The Journal of clinical investigation
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Macrophages are induced by LPS to release a number of products that determine the host response during gram negative sepsis. To examine the role of one such substance, tumor necrosis factor (TNF), in mediating LPS-induced injury, we employed a rabbit model of endotoxic shock to (a) determine the kinetics and extent of release of TNF into plasma after injection of LPS, and (b) to evaluate the protective effect of in vivo neutralization of LPS-induced TNF by prior infusion of anti-TNF antibody. TNF was maximally induced 45-100 min after injection of 10 micrograms i.v. parent Salmonella minnesota Re595 LPS or 250 micrograms Re595 LPS-HDL complexes. ⋯ Based on (a) the peak levels of TNF observed in serum, 2.5 X 10(3) U/ml, (b) the specific activity of purified rabbit macrophage-derived TNF, 1 X 10(8) U/mg, and (c) the biphasic disappearance of intravenously injected purified TNF (t1/2 = 0.5 min, 11 min) we constructed a kinetic model showing that at least 130 micrograms of TNF (1.3 X 10(7) U) was released into plasma 30-200 min postinjection of LPS. Prior infusion of anti-TNF antibody (30-45 min before LPS injection) resulted in neutralization of the LPS-induced serum TNF activity and provided significant protection from the development of hypotension, fibrin deposition, and lethality. Thus, these results provide further evidence that TNF plays a central role mediating the pathophysiologic changes that occur during gram negative endotoxic shock.
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Most patients with obstructive sleep apnea have increased pharyngeal collapsibility (defined in the present study as an increased lung volume dependence of pharyngeal area), which predisposes them to upper airway occlusion during sleep. However, there are patients with severe obstructive sleep apnea who have low-normal pharyngeal collapsibility. The factors leading to nocturnal upper airway obstruction in such patients have not been ascertained. ⋯ We found that all 10 patients exhibited paradoxical inspiratory narrowing of the glottis during quiet tidal breathing. This phenomenon was not observed in a matched group of 10 snoring, nonapneic male controls. We conclude that paradoxical glottic narrowing may be a contributing factor in the pathogenesis of upper airway obstruction in patients with severe obstructive sleep apnea who have low-normal pharyngeal collapsibility.
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Previous studies in adrenalectomized (Adx) rats suggest that aldosterone may regulate ion transport in the ascending portion of Helen's loop. In order to examine directly the effect of adrenalectomy on transport, medullary thick ascending limb (Mtal) segments were isolated from Adx, Adx replaced with aldosterone (Adx + Ald, 0.5 micrograms X 100 g X body wt X d), and control Sprague-Dawley rats. Both net sodium and net chloride fluxes were significantly less in the Mtal segments from Adx rats compared with those in the control or Adx + Ald group. ⋯ Net potassium flux was not different among the three groups. We conclude that adrenalectomy impairs reabsorptive NaCl but not K transport in the Mtal, and that aldosterone restores this process. This reabsorptive defect may contribute to the urinary concentrating and diluting abnormality associated with adrenal insufficiency.
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The function of macrophage C3 receptors was assessed in vivo by measuring the clearance of C3-sensitized autologous erythrocytes in seven acquired immunodeficiency syndrome (AIDS) patients, eight healthy homosexual men, eight healthy heterosexual men, and four infected controls. Healthy heterosexual men had an initial clearance of 50.1 +/- 2.0% of the inoculum, with a release of a small portion of these cells (10.9 +/- 1.3%) into the circulation. Healthy homosexual men had a greater initial clearance of 66.0 +/- 4.2% (P less than 0.01) followed by a similar release (14.0 +/- 3.3%). ⋯ AIDS). These data, in addition to Fc-receptor dysfunction, demonstrate a global reticuloendothelial system dysfunction in AIDS patients. This may contribute to their frequent infections with opportunistic pathogens and inappropriate immune responses against these microorganisms.
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Comparative Study
Role of plasma gelsolin and the vitamin D-binding protein in clearing actin from the circulation.
We determined the plasma kinetics of both actin and complexes of actin with the two high affinity actin-binding proteins of plasma, gelsolin, and vitamin D-binding protein (DBP). Actin is cleared rapidly from the plasma by the liver (half-disappearance time, 0.5 h). Using radiolabeled actin-binding proteins, we found that actin accelerated the clearance of both plasma gelsolin and the vitamin D-binding protein. ⋯ A low affinity interaction (dissociation constant, 2.9 X 10(-4) M) between actin and fibronectin was found, suggesting that little actin will bind to fibronectin in plasma. We conclude that while plasma gelsolin and DBP may both clear actin from the circulation, DBP appears to play a more important role. By so doing, DBP may conserve the filament-severing activity of plasma gelsolin.