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Biomedical subjects

Tom E Mollnes

Publications and source records attributed to Tom E Mollnes.

12 recordsLinked to original sources
PubMed2004

Complement activation reflects severity of meconium aspiration syndrome in newborn pigs.

Meconium aspiration syndrome (MAS) is a serious condition in newborns, associated with a poorly characterized inflammatory reaction. The aim of this study was to investigate a possible role for complement in pulmonary pathophysiology and systemic inflammation in experimental MAS. MAS was induced by instillation of meconium into the lungs of 12 hypoxic piglets. Six controls received saline under otherwise identical conditions. Hemo- and lung dynamics were recorded for 5 h. Plasma complement activation, revealed by the terminal sC5b-9 complex (TCC), and cytokines were measured by enzyme immunoassays. TCC increased substantially in MAS animals compared with controls (p <0.0005). The increase in TCC correlated with lung dysfunction: closely with oxygenation index (r=0.51, p <0.0001) and ventilation index (r=0.64, p < 0.0001) and inversely with lung compliance (r=-0.22, p=0.05). IL-1beta and tumor necrosis factor-alpha increased significantly in MAS animals compared with the controls (p=0.004 and 0.008, respectively). The cytokine increase occurred later than TCC and showed correlations with lung dysfunction similar to TCC. IL-10 did not discriminate between MAS animals and controls (p=0.32). Finally, the subgroup of MAS animals that died (n=5) had substantially higher TCC concentration compared with the surviving MAS animals (n=7; p <0.0005). TCC increased substantially in MAS and was closely correlated to lung dysfunction. Complement activation preceded cytokine release, which may suggest a primary role for complement in the pathophysiology of MAS.

Animals↗
PubMed2004

Exercise reduces plasma levels of the chemokines MCP-1 and IL-8 in subjects with the metabolic syndrome.

AIMS: Inflammation plays an essential role in the atherosclerotic process, and chemokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) seem to play a pivotal role in the pathogenesis of atherosclerosis. A possible common inflammatory basis for the pathogenesis of type 2 diabetes, metabolic syndrome and atherosclerosis has been suggested. In this study we investigated the effect of physical exercise and the HMG-CoA reductase inhibitor pravastatin on peripheral markers of inflammation in subjects with the metabolic syndrome. METHODS: The study was an unmasked randomized 2x2 factorial trial of 12 weeks duration. RESULTS: In the combined exercise groups there was a significant reduction in MCP-1 and IL-8 of 48 pg/ml (P=0.04) and 1.0 pg/ml (P=0.007), respectively, as compared to the combined non-exercise groups. There was also a significant reduction vs baseline of 50 pg/ml (33%) (P=0.002) and 0.35 pg/ml (13%) (P=0.03) for MCP-1 and IL-8, respectively. Changes in MCP-1 were significantly correlated to changes in visceral fat (r=0.41, P=0.02). CONCLUSION: The protective effect of exercise might in part be due to suppression of the inflammatory process.

Adult↗
PubMed2004

Comparison of a Duraflo II-coated cardiopulmonary bypass circuit and a trillium-coated oxygenator during open-heart surgery.

BACKGROUND: Cardiopulmonary bypass (CPB) evokes a systemic inflammatory response. In attempting to improve the biocompatibility of the equipment, various methods to coat the inner surfaces of the CPB systems have been developed. The present study compares a Trillium Biopassive surface-coated Affinity oxygenator with a Duraflo II totally heparin-coated CPB system. METHODS: Low-risk patients admitted for primary coronary artery bypass grafting or aortic valve replacement were randomized to operation using the Trillium- or the Duraflo II-coated setups. Heparin concentration, complement activation (C3bc activation products and terminal complement complex (TCC)), platelet activation (platelet numbers and beta-thromboglobulin (BTG)), leukocyte activation (leukocyte numbers and myeloperoxidase (MPO)), coagulation (thrombin/antithrombin complexes (TAT)) and fibrinolytic activity (plasmin/alpha2-antiplasmin complexes (PAP)) were measured during CPB and two hours postoperatively. RESULTS: Platelet counts decreased during CPB, without significant intergroup differences. The median BTG concentration increased moderately in both groups and were slightly higher in the Trillium group during CPB (p < 0.05), but not postoperatively. Complement activation products (C3bc and TCC), leukocyte counts, MPO, TAT and PAP activity showed no differences between the two groups. CONCLUSIONS: There were small differences in the inflammatory response between the two extracorporeal circulation devices compared in this study.

Blood Coagulation↗
PubMed2003

Meconium is a potent activator of complement in human serum and in piglets.

