgG subclass expression.

Hemodynamic properties of a new quinidine analog, cupreidine (6'-hydroxycinchonine).

Cupreidine 96'-hydroxycinchonine) is a recently synthesized analog of quinidine (6'-methoxycinchonine). Previous studies in mice have shown that quinidine and cupreidine have equivalent antiarrhythmic potencies, whereas the acute toxicity of cupreidine is about 50% less than that of quinidine. Many of the serious adverse effects of quinidine are due to undesirable cardiovascular properties. We have, therefore, compared the effects of the two drugs on blood pressure, heart rate, and peripheral vasodilation in rats, and on myocardial contractility in isolated rabbit hearts at a series of comparable doses. Quinidine produces a more marked bradycardia and depression of blood pressure than does cupreidine. The vasodilation produced by intraarterial administration of quinidine was significantly greater than cupreidine. Furthermore, quinidine elicited a greater negative inotropic effect. Cupreidine exhibited a much more favorable hemodynamic profile than quinidine with regard to the properties that were examined. These results, coupled with the fact that cupreidine has significant antiarrhythmic activity and a lower acute toxicity profile, suggest that this drug may be useful in the therapy of cardiac arrhythmias.

Estimation of infarct size by determination of myocardial 3H-tetracycline accumulation in the coronary ligated rat.

Myocardial infarction was produced in rats by ligation of the left coronary artery. Rats were injected with 3H-tetracycline (50 muCi/kg) i.p., 10 minutes prior to ligation. The rats were killed at various time periods after ligation and the myocardial accumulation of 3H-tetracycline determined in the left ventricle or in whole heart homogenates. CPK was also determined in the myocardium or serum. Myocardial 3H-tetracycline was not significantly elevated in the whole heart homogenates. However, there was a significant increase in 3H-tetracycline in the digests of the left ventricle 6 h post-infarct. This increase correlated very well with serum CPK activity. This suggest that this method could be a useful tool in the estimation of infarct size.

Effect of tetracycline on adriamycin cardiotoxicity.

Male rats were treated with either adriamycin (2 mg/kg, i.v. weekly) or adriamycin and tetracycline (10 mg/kg, i.p., daily) for 8 weeks. Serum creatine phosphokinase (CPK) activity was measured after 8 weeks as an index of cardiotoxicity. Serum CPK was significantly elevated in the adriamycin-treated rats. Tetracycline failed to inhibit the adriamycin-induced increase in serum CPK. These results indicated that tetracycline does not prevent adriamycin-induced cardiotoxicity.

Alteration of collagen synthesis in different tissues of the atherosclerotic rabbit.

The effect of hypercholesterolemia on the rate of collagen synthesis in different tissues of the rabbit was investigated. Following 60-70 days of an atherogenic diet cholesterol content and collagen synthesis was estimated in rabbit aorta, liver and lung. All three tissues demonstrated significant increases in cholesterol and cholesterol ester content, but only the aorta and liver had a significant increase in collagen synthetic rate. These data demonstrate 1) that serum hypercholesterolemia does not cause a generalized increase in collagen synthesis in all tissues and 2) that tissue hypercholesterolemia does not always increase tissue collagen synthesis.

Possible relationship of cholesterol accumulation and collagen synthesis in rabbit aortic tissues.

Male adult New Zealand rabbits were fed a 2% cholesterol diet for 60 days followed by 10, 20, or 30 days of normal low cholesterol diet. Collagen synthesis was estimated by measuring aortic prolyl hydroxylase activity. Tissue cholesterol accumulation rates were estimated by dividing total tissue cholesterol by the number of experimental days. It was found there was a high degree of correlation between aortic collagen synthetic activity and the rate of aortic cholesterol accumulation. These data were interpreted as suggesting that increased collagen synthesis may be associated with the accumulation and/or retention of increased aortic cholesterol.

Collagen metabolism in the myocardium from streptozotocin-diabetic rats.

The effect of diabetes on myocardial collagen metabolism was investigated in rats. Diabetes was induced by an i.v. injection of streptozotocin (60 mg/kg). The animals were killed after 3, 6, 18, or 26 wk of diabetes. Urinary glucose levels were measured by Tes-Tape. The myocardium was quickly removed and homogenized. Collagen was estimated by hydroxyproline content. Collagen synthesis was measured by 14C-proline incorporation. Myocardial collagen concentration and collagen synthesis was not altered in the diabetic rats. Collagen concentration did appear to increase in the 18- and 26-wk rats, but this was probably an age-related phenomenon. These results suggest that diabetes does not alter collagen metabolism in rats.

Hypercholesterolemia and aortic collagen synthesis in rabbit aortas.

Male adult New Zealand rabbits were fed a 2% cholesterol diet for 30 of 60 days in order to determine the effect of hypercholesterolemia on aortic collagen synthesis. Collagen synthetic activity was estimated by measuring tissue prolyl hydroxylase activity and the amount of tissue collagen was estimated by measuring tissue hydroxyproline levels. Following 30 or 60 days of feeding there was a significant increase in both tissue and serum cholesterol indicating the onset of hypercholesterolemia. Measurement of collagen synthetic activity and tissue collagen levels demonstrated no increase over control tissues. These data therefore indicate that hypercholesterolemia is not a direct stimulus of tissue collagen synthetic activity.

Collagen metabolism during the early stages of cholesterol-induced atherogenesis in rabbits.

The involvement of collagen in cholesterol-induced atherosclerosis in rabbits was investigated. Rabbits were fed a 2% cholesterol diet for 8, 16, 30, 60 and 90 days. Histological sections were taken and aortic free and esterified cholesterol were determined after separation on thin-layer chromatography. Prolyl hydroxylase activity was used as a measure of collagen synthetic rate and hydroxyproline levels as an estimate of collagen content. Cholesterol content was a significantly increased after 8 days, while at this time there were no gross aortic lesions. After 30 days there was some aortic disease and by 60 days most of the rabbits exhibited pronounced aortic lesions. Histologically, the lesions consisted mainly of intimal foam cells. There was no alteration in collagen synthetic rate or content at 8, 16, 30 or 60 days. These data indicate that 60 days of continuous cholesterol feeding results in a foam cell aortic lesion with no alteration in collagen metabolism. After 90 days of cholesterol feeding there was significant increase in collagen synthetic activity in the thoracic aorta. These data suggest that alteration of collagen synthetic activity is secondary response, resulting from injury induced by the aortic accumulation of large amounts of cholesterol.