Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes.

Phagocyte recognition, uptake, and nonphlogistic degradation of neutrophils and other leukocytes undergoing apoptosis promote the resolution of inflammation. This study assessed the effects of anti-inflammatory glucocorticoids on this leukocyte clearance mechanism. Pretreatment of "semimature" 5-day human monocyte-derived macrophages (M phi) for 24 h with methylprednisolone, dexamethasone, and hydrocortisone, but not the nonglucocorticoid steroids aldosterone, estradiol, and progesterone, potentiated phagocytosis of apoptotic neutrophils. These effects were specific in that the potentiated phagocytosis of apoptotic neutrophils was completely blocked by the glucocorticoid receptor antagonist RU38486, and glucocorticoids did not promote 5-day M phi ingestion of opsonized erythrocytes. Similar glucocorticoid-mediated potentiation was observed with 5-day M phi uptake of alternative apoptotic "targets" (eosinophils and Jurkat T cells) and in uptake of apoptotic neutrophils by alternative phagocytes (human glomerular mesangial cells and murine M phi elicited into the peritoneum or derived from bone marrow). Importantly, methylprednisolone-mediated enhancement of the uptake of apoptotic neutrophils did not trigger the release of the chemokines IL-8 and monocyte chemoattractant protein-1. Furthermore, longer-term potentiation by methylprednisolone was observed in maturing human monocyte-derived M phi, with greater increases in 5-day M phi uptake of apoptotic cells being observed the earlier glucocorticoids were added during monocyte maturation into M phi. We conclude that potentiation of nonphlogistic clearance of apoptotic leukocytes by phagocytes is a hitherto unrecognized property of glucocorticoids that has potential implications for therapies aimed at promoting the resolution of inflammatory diseases.

Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes.

Eosinophils and neutrophils are closely related, terminally differentiated cells that in vitro undergo constitutive cell death by apoptosis. The onset of apoptosis in both cell types can be delayed by hemopoietins and inflammatory mediators. Although there have been a number of reports demonstrating that glucocorticoids (in particular dexamethasone) antagonize the eosinophil life-prolonging effects of hemopoietins, direct effects of dexamethasone on eosinophil apoptosis have not been documented. In this study we examined the direct effects of glucocorticoids on eosinophil and neutrophil apoptosis in light of their common therapeutic use as anti-inflammatory and anti-allergic/hypereosinophilic agents. We found that treatment with dexamethasone induced eosinophil apoptosis. In contrast, dexamethasone was a potent inhibitor of neutrophil apoptosis. The effect of dexamethasone on both cell types was mediated through the glucocorticoid receptor, i.e., it was abolished by the glucocorticoid receptor antagonist RU38486. This is the first description of an agent that promotes eosinophil apoptosis while inhibiting neutrophil apoptosis, and thus presents a novel approach to the study of control of apoptosis in these closely related cell types as well as increases our understanding of the clinical action of glucocorticoids in inflammation.

Agents that elevate cAMP inhibit human neutrophil apoptosis.

Neutrophil apoptosis, determined after 20 h in culture using standard criteria and shedding of cell surface CD16 (Fc gamma RIII), is dramatically inhibited, in a concentration-dependent manner, by the cAMP analogs, dibutyryl-cAMP and 8-Br-cAMP, and the adenylyl cyclase activator, forskolin. Furthermore, the stable receptor-directed PGD2 mimetic, ZK 118.182, and the PGE2 mimetic, 11-deoxy PGE1, similarly inhibited apoptosis. The DP-receptor antagonist BW A868C blocked the effect of ZK 118.182 and the protein kinase A inhibitor H-89 reversed the inhibition of apoptosis induced by dibutyryl-cAMP. These results clearly show that neutrophil apoptosis is markedly attenuated by cAMP elevating agents. This nucleotide second messenger may play a fundamental role in controlling neutrophil longevity and pharmacological regulation of cAMP levels or actions may influence neutrophil apoptosis in vivo.

[New data in cardiology: the electric charge of the heart]. / Nouvelle donnée en cardiologie: la charge électrique du coeur.

This study emerging from profound consideration of the basis of vectorcardiography reveals a new electric model of the heart, the starting point for a computer programme of which only the principle is described. Noting inadequacies of vectorcardiography linked to necessary but possibly excessive simplifications, the author suggests a solution based only on Einthoven's postulate of a single dipole: at each instant during the cardiac revolution, the positions of point N, the centre of negative charges and origin of the dipole, of point P, the centre of positive charges and extremity of the dipole, and the value of the load borne by this dipole are calculated. The classical orientations of septal, parietal and basal vectors are thus found. It is shown that electric charge follows a bell-shaped curve and that the velocity of the dipole is compatible with that of the depolarisation wave, in contrast to velocities given by vectorcardiography. The trajectory of the dipole, a veritable "dipologram" visualises breaks in continuity which are interpreted. This new method has the advantage of being entirely confirmable: the dipole provided by the programme enables the calculation of potentials. Comparison between measured potentials and calculated potentials ensures the reliability of results provided by this programme. This method is totally in contrast with conventional vectorcardiography: the dipole is entirely mobile regarding both its origin and extremity, its site in the thorax is precisely identified, and its length is calculated, together with its velocity and the charge which it carries.(ABSTRACT TRUNCATED AT 250 WORDS)