Membrane fragments from aortic and heart tissues of immature chicks were observed to bind highly purified, 125I-labeled chick ceruloplasmin. The binding reaction exhibited a linear Scatchard plot for both tissues and showed for each an apparent dissociation constant (Kd) of about 10(-8) M. On the basis of Scatchard analyses, aorta contained 1.5 pmol of receptors/mg of membrane protein, whereas receptors in the membranes from heart tissue were at least 5 times more dense. The binding of chick ceruloplasmin to aorta membranes was trypsin sensitive and neuraminidase insensitive, and showed both saturation and reversibility. Various sialoglycoproteins in 500 molar excess had very little effect on the binding. The asialo derivatives of these proteins likewise did not inhibit the binding. Human ceruloplasmin was found to bind very weakly to the chick membranes. Asialo chick ceruloplasmin bound with the same efficacy as native chick ceruloplasmin. Heat-denatured chick ceruloplasmin, however, was very ineffectual in displacing native 125I-ceruloplasmin from the membranes. These studies provide the first evidence for a homologous membrane receptor for native ceruloplasmin in the plasma membranes of animal cells.
The alpha ACTH-(1-24) threshold dose and the response slope were determined for cortisol (F), delta 4-androstenedione (A), and dehydroepiandrosterone (DHEA) in 10 normal and 16 obese eumenorrheic nonhirsute women matched for age. Each woman received 1 mg dexamethasone at 2300 h and again at 0700 h the next morning. At 0700 h, a continuous alpha ACTH-(1-24) infusion was begun at an initial dose of 30 ng/1.5 m2 body surface area X hr. The ACTH infusion rate was doubled every hour for 5 consecutive h to a maximum dose of 480 ng/1.5 m2 X h. Blood samples were collected for steroid assays before the infusion and at the end of each hour. The ACTH threshold dose was defined as the dose that produced a steroid response significantly above the basal level. The ACTH threshold dose for serum F and DHEA stimulation was not different between the groups, but the threshold dose for A was significantly lower in the obese women. Basal and stimulated serum DHEA to F ratios were significantly higher in the obese women. In both groups, the mean F response slope was significantly higher than that for DHEA, which in turn, was significantly higher than that for A. The mean DHEA response slope was significantly greater in the obese women. The F and A response slopes were not different between the groups. We conclude that the relative responsivity of the steroids to ACTH was the same in both groups: F greater than DHEA greater than A; in the obese women, the ACTH threshold dose for F stimulation was lower (greater sensitivity) than for DHEA or A stimulation; and in the obese women, the ACTH threshold dose for A was significantly lower (increased sensitivity) and the slope of the DHEA response to ACTH was steeper (greater responsivity) than in normal women.
The neutrophil-activating peptide-2 (NAP-2) is a cytokine that is generated by the proteolytic cleavage of a precursor protein and that causes neutrophil degranulation and chemotaxis. NAP-2 precursors are produced in platelets and are normally found in the circulation. We showed that NAP-2 is generated by the action of neutrophil cathepsin G on two of the precursors, the connective tissue-activating peptide-III (CTAP-III) and beta-thromboglobulin (beta-TG). However, neutrophil elastase degraded the precursors to inactive peptides. The specific binding of cathepsin G to platelets caused the platelets to secrete NAP-2, and cathepsin G bound to the platelets could still generate NAP-2 from its precursor proteins. In addition, activated neutrophils in the presence of platelets generated NAP-2 from its precursors and caused platelets to secrete NAP-2. These studies demonstrate a unique mechanism for the activation of neutrophils through the interaction of neutrophils, platelets, and NAP-2 precursors that are released either by activated platelets or are present in circulation. It is therefore possible that NAP-2 may be generated at sites where aggregations of neutrophils and platelets occur in vessels such as pulmonary capillaries in patients with the adult respiratory distress syndrome and coronary arteries in patients with evolving myocardial infarctions.
To study the effect of obesity on the metabolism of adrenal androgens not bound to testosterone-estradiol-binding globulin, the MCRs of delta 4-androstenedione (A) and dehydroepiandrosterone (DHEA) were determined using constant infusion of unlabeled steroids to steady state in 8 normal weight and 19 obese nonhirsute eumenorrheic women. The blood production rates (PR) were calculated as the product of the MCR and the 24-h integrated serum concentrations (IC). The mean MCR and PR of A and DHEA were significantly higher in the obese women than in the normal weight women. There was, however, no difference in the mean IC of each androgen in the 2 groups. The MCR and PR of A and DHEA were each correlated with the body mass index (BMI; kilograms per m2). The MCR and PR of A and the MCR of DHEA were also correlated with the ratio of waist circumference to hip circumference (WHR). However, the PR of DHEA was not correlated with WHR. There was no correlation between the IC of either androgen and BMI or WHR. However, partial correlation analysis revealed that correction of the BMI for WHR resulted in a significant negative correlation between BMI and IC of A. We conclude that the MCR and PR of A and DHEA were increased in obese nonhirsute eumenorrheic women; there was a strong correlation between BMI and the MCR and PR of A and DHEA; upper segment obesity, as measured by WHR, was correlated with the MCR and PR of A and the MCR of DHEA, but not with the PR of DHEA; and circulating DHEA and A were maintained at normal levels in the obese eumenorrheic women despite an increase in the MCR, which suggests that a servo-mechanism is operative which registers the body size and adjusts the PR according to the MCR.
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