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PubMed1991

Effects of iodothyronines on chemotactic peptide-receptor binding and superoxide production of human neutrophils.

We studied the action of iodinated thyronines on the superoxide (O2-) production of human neutrophils stimulated with a chemotactic peptide N-formylmethionylleucylphenylalanine (FMLP) in vitro. L-Thyroxine and L-triiodothyronine elicited dose dependently a potent inhibitory action on the FMLP-induced O2- production with IC50 values of about 10(-6) M and 7.10(-6) M, respectively, but L-diiodothyronine did not. No difference in the inhibition was observed between the L-form and the D-form of the compounds. Inhibition of the O2- production by L-thyroxine was restored by the washing of the cells. L-Thyroxine did not affect the O2- production stimulated with either the fifth component of the complement (C5a) or phorbol 12-myristate 13-acetate. L-Thyroxine and L-triiodothyronine were found to block [3H]FMLP binding to its own receptor with IC50 values similar to those for the inhibition of the O2- production by changing the affinity for the peptide but not the number of the receptors. These results suggest that thyroxine and triiodothyronine interfere with the binding of FMLP to the receptors, leading to the inhibition of neutrophil functions, such as O2- production, and that the inhibitory effects result from extranuclear actions rather than nuclear receptor-mediated ones.

Chemoreceptor Cells↗
PubMed1987

Biochemical investigations after burning injury: complement system, protease-antiprotease balance and acute-phase reactants.

Seventeen burned patients were investigated--Group I (n=10) with a mean burned area expressed as unit burn standard (UBS) of 69 +/- 24 and Group II (n = 7) with a mean UBS of 23 +/- 8. Blood samples were collected immediately after admission, 6-12 h after injury, during the morning and evening of day 1, and then daily for 2 weeks. This prospective study demonstrated complement activation in vivo in all burned patients, measured by C3d/C3 ratio index which was not related to the extent of the burned surface. A significant protease-antiprotease imbalance, correlated to the severity of burns, was found, leukocyte elastase was increased throughout the observation period, alpha 2-macroglobulin drastically decreased in severely burned patients, and alpha 1-proteinase inhibitor promptly decreased below the normal level in patients with more than 40 UBS. Finally, there was a delayed but then persistent acute-phase reactant protein response involving C-reactive protein, haptoglobin and alpha 1-acid glycoprotein, the concentrations of which reached a plateau on days 6 or 7.

Acute-Phase Proteins↗
PubMedDate not supplied

In vitro function of granulocyte concentrates following passage through an electromechanical infusion pump.

Six units of granulocytes stored for 18 hours at 20 to 24 degrees C without agitation were passed through an electromechanical infusion device pump system (test) (Abbott) and through a 170-micron filter (control). To determine the effect of needle gauge, a 19 or 23 gauge needle was attached to the end of the pump administration set. After passage through the pump, granulocytes were evaluated for signs of cytolysis and functional loss, red cells for hemolysis, platelets for release of beta-thromboglobulin, and plasma for C3a and C5a complement activation. There was no evidence (mean +/- 1 SD) of hemolysis (less than 1.0 vs. less than 1.0 mg/dl), loss of granulocytes (123 +/- 38 X 10(3)/microliters vs. 118 +/- 29 X 10(3)/microliters), changes in any of several tests of neutrophil function, increased release of beta-thromboglobulin (15.8 +/- 5.8 vs. 17.0 +/- 6.6%), or C3a complement activation (483 +/- 221 vs. 500 +/- 200 ng/ml) after passage through the pump system (p greater than 0.05). No significant differences were seen between the use of a 19 or 23 gauge needle. Based on these in vitro data, we conclude that this pump system is acceptable for use in clinical practice when control over rate and volume of granulocyte administration is important.

Cell Survival↗
PubMed1987

Is contact activation of the coagulation system involved in the genesis of the first-use syndrome?

A number of mechanisms have been thought to be involved in the pathogenesis of the first-use syndrome. These include IgE antibody-mediated response to ethylene oxide-related antigens, membrane activation of the alternative complement pathway, activation of tissue mast cells and basophils by materials released from the dialyzer into the circulation, and transfer of bacterial products through high flux dialyzer. However, the possible role of the activation of blood coagulation system and platelets during dialysis has not been considered. The present communication reviews the theoretical basis for a possible connection between dialysis-induced activation of platelets and coagulation system with the first-use syndrome. Although the available data concerning the activation of intrinsic coagulation pathway during dialysis are conflicting, there is no controversy as to the occurrence of platelet activation. It is suggested that biochemical events triggered by activation of these systems may in part contribute to the genesis of first-use syndrome.

Anaphylaxis↗
PubMed1985

New developments in immunopathology with special reference to complement and immune complexes.

The last few years have seen rapid advances in our understanding of immune phenomena, and these are now being translated into a new understanding of immunopathology. This paper reviews a number of areas where important new knowledge has been gained in the area of complement and immune complexes as a cause of disease. An understanding of the role of the metabolism of complement proteins has led to an understanding of how these proteins interact with receptors to cause phagocytosis. New understanding of the lysis-producing steps has led to new diagnostic tests for complement-induced damage as well as new knowledge of how complement functions to kill microorganisms. New methods for purifying anaphylatoxins have made these proteins available for study in man. A model of serum sickness in man has allowed for the more detailed understanding of how immune complexes cause disease and has led to the appreciation of new clinical signs of immune-complex-mediated disease in man.

Antigen-Antibody Complex↗
PubMed1988

Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

The binary botulinum C2 toxin ADP-ribosylated the actin of human neutrophils. Treatment of human neutrophils with botulinum C2 toxin for 45 min increased FMLP-stimulated superoxide anion (O2-) production 1.5-5-fold, whereas only a minor fraction of the cellular actin pool (approximately 20%) was ADP-ribosylated. Effects of botulinum C2 toxin depended on toxin concentrations, presence of both components of the toxin, and incubation time. Cytochalasin B similarly enhanced O2- production. The effects of botulinum C2 toxin and cytochalasin B were additive at submaximally, but not maximally effective concentrations and incubation time of either toxin. Botulinum C2 toxin also enhanced stimulation of O2- production by Con A and platelet-activating factor, but not by phorbol 12-myristate 13-acetate (PMA). Botulinum C2 toxin increased FMLP-induced release of N-acetyl-glucosaminidase by 100-250%; release of vitamin B12-binding protein induced by FMLP and PMA was enhanced by approximately 150 and 50%, respectively. Botulinum C2 toxin blocked both random migration of neutrophils and migration induced by FMLP, complement C5a, leukotriene B4, and a novel monocyte-derived chemotactic agent. The data suggest that botulinum C2 toxin-catalyzed ADP-ribosylation of a minor actin pool has a pronounced effect on the activation of human neutrophils by various stimulants.

Acetylglucosaminidase↗
PubMed1992

Cytokine-induced neutrophil-derived interleukin-8.

During acute inflammation, the first line of cellular response for host defense is the neutrophil. In addition to the historic role of the neutrophil as a phagocyte, recent studies have identified this cell as an important source of a number of cytokines. In this study, we provide evidence that the neutrophil is a significant source of interleukin-8 (IL-8). Neutrophils freshly isolated from whole blood were not found to constitutively express IL-8 mRNA. In contrast, when these leukocytes were cultured on plastic they were activated, leading to the significant expression of de novo steady-state levels of IL-8 mRNA. In addition, when neutrophils were treated with cycloheximide, there was evidence for "superinduction" of steady-state levels of IL-8 mRNA and inhibition of antigenic IL-8 production. Neutrophils were subsequently stimulated with lipopolysaccharide (LPS), tumor necrosis factor-alpha, or interleukin-1-beta and were found to express IL-8 mRNA and antigen in both a time- and dose-dependent manner. Furthermore, neutrophils stimulated with traditional chemotactic/activating factors, such as the split product of the fifth component of complement (C5a), formylmethionyleucylphenylalanine (fMLP), and leukotriene B4 (LTB4) in a dose-dependent manner did not produce significant antigenic IL-8, as compared with unstimulated controls. In contrast, when neutrophils were exposed to either of these neutrophil agonists in the presence of LPS, the production of antigenic IL-8 was significantly elevated, as compared with either of the stimuli alone, suggesting a synergistic response. These data would suggest that the neutrophil can no longer be viewed as only a phagocyte or warehouse for proteolytic enzymes, but is a pivotal effector cell that is able to respond to mediators in its environment and generate cytokines. This latter neutrophil response may be important for either the elicitation of additional neutrophils or to orchestrate the conventional immune response at sites of inflammation.

Antigens↗
PubMed1992

[Modulation of vascular tone of normal and arteriosclerotic arteries by leukocytes].

Leukocytes, in particular mononuclear cells, play a central role in the pathogenesis of arteriosclerosis. The arteriosclerotic vessel wall is chemotactic for circulating leukocytes. Activated leukocytes are known to release a variety of vasoactive substances. Thus, activation of leukocytes in diseased arteries is not only an epiphenomenon of an inflammatory process, but instead may contribute to arteriosclerosis-associated complications such as vasoconstriction/vasospasm and thrombotic vessel occlusion. Influence of leukocytes on vascular tone appears to be complex and may be modulated by the presence of intact endothelium and additional blood constituents such as platelets. In vitro, mononuclear and polymorphonuclear leukocytes both relax and contract isolated arteries according to experimental conditions and leukocyte isolation protocols. In vivo, activation of leukocytes by chemotactic peptides f-met-leu-phe or complement C5a produces pronounced vasoconstriction. Mediators of these leukocyte-induced vascular responses are partially characterized and consist of nitric oxide (or EDRF-like factor), superoxide anions, thromboxane A2, peptidoleukotrienes, and an unknown contractile factor. In addition, leukocytes may indirectly modulate vascular tone by cleavage of angiotensin II from angiotensinogen or angiotensin I, and by inhibiting or stimulating platelet aggregation. Thus, leukocytes and their products may have several pathways to modulate vascular tone. Abnormal interactions between endothelium-platelet-leukocytes with vascular tone may play an important role in the pathogenesis of vascular complications in patients with coronary artery disease.

Animals↗
PubMed1991

Complement activation in cancer patients undergoing immunotherapy with interleukin-2 (IL-2): binding of complement and C-reactive protein by IL-2-activated lymphocytes.

Plasma samples from cancer patients undergoing immunotherapy with high-dose recombinant interleukin-2 (IL-2) were obtained over a 5-day course of treatment and assayed by radioimmunoassay or enzyme-linked immunosorbent assay for the complement degradation products, C3a, iC3b, Ba, Bb, C4d, and SC5b-9. In the majority of patients, pretreatment C3a, Ba, Bb, and SC5b-9 plasma levels were comparable with those measured in normal donor plasma. However, by the end of the 5-day treatment course, C3a levels had increased 15.6-fold. In several patients, peak concentrations of C3a were as high as those reported in patients with sepsis or burn injury. Plasma levels of alternative pathway components Ba and Bb also increased, 8.0- and 5.0-fold, respectively, during IL-2 treatment. Likewise, levels of one of the terminal complexes, SC5b-9, increased 5.0-fold and the plasma C4d and iC3b concentrations increased 4.8- and 2.9-fold, respectively, by the fifth day of treatment. To determine whether activated lymphocytes participate in IL-2-induced complement activation, peripheral blood mononuclear cells (PBMC) obtained from IL-2 recipients before and 5 days after beginning therapy were reacted with monoclonal antibodies (MoAbs) against C3c and the terminal complement complex SC5b-9. Dual-color cytofluorographic analysis showed that within the CD3(+) population, the percentage of cells binding the anti-C3c and anti-SC5b-9 MoAbs increased 6.2-fold and 5.1-fold, respectively, by day 5. The anti-C3c MoAb also bound to CD3(+) cells stimulated in vitro with IL-2 and then exposed to serum. Moreover, fluid-phase iC3b was generated from purified C3 by PBMC activated in vitro with IL-2, but not by unstimulated cells. Serum levels of C-reactive protein (CRP) are markedly elevated in patients undergoing IL-2 immunotherapy. This hepatic acute phase reactant has been shown to activate the classical pathway when bound to cell surfaces. Because levels of the classical component C4d increase markedly during IL-2 treatment, we sought to determine if CRP became bound to PBMC during IL-2 treatment and found that during therapy, the percentage of CD3(+) cells reactive with an anti-CRP MoAb increased from less than 2% to greater than 18%. When PBMC were activated with IL-2 in vitro and then exposed to exogenous CRP, greater than 20% of the CD3(+) cells reacted with the anti-CRP MoAb.(ABSTRACT TRUNCATED AT 400 WORDS)

C-Reactive Protein↗
PubMed1988

Pustular irritant dermatitis due to croton oil. Evaluation of the role played by leukocytes and complement.

To elucidate the pathomechanisms of irritant pustular dermatitis and to evaluate the role of leukocytes in pustulation induced by croton oil, we compared the skin responses in leukopenic-and decomplemented guinea pigs with those in control saline-injected animals, to 1% croton oil application. Both decomplemented and control animals responded similarly to croton oil, showing erythema and pustulation at 24 h after topical application; microscopically numerous mononuclear and polymorphonuclear cells infiltrated the skin. Meanwhile, the clinical and histopathological response of leukopenic animals to croton oil was significantly depressed. Time-course study of inflammatory infiltrate in the dermis of controls revealed that mononuclear cells preceded the infiltration of polymorphonuclears. Although leukocytes constitute an important component in croton oil dermatitis, our results suggest that unclarified chemical mediators, other than complement-derived chemotactic factors, play a crucial role as a primary chemoattractant in the production of pustulation at the croton oil-applied site.

Administration, Cutaneous↗