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Nitric oxide: An ally in extracorporeal circulation?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many complications associated with heart surgery are due to the negative effects of extracorporeal circulation (ECC). Some of these complications may be attributed to ECC-induced activation of inflammation and coagulation pathways. The inflammatory reaction may be caused by the interaction of blood components with air and the artificial surfaces of the ECC, from substances produced due to ischaemia-reperfusion injury of the heart and lungs, and from increased release of endotoxin from ischemic intestines. Staphylococcus aureus (S. aureus) infections are the leading cause of respiratory, skin and soft tissue, and bloodstream infections. Nitric oxide (NO) is a gaseous signaling molecule involved in many physiological and pathological processes. The role of NO in infection and inflammation is complex. NO may contribute to morbidity by acting as a vasodilator, myocardial depressant, and cytotoxic mediator. On the other hand, NO may have a salutary role through microvascular, cytoprotective, immunoregulatory, and antimicrobial properties. A simulated extracorporeal circulation (SECC) model is a closed circuit, including a roller pump, an oxygenator, a venous reservoir and polyvinyl chloride (PVC) tubing, where human blood is circulated. The SECC model allows studies of the blood and its components, without any influence from other organ systems. The aim of this work was to investigate NO effects during SECC and in S. aureus infection.

Study I. Human blood was circulated through SECC during 3 hours, and leukocyte granule release was studied. Results indicated that NO addition during SECC is pro-inflammatory by stimulating leukocyte activation and granule release, and has no effect on oxygen free radical production and interleukin release.

Study II. Investigating the effect of NO on S. aureus growth in whole blood during 180 min SECC, results showed a 6.2 fold growth in the presence of NO. Results indicated that by stimulating the expression of inducible lactate dehydrogenase, specific to S. aureus, NO may improve S. aureus resistance to oxidative stress, giving the pathogen a survival advantage.

Study III. In an in vitro system of SECC, we measured glyceryl trinitrate (GTN) induced changes in leukocyte activation in whole blood caused by S. aureus infestation, as well as the effect of GTN on S. aureus growth. Results indicated that GTN does not affect S. aureus growth during SECC and has no effect on SECC-induced leukocyte activation.

Study IV. Whole blood concentrations of selected leukocyte adhesion molecules, complement system components and myeloperoxidase  were measured in an in vitro system of SECC. Results indicated that SECC induces the increased expression of some leukocyte markers and that GTN addition significantly reduces the expression of some leukocyte activation markers.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 81 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1238
Keyword [en]
Simulated extracorporeal circulation, Inflammation, Nitric oxide, Leukocyte activation, Staphylococcus aureus, Glyceryl trinitrate, Postoperative infection
National Category
Surgery
Research subject
Thorax Surgery
Identifiers
URN: urn:nbn:se:uu:diva-298782ISBN: 978-91-554-9626-5 (print)OAI: oai:DiVA.org:uu-298782DiVA: diva2:947313
Public defence
2016-09-15, Gunnesalen, Ingång 10, Uppsala Akademiska Sjukhus, 751 85, Uppsala, 12:00 (English)
Opponent
Supervisors
Available from: 2016-08-25 Created: 2016-07-07 Last updated: 2016-10-14
List of papers
1. Nitric oxide and inflammatory response in simulated extracorporeal circulation.
Open this publication in new window or tab >>Nitric oxide and inflammatory response in simulated extracorporeal circulation.
2003 (English)In: The thoracic and cardiovascular surgeon, ISSN 0171-6425, E-ISSN 1439-1902, Vol. 51, 130-137 p.Article in journal (Refereed) Published
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-298775 (URN)
Available from: 2016-07-07 Created: 2016-07-07 Last updated: 2016-09-05
2. Enhanced growth of Staphylococcus aureus after nitric oxide supplementation during simulated extracorporeal circulation
Open this publication in new window or tab >>Enhanced growth of Staphylococcus aureus after nitric oxide supplementation during simulated extracorporeal circulation
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2010 (English)In: The thoracic and cardiovascular surgeon, ISSN 0171-6425, E-ISSN 1439-1902, Vol. 58, no 2, 81-85 p.Article in journal (Refereed) Published
Abstract [en]

Background: Several factors contribute to postoperative bacterial infections in cardiac surgery. Long operation times and the use of extracorporeal circulation increase the risk of infection. Nitric oxide has been shown to possess a broad spectrum antimicrobial effect. Methods: In this study, we investigated the effect of nitric oxide on S. aureus growth in whole blood during simulated extracorporeal circulation. Results: S. aureus growth increased 6.2-fold after 180 min SECC in the presence of nitric oxide. Leukocyte counts remained unchanged without any differences between the groups. We observed a steady increase in markers of oxidative stress and activity of the innate immune system. Myeloperoxidase levels increased 8-fold, and C3a and terminal complement complex by 2-fold after 180 min. Conclusion: S. aureus growth is not due to the effect of nitric oxide on the innate immune system but from its effect on the bacteria itself. It has been shown that nitric oxide stimulates the expression of inducible lactate dehydrogenase, specific to S. aureus, which improves its resistance to oxidative stress, and may give S. aureus a survival advantage resulting in increased growth.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-298778 (URN)10.1055/s-0029-1186135 (DOI)
Available from: 2016-07-07 Created: 2016-07-07 Last updated: 2017-05-18Bibliographically approved
3. Effect of Glyceryl Trinitrate on Staphylococcus aureus Growth and Leukocyte Activation during Simulated Extracorporeal Circulation
Open this publication in new window or tab >>Effect of Glyceryl Trinitrate on Staphylococcus aureus Growth and Leukocyte Activation during Simulated Extracorporeal Circulation
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2014 (English)In: The thoracic and cardiovascular surgeon, ISSN 0171-6425, Vol. 62, no 5, 402-408 p.Article in journal (Refereed) Published
Abstract [en]

Background Previously, nitric oxide has been shown to possess antimicrobial effects. In this study, we aim to test the effect of glyceryl trinitrate (GTN) on Staphylococcus aureus growth during simulated extracorporeal circulation (SECC) and also to examine the effect of S. aureus, alone and in combination with GTN, on activation markers of the innate immune system during SECC. Methods In an in vitro system of SECC, we measured GTN-induced changes in markers of leukocyte activation in whole blood