Abstract
Antithrombin inhibits chemokine-induced migration of neutrophils by activating heparan sulfate proteoglycan-dependent signaling. Whether antithrombin affects migration of other types of leukocytes is unknown. We investigated the effects of antithrombin on spontaneous and chemokine-triggered migration of lymphocytes and monocytes from human peripheral blood in modified Boyden chamber micropore filter assays. Lymphocyte and monocyte populations from human peripheral blood were purified using magnetic antibody cell sorting. Signaling mechanisms in antithrombin-dependent migration were studied by Western blot analyses of protein kinases and Rho activation, or were tested functionally by using signaling enzyme blockers. Expression of heparan sulfate proteoglycan core protein was studied by RT-PCR and flow cytometry. As antithrombins, the concentrate Kybernin®P from human plasma and a monoclonal antibody-purified preparation therefrom were used. Pretreatment of lymphocytes and monocytes with antithrombin inhibited chemotaxis toward optimal concentrations of interleukin-8 or Rantes at concentrations of antithrombin as low as 10 nU/ml; in the absence of the chemokines, direct exposure of cells to gradients of antithrombin stimulated migration. Effects of antithrombin were abolished by pretreating cells with heparinase-1, chondroitinase, sodium chlorate and anti-syndecan-4 antibodies. Expression of syndecan-4 mRNA and protein in monocytes and lymphocytes was demonstrated in RT-PCR and anti-syndecan-4 immunoreactivity assay, respectively. In the presence of pentasaccharide, antithrombin lost its activity on the cells. Antithrombin induced chondroitinase- and heparinase I-dependent phophorylation of protein kinase C-alpha and dissociation of Rho-GTPase. Data indicate that antithrombin directly inhibits chemokine-stimulated migration of monocytes and lymphocytes via effects of its heparin-binding site on cell surface syndecan-4 by activation of protein kinase C and Rho signaling.
Highlights
Intra-abdominal pressure (IAP) is an important parameter and prognostic indicator of the patient’s underlying physiologic status [1]
Smaller aerosol particles resulted in greater drug delivery in vitro when using the modified Aeroneb Pro during controlled mechanical ventilation (CMV)
We retrospectively reviewed 107 procedures performed on 48 patients in the period between March 2000 and November 2001
Summary
Intra-abdominal pressure (IAP) is an important parameter and prognostic indicator of the patient’s underlying physiologic status [1]. The aim of this study was to assess the respiratory effects of sufentanil and remifentanil in postsurgical critically ill patients during spontaneous ventilation since the drugs show pharmacokinetic and pharmacodynamic properties which make them attractive for intensive care use. Preliminary evidence suggests that hU-II levels during cardiac surgery are increased in patients with myocardial dysfunction [2] It is not known, if hU-II plasma concentrations are related to pulmonary capillary wedge pressure (PCWP) as an estimate of left ventricular filling pressure. AAF in cardiac surgery postoperative period has been implicated as a complication that leads to longer ICU and hospital stay and to augmented costs It has not been associated with increased mortality rates. We aimed to investigate the effects of use of preoperative and early postoperative standard and immunonutrient products on immune system and acute inflammatory response in the patients undergoing gastrointestinal malignancy surgery.
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