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Biomedical subjects

G M Vercellotti

Publications and source records attributed to G M Vercellotti.

114 records · Page 7Linked to original sources
PubMed1982

Acquired factor XI deficiency in systemic lupus erythematosus.

A variety of coagulation abnormalities has been described in systemic lupus erythematosus (SLE). We report a unique SLE patient with an acquired factor XI deficiency. The low factor XI levels were not due to a classical coagulation inhibitor, but to a plasma factor (probably an immunoglobulin) that selectively bound factor XI. The factor XI deficiency improved after treatment with corticosteroids. Thus it is possible that in SLE immune complexes may bind clotting factors making them unavailable for use in the coagulation cascade.

Blood Coagulation Tests↗
PubMed1982

Therapeutic ramifications of the interaction of complement, granulocytes, and platelets in the production of acute lung injury.

Evidence is reviewed that activation of complement through its ability to cause adhesion of granulocytes to the pulmonary endothelium (margination) and aggregation and embolization of these cells to the lung microvasculature is an important cause of pulmonary injury. Agents capable of diminishing such stimulated adhesiveness might be rational therapeutic adjuncts in vascular-damaging syndromes and are being investigated. To date, corticosteroids, such as methylprednisolone (in enormous doses), and certain nonsteroidal anti-inflammatory drugs, such as ibuprofen, have been shown to diminish granulocyte stickiness in vitro and diminish complement-mediated tissue damage in vivo. Moreover, platelets amplify complement/granulocyte-induced endothelial damage by releasing serotonin, which, in turn, potentiates granulocyte adhesion to endothelium. This potentiation is abrogated by the serotonin antagonists imiprimine and methysergide. Since these diverse agents inhibit granulocyte-adhesion phenomena by different mechanisms, they might predictably be synergistic in their beneficial effect. This prediction is validated for methylprednisolone and ibuprofen, for which we report a threefold synergism in preventing complement-mediated granulocyte aggregation in vitro. Preliminary studies indicate utility of this synergism in vivo as well, in that the degree of myocardial infarction [a complement-activating phenomenon) is diminished in coronary-ligated animals in which rather small doses of the two drugs administered together.

Adrenal Cortex Hormones↗
PubMed1982

Activation of plasma complement by perfluorocarbon artificial blood: probable mechanism of adverse pulmonary reactions in treated patients and rationale for corticosteroids prophylaxis.

Perfluorocarbons have shown promise as clinical blood substitutes. Although early experience in Japan with one such product--Fluosol-DA--has been uncomplicated, we observed an adverse pulmonary reaction in the first American patient to receive it and know of similar reactions in two other Americans so treated. Postulating that activation of plasma complement (C) by the perfluorocarbon emulsion might have caused the reaction, we tested the product to determine if it is an activator of complement. Incubation of Fluosol with plasma led to C3 conversion, decrement in CH50, and generation of C5a-related PMN aggregating activity; EDTA prevented such activation, while EGTA did not, suggesting that it proceeded via the alternative C pathway. Infusion of Fluosol into rabbits produced hypoxemia, neutropenia, thrombocytopenia, and pulmonary leukostasis, mimicking abnormalities previously demonstrated in rabbits receiving infusions of zymosan-activated plasma C. These deleterious responses to Fluosol were diminished by premedicating rabbits with corticosteroids (which had seemed to benefit when used empirically in our patient). In vitro and in vivo, Fluosol's effects were reproduced by Pluronic F-68, the nonionic detergent used to maintain the emulsion stability of Fluosol-DA. We conclude that adverse reactions to Fluosol are probably mediated by C activation and that steroid premedication may prevent them in susceptible patients.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury.

Oxidized low density lipoprotein (LDL), formed in vivo from presently unknown reactions, may play a role in atherogenesis. In vitro, transition metals such as iron and copper will facilitate LDL oxidation, but these metals are unlikely to exist in free form in normal body fluids. We have explored the possibility that LDL oxidation may be promoted by heme, a physiologically ubiquitous, hydrophobic, iron-containing compound. Indeed, during several-hour incubation, heme caused extensive oxidative modification of LDL; however, such modification requires only minutes in the presence of small amounts of H2O2 or preformed lipid hydroperoxides within the LDL. Oxidative interactions between heme, LDL, and peroxides lead to degradation of the heme ring and consequent release of heme iron, which further accelerates heme degradation. Coupled (evidently iron-catalyzed) heme degradation and LDL oxidation are both effectively inhibited by hydrophobic antioxidants and iron chelators. That such hemin-induced LDL oxidation may be involved in atherogenesis is supported by the finding that LDL oxidized by hemin is extremely cytotoxic to cultured aortic endothelial cells. Overall, these investigations not only lend support to the idea that LDL oxidation by physiological substances such as heme may play a role in the process of atherogenesis but also may have broader implications, as similar oxidative reactions between heme and unsaturated fatty acids may occur consequent to hemorrhagic injury.

Catalysis↗
PubMedDate not supplied

Neutrophil oxidants inactivate alpha-1-protease inhibitor and promote PMN-mediated detachment of cultured endothelium. Protection by free methionine.

Activated granulocytes have been implicated in mediating pulmonary endothelial damage in the Adult Respiratory Distress Syndrome. In another lung disease, emphysema, pulmonary granulocytes (PMNs) are thought to be doubly responsible for lung dissolution: they release potent proteolytic enzymes including elastase, and they generate reactive oxygen species that oxidize a reactive site methionine group in alpha-1-protease inhibitor (alpha-1-PI) rendering it, in turn, impotent as an anti-elastase. This suggested an analogous scenario for pulmonary vascular damage: namely, undefended PMN elastase might also mediate endothelial injury. Our strategy to prove this notion used 51chromium-labeled human endothelial cells exposed to intact PMN or to enucleate "neutroplasts." The latter are elastase-free cytoplasmic blebs derived from PMN. When activated, both PMN and neutroplasts generate similar amounts of toxic oxygen species; yet neutroplasts caused insignificant endothelial damage, measured as 51Cr "lift-off"from anchoring matrix (PMN = 24.3% +/- 1.8% vs neutroplast = 1.2% +/- 0.4%; p less than 0.001). Adding pure elastase back to neutroplasts increased endothelial cell lift-off (7% +/- 0.2%). Although the prototypic serine protease inhibitor phenyl methylsulfonylfluoride (PMSF) protected endothelium from PMNs, pure alpha-1-PI (also a potent anti-elastase) when added in physiologic amounts did not protect endothelial cells from PMN assault, suggesting that PMN oxidants might inactivate it. By adding exogenous myeloperoxidase (MPO) to MPO-deficient neutroplasts, we demonstrated that MPO-dependent oxidants, probably N-chloramines, are critical inactivators of alpha-1-PI. This was further confirmed since added free methionine, a scavenger of chloramine, protected alpha-1-PI from inactivation by reagent chloramine or that produced by rearmed neutroplasts or PMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Proteins↗