Biomedical subjects

J B Tracey

Publications and source records attributed to J B Tracey.

13 recordsLinked to original sources

PubMed1997

Lymphocyte and monocyte subset changes during cardiopulmonary bypass: effects of aging and gender.

Complications of cardiopulmonary bypass (CPB) may be associated with either immune suppression or immune activation, but the specific effects of CPB on many lymphocyte and monocyte subsets are unclear. In addition, the increasing age of patients undergoing cardiac surgery raises the possibility of even greater effects on the immune system in elderly patients. We measured immunophenotypic alterations of circulating lymphocytes and monocytes after CPB in male and female cardiac surgery patients who were either younger than 60 or older than 75 years of age. The total lymphocyte counts in all patients decreased postoperatively; older patients had significantly lower counts at all time points. The absolute decline was greatest among T cells and particularly CD4+ T cells, which reached an average nadir of 251 cells/microl on postoperative day 1 in the older patients. The percentages of CD8+, CD4+CD45RA+, and CD4+CD45RO+ T cells did not change significantly, whereas the percentages of B cells and natural killer cells increased. Both T and B lymphocytes and monocytes showed evidence of activation, with increased percentages of CD3+HLADr+, CD3+IL2R+, and CD19+CD23+ lymphocytes and increased expression of CD11b on monocytes. By contrast, expression of class II major histocompatibility antigen (HLADr) monocytes decreased significantly. We conclude that CPB produces a profound alteration in the pool of circulating lymphocytes and monocytes, evidenced by decreased numbers of lymphocyte subsets including CD4+ cells and decreased expression of monocyte surface membrane proteins important for antigen presentation; CPB also activates a variety of specific circulating mononuclear cell subsets. Older patients showed patterns of lymphocyte and monocyte activation comparable to those of younger patients; however, they had consistently lower lymphocyte numbers and a trend toward decreased monocyte HLADr expression, potentially placing them at greater risk for infectious complications. Gender had no effect.

Age Factors↗

PubMed1996

Characterization of the P-selectin ligand on human hematopoietic progenitors.

The adhesive characteristics of hematopoietic stem and progenitor cells may partly regulate their proliferation and differentiation and may be critical in the homing of transplanted stem cells. Using quantitative adhesion assays, we have examined the characteristics of activated platelet adhesion to CD34+ cells in human blood and to the KG1a cell line. Approximately 85-95% of CD34+ cells from both sources bound thrombin-activated platelets; like mature neutrophils, activated platelet binding was maximal within 2 minutes of coincubation. Activated platelet adhesion to CD34+ cells was completely inhibited by chelation of calcium or by preincubation with the G1 blocking monoclonal antibody (MoAb) to platelet P-selectin. Using MoAbs to P-selectin glycoprotein ligand-1 (PSGL-1), we demonstrated that PSGL-1 was present on the surface of CD34+ cells; preincubation of CD34+ cells with the PL1 blocking MoAb to PSGL-1 completely inhibited activated platelet adhesion to CD34+ cells. Furthermore, treatment of CD34+ cells with O-sialoglycoprotein endopeptidase, which destroyed the PL1 epitope of PSGL-1, also abolished activated platelet-CD34+ cell binding. By contrast, MoAb directed against control epitopes of PSGL-1 or endopeptidase-sensitive epitopes of the CD34 molecule had no effect on activated platelet adhesion to CD34+ cells. Unlike mature neutrophils that, when activated, decrease P-selectin-dependent platelet adhesion because of redistribution of PSGL-1, phorbol ester treatment of CD34+ cells had no effect on their ability to bind activated platelets or PSGL-1 MoAbs. This study identifies PSGL-1 on CD34+ cells as the ligand for platelet P-selectin and suggests functional differences between mature and precursor hematopoietic cells in the regulation of surface PSGL-1 expression.

Antigens, CD34↗

PubMed1995

Acadesine inhibits neutrophil CD11b up-regulation in vitro and during in vivo cardiopulmonary bypass.

Granulocyte adhesion to ischemic tissue, mediated in large part by beta 2 integrin receptors, is important in the pathophysiology of reperfusion injury. Acadesine, a drug that modulates adenosine levels in ischemic tissue, has been shown to reduce reperfusion injury in animal models of ischemia. The purpose of this study was to measure changes in granulocyte CD11b/CD18 in an in vitro assay and in an in vivo trial of acadesine administered during cardiopulmonary bypass to determine whether this agent might modulate up-regulation of this adhesion receptor. In vitro, whole blood was incubated with acadesine or control diluent, stimulated with N-formyl-methionyl-leucyl-phenylalanine, and granulocyte CD11b measured. Acadesine significantly (p < 0.01) inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation by a mean of 61%. In similar experiments, adenosine also inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation (p < 0.01). In vivo, 34 patients at our institution participating in a multicenter trial of acadesine during cardiopulmonary bypass were randomized to placebo, low-dose, or high-dose acadesine infusion perioperatively. Combining low- and high-dose treatment groups, there was significant (p = 0.05) inhibition of granulocyte CD11b up-regulation in patients receiving acadesine; granulocyte CD11b expression in the acadesine group peaked at 2.8 times baseline versus 4.3 for placebo. By contrast, monocyte CD11b up-regulation (peaking after cardiopulmonary bypass at 3 times baseline) was not affected by acadesine. Acadesine and adenosine inhibit up-regulation of granulocyte CD11b in vitro, and acadesine is capable of a similar inhibition during in vivo cardiopulmonary bypass. This inhibition may contribute to the ability of these agents to decrease in vivo reperfusion injury.

Adenosine↗

PubMed1995

Nitroprusside inhibition of platelet function is transient and reversible by catecholamine priming.

BACKGROUND: The time course and reversibility of sodium nitroprusside's in vivo inhibition of platelet function are unclear. METHODS: Platelet aggregation and P-selectin expression as measures of platelet dense and alpha-granule release, respectively, were examined before and after administration of sodium nitroprusside (18 mg) to human volunteers and in in vitro studies. Hypotension occurring with sodium nitroprusside administration was treated with intravenous crystalloid and/or phenylephrine. RESULTS: Compared with preinfusion studies, platelet aggregation to epinephrine was significantly inhibited immediately and 4 min after discontinuation of the sodium nitroprusside infusion but returned to baseline at 8 and 12 min after discontinuing sodium nitroprusside. However, both dense and alpha-granule release to adenosine diphosphate after in vivo sodium nitroprusside were never significantly inhibited even at the time when sodium nitroprusside infusion was maximal. In contrast to our in vivo findings, in vitro incubation of platelet-rich plasma with sodium nitroprusside resulted in significant inhibition of dense and alpha-granule release to adenosine diphosphate. These in vitro inhibitory effects of sodium nitroprusside were reversed by pretreatment with epinephrine but not phenylephrine. CONCLUSIONS: In normal volunteers, sodium nitroprusside inhibits platelet aggregation to epinephrine but not adenosine diphosphate; inhibition was reversed within 8-12 min after discontinuing sodium nitroprusside. Sodium nitroprusside in vitro inhibition of platelet function to adenosine diphosphate was reversed by epinephrine pretreatment. Because of the rapid reversibility of its antiplatelet effect, sodium nitroprusside may be clinically useful even when there is the potential for impaired coagulation.

Adenosine Diphosphate↗

PubMed1995

Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.

Complement activation contributes to the systemic inflammatory response induced by cardiopulmonary bypass. At the cellular level, cardiopulmonary bypass activates leukocytes and platelets; however the contribution of early (3a) versus late (C5a, soluble C5b-9) complement components to this activation is unclear. We used a model of simulated extracorporeal circulation that activates complement (C3a, C5a, and C5b-9 formation), platelets (increased percentages of P-selectin-positive platelets and leukocyte-platelet conjugates), and neutrophils (upregulated CD11b expression). to specifically target complement activation in this model, we added a blocking mAb directed at the human C5 complement component and assessed its effect on complement and cellular activation. Compared with a control mAB, the anti-human C5 mAb profoundly inhibited C5a and soluble C5b-9 generation and serum complement hemolytic activity but had no effect on C3a generation. Additionally, the anti-human C5 mAb significantly inhibited neutrophil CD11b upregulation and abolished the increase in P-selectin-positive platelets and leukocyte-platelet conjugate formation compared to experiments performed with the control mAb. This suggests that the terminal components C5a and C5b-9, but not C3a, directly contribute to platelet and neutrophil activation during extracorporeal circulation. Furthermore, these data identify the C5 component as a site for therapeutic intervention in cardiopulmonary bypass.

Antibodies, Monoclonal↗

PubMed1980