Meconium aspiration syndrome (MAS) is a clinical condition in the newborn infant with a significant morbidity and mortality. The complex pathophysiology of MAS, leading to both pulmonary and systemic complications, is characterized by an incompletely understood inflammatory reaction. Treatment is symptomatic, mainly limited to airway cleaning and ventilatory support. In this study, we show for the first time that meconium is a potent activator of complement, a key mediator of inflammation. In vitro, meconium activated the alternative complement pathway in human umbilical cord serum as judged by a substantial increase in the alternative pathway convertase C3bBbP. The activation proceeded through C3 (C3bc) and the terminal C5-9 pathway (terminal SC5b-9 complement complex), whereas the classical and lectin pathways were not activated (C1rs-C1-inhibitor complexes and C4bc). The lipid fraction, containing, e.g. free fatty acids, and the water fraction, containing, e.g. bile acids, contributed equally to the complement activation. A blocking antibody to factor D (alternative pathway) completely inhibited the meconium-induced complement activation, whereas blocking antibodies to mannose-binding lectin (lectin pathway) and C2 (classical and lectin pathway) had no effect. In vivo, meconium induced systemic complement activation in a piglet model of MAS, paralleling the increase in lung dysfunction. In conclusion, meconium is a potent activator of the complement system both in vitro and in vivo. Complement may be important in the pathogenesis of MAS, and specific complement inhibition might be a possible treatment approach in MAS.

Age Factors↗
PubMed2003

Mechanism of complement activation and its role in the inflammatory response after thoracoabdominal aortic aneurysm repair.

BACKGROUND: Complement activation contributes to ischemia-reperfusion injury. Patients undergoing thoracoabdominal aortic aneurysm (TAAA) repair suffer extensive ischemia-reperfusion and considerable systemic inflammation. METHODS AND RESULTS: The degree and mechanism of complement activation and its role in inflammation were investigated in 19 patients undergoing TAAA repair. Patients undergoing open infrarenal aortic surgery (n=5) or endovascular descending aortic aneurysm repair (n=6) served as control subjects. Substantial complement activation was seen in TAAA patients but not in controls. C1rs-C1-inhibitor complexes increased moderately, whereas C4bc, C3bBbP, C3bc, and the terminal SC5b-9 complex (TCC) increased markedly after reperfusion, reaching a maximum 8 hours after reperfusion. Interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), and IL-8 increased significantly in TAAA patients but not in controls, peaking at 24 hours postoperatively and correlating closely with the degree of complement activation. IL-6 and IL-10 increased to a maximum 8 hours after reperfusion in the TAAA patients, were not correlated with complement activation, and increased moderately in the control subjects. Myeloperoxidase and lactoferrin increased markedly before reperfusion in all groups, whereas sICAM-1, sP-selectin, and sE-selectin were unchanged. No increase was observed in complement activation products, IL-1beta, TNF-alpha, or IL-8 in a mannose-binding lectin (MBL)-deficient TAAA patient, whereas IL-6, IL-10, myeloperoxidase, and lactoferrin increased as in the controls. Two other MBL-deficient TAAA patients receiving plasma attained significant MBL levels and showed complement and cytokine patterns identical to the MBL-sufficient TAAA patients. CONCLUSIONS: The data suggest that complement activation during TAAA repair is MBL mediated, amplified through the alternative pathway, and responsible in part for the inflammatory response.

Aged↗
PubMed2003

Inhibition of C5a-induced inflammation with preserved C5b-9-mediated bactericidal activity in a human whole blood model of meningococcal sepsis.

The complement system plays an important role in the initial defense against Neisseria meningitidis. In contrast, uncontrolled activation in meningococcal sepsis contributes to the development of tissue damage and shock. In a novel human whole blood model of meningococcal sepsis, we studied the effect of complement inhibition on inflammation and bacterial killing. Monoclonal antibodies (mAbs) blocking lectin and alternative pathways inhibited complement activation by N meningitidis and oxidative burst induced in granulocytes and monocytes. Oxidative burst was critically dependent on CD11b/CD18 (CR3) expression but not on Fc gamma-receptors. Specific inhibition of C5a using mAb 137-26 binding the C5a moiety of C5 before cleavage prohibited CR3 up-regulation, phagocytosis, and oxidative burst but had no effect on C5b-9 (TCC) formation, lysis, and bacterial killing. An mAb-blocking cleavage of C5, preventing C5a and TCC formation, showed the same effect on CR3, phagocytosis, and oxidative burst as the anti-C5a mAb but additionally inhibited TCC formation, lysis, and bacterial killing, consistent with a C5b-9-dependent killing mechanism. In conclusion, the anti-C5a mAb 137-26 inhibits the potentially harmful effects of N meningitidis-induced C5a formation while preserving complement-mediated bacterial killing. We suggest that this may be an attractive approach for the treatment of meningococcal sepsis.

Antibodies, Monoclonal↗
PubMed2003

Perspectives on complement in xenotransplantation.

The crucial role of complement and naturally occurring anti-Gal antibodies in hyperacute rejection of pig transplants to Old World monkeys, apes and humans is well established. This rejection can be prevented by manipulating either system. Although cells, tissues or organs from pigs made transgenic for human complement regulatory proteins escape hyperacute rejection, there is an increasing evidence of a role for complement also in the subsequent acute vascular or delayed xenograft rejection. Furthermore, complement contributes in a general manner to ischemia-reperfusion injury (IRI), irrespective of the organ source. Early complement-mediated endothelial cell activation, although not sufficient to induce hyperacute rejection, may contribute to reduced long-time graft performance. Control of fluid-phase complement activation by soluble complement inhibitors might be an important adjuvant to transgenic organs from the time of organ harvesting through the first post-transplant period. Pharmacologic manipulation of complement is a field in expansion, though still in its infancy. Although an optimal transgenic and cloned pig may be close to reality, the role of complement in xenotransplantation needs to be fully elucidated and a treatment regimen for fluid-phase inhibition is warranted. The story of complement in xenotransplantation is not completed but under continuous revision.

Animals↗
PubMed2002

[Ethical aspects of xenotransplantation].

The motivation for research on animals as a source of cells, tissues and organs for human transplantation (xenotransplantation) is the scarcity of suitable donors for patients with end-stage organ failure. Use of animals in both experimental and clinical settings raise considerable ethical concerns, especially when non-human primates are used. The pig may represent an acceptable source animal for xenotransplantation and is today regarded as the animal of choice. Xenotransplantation seems defensible from an ethical perspective, but should not be performed in humans until preclinical animal-to-animal xenotransplantations have a predictable rate of success and the risk to society at large is negligible. For the individual patient and his or her next of kin involved, issues of autonomy and proper consent procedures must be given high priority. Safeguards must be established, for the patient and for society at large, in relation to health hazards from infectious organisms, particularly retroviruses. Public monitoring of research on and clinical use of xenotransplantation is mandatory.

Animal Rights↗
PubMed2002

Human serum-induced porcine endothelial cell E-selectin expression is associated with IgG3 and IgM anti-Gal antibodies.

Naturally occurring anti-Galalpha1-3Gal (anti-Gal) antibodies and complement induce hyperacute rejection (HAR) of porcine organs transplanted to primates. If the hyperacute reaction is prevented, an acute vascular rejection (AVR) occurs within hours to few days. Antibodies are important for the development of AVR, whereas the role of complement is still not clarified. AVR is characterized by protein synthesis-dependent endothelial cell (EC) activation. In the present study we investigated the relation between EC activation as measured by E-selectin expression, and the concentrations of anti-Gal antibodies of IgM, IgG and IgG subclasses in sera from 80 healthy blood donors selected on the basis of sex and age. There was a significant correlation between E-selectin expression and the concentration of IgG3 anti-Gal (r=0.39; P=0.019), which was not seen for the other IgG subclasses or for total IgG anti-Gal. A modest, but significant correlation was found between the concentration of IgM anti-Gal and E-selectin expression (r=0.38; P=0.040), but not between IgM and IgG3 anti-Gal. There was a large interindividual variation in anti-Gal antibodies, 50-fold for IgM and 70-fold for IgG. Females had significantly higher concentrations of IgM anti-Gal than males (P=0.0006), which was explained by a substantial increase in IgM anti-Gal concentration in younger women. The concentration of IgG anti-Gal and the degree of E-selectin expression did not differ between sex or age groups. In conclusion, the close correlation between anti-Gal antibodies of the potent complement activating IgG3 subclass and porcine EC activation, may imply that these antibodies play a role in EC activation characteristic of AVR.

Adult↗
PubMed2002

The significance of heparin-coated veno-venous bypass circuits in liver transplantation.

We studied the effects of veno-venous bypass (VVBP) circuit surface heparinization on the activation of the plasma defence systems (coagulation, fibrinolysis, kallikrein-kinin and complement) and leukocyte activation in a prospective randomized study in 20 patients during and 1 day after liver transplantation (OLT). To our knowledge, this is the first study of this kind where the possible benefits of surface heparinization of the VVBP circuit in OLT have been investigated. Twenty patients were randomized to either heparin-coated (HC) VVBP equipment or to otherwise identical noncoated (NC) circuits. Five blood samples were drawn during the OLT procedure: one just before VVBP, three during VVBP and one 5 min after portal venous reperfusion (PVR). A further sample was taken 1 day after the operation. Components of the blood coagulation, fibrinolytic and kallikrein-kinin systems were analysed using functional assays (chromogenic peptide substrate assays) or enzyme immunoassays (EIA). Complement system factors and granulocyte activation, represented by myeloperoxidase (MPO) release, were analyzed by EIA. Activation of the plasma defence systems occurred in both groups at an early stage during OLT and a further activation occurred 5 min after PVR. MPO levels were slightly elevated 5 min after PVR. However, no significant differences between the two groups were observed. Significant activation of the humoral defense systems was found in both groups during OLT. A considerably larger study, including at least 330 patients, is necessary to fully assess the possible benefits of surface heparinization of the VVBP circuit.

Adolescent↗