Chemotactic response of splenic mononuclear cells to angiotensin II in murine schistosomiasis

Murine Schistosomiasis mansoni is a parasitic infection associated with a delayed-type hypersensitivity granulomatous reaction to the schistosome eggs. This reaction is characterized by the accumulation of mononuclear cells and other inflammatory cell types around the eggs. Granuloma macrophages produce angiotensin II (AII), which appears to have immunoregulatory function. By using an in vitro chemotaxis assay, this study demonstrated that AII is a chemotactic factor for splenic mononuclear cells derived from infected mice. The response was bimodal, with peak activities occurring at 10(-10) and 10(-6) M. AII was chemotactic for T lymphocytes, B lymphocytes, and a large population of unidentified mononuclear cells at the optimal chemotactic concentrations of the peptide. At high concentrations, AII was also chemotactic for phagocytic mononuclear cells. Sar1, ala8-AII, an analog of AII with antagonist activity, completely blocked AII-induced chemotaxis. A [3H]-AII binding assay revealed high-affinity specific binding on spleen cells. The binding was rapid, was dependent on radioligand concentration, and was reversible. These latter observations suggest that the chemotactic activity of AII for subpopulations of splenic mononuclear cells is mediated via AII receptors.     

Comparison of particle clearance and macrophage phagosomal motion in liver and lungs of rats

Magnetic particles and magnetometry were used to noninvasively measure motion of particle-containing organelles in macrophages as well as to monitor the disappearance of particles from tissues. We compared these parameters in the liver (where macrophages are attached to the endothelium) and in the lungs (where macrophages were mobile on epithelial surfaces). Submicrometric magnetic particles were injected intravenously (1.5 mg/kg) into rats; 94% was taken up by the liver. Rats were also instilled intratracheally (1.0 mg/kg) with the same particles. Ultrastructural analyses showed that almost all particles were ingested by macrophages in both organs. Periodically, the retained particles were magnetized and aligned with an external magnet. After the magnet was removed, the decay of the resulting remanent field (relaxation) was followed for 25 min. Relaxation parameters (t1/2 and lambda 0) in the liver were constant from 30 min to 30 days after particle administration, but relaxation in lungs showed a time-dependent increase during the 1st day due to the slower rate of particle phagocytosis. Relaxation in both organs primarily reflects the motion of particle-containing organelles as they are rotated by the cytoskeleton. Relaxation in the lungs may also reflect cell translocation or even changes in alveolar shape. Clearance of particles from the lungs or liver was measured by following B0 (initial magnetic field strength). After correction for growth, the clearance t1/2 was 17.7 and 27.3 days for the lungs and liver, respectively. Bulk transport of particles is probably a more important clearance mechanism in the lungs than in the liver.     

Potential usefulness of renal vasodilators in hypertension and renal disease: SK&F 82526

SK&F 82526 and its enantiomers have been shown to increase renal blood flow and decrease renal vascular resistance in the anesthetized dog. The effect of the racemate on lowering systemic blood pressure in the anesthetized dog and the spontaneously hypertensive rat has been shown to be caused by the R-enantiomer with the S-enantiomer being devoid of significant activity on blood pressure. The mechanism by which the R-enantiomer decreases blood pressure is not systemic vasodilatation or prejunctional inhibition of norepinephrine release but appears to result from a unique stimulation of the postjunctional dopamine receptor. Racemic SK&F 82526 also has been shown to increase renal blood flow in an ischemic model of acute renal failure.     

Characterization of the hemodynamic activities of fenoldopam and its enantiomers in the dog

Fenoldopam (SK&F 82526) is a potent and selective dopamine DA-1 agonist with demonstrated renal vasodilator and antihypertensive activities in experimental animals and humans. Fenoldopam is a racemic mixture of two enantiomers, SK&F R-82526 and SK&F S-82526. The R-enantiomer is uniformly reported to be more potent than the racemate; in contrast, there is controversy regarding potency of the S-enantiomer. In these studies, the renal and systemic hemodynamic activities of fenoldopam and its enantiomers are characterized in anesthetized, phenoxybenzamine-treated dogs. The results show that the renal and systemic vasodilator activities of fenoldopam are properties of the R-enantiomer; the S-enantiomer is essentially inactive. The renal and systemic vasodilator properties of SK&F R-82526 are antagonized in a competitive fashion by the DA-1 antagonist, SK&F R-83566, but not the DA-2 antagonist, domperidone. Ganglionic blockade did not attenuate renal vasodilation associated with SK&F R-82526. Thus, the mechanism of SK&F R-82526-associated vasodilation, like that previously established for fenoldopam, is via stimulation of postganglionic DA-1 receptors.     

The effect of oxotremorine on blood pressure and plasma catecholamines in conscious and anesthetized rats.

This review summarizes the evidence suggesting a role for second messengers in the thymus dependent differentiation of lymphocytes. Special emphasis will be placed on the potential for such studies to indicate differences and similarities not only between thymosin and other thumus factors but between the various peptides which are present in thymosin fraction 5.     

Interleukin 12 and antigen independently induce substance P receptor expression in T cells in murine schistosomiasis mansoni.

Substance P (SP) regulates interferon-gamma (IFN-gamma) production through interaction with the SP receptor NK1 (SPr) on T cells at sites of inflammation. Using murine schistosomiasis, we evaluated whether SPr expression was subject to immunoregulation. Splenocytes from schistosome-infected mice cultured for < or =18 h did not express SPr, as determined by quantitative polymerase chain reaction assay. However, exposure to schistosome egg antigen (SEA) for < or =4 h induced strong receptor expression. Experiments using splenocytes fractionated with antibody-coupled, paramagnetic beads showed that induction localized exclusively to T cells. Receptor protein expression was confirmed with Western blot. Interleukin 12 (IL-12) also induced strong T-cell SPr expression. Both SEA and IL-12 remained strong inducers of T-cell SPr in lymphocytes from the IL-12 (p40) and IFN-gamma R double-knockout mouse, which suggested that SEA did not require IL-12 to induce SPr and that both worked independently of IFN-gamma. Splenocytes from wild-type mice cultured with SEA and neutralizing anti-IL-12 monoclonal antibody (mAb) also showed SPr induction. However, anti-Ia mAb inhibited SEA induction of SPR: Thus, SPr is inducible on T cells. SEA induces SPr through interaction with T-cell receptor (TCR), independently of IL-12 and IFN-gamma. IL-12 induces SPr independently of TCR activation and IFN-gamma expression. SP and its receptor, which regulate IFN-gamma production, are probably part of the IL-12-Th1 circuit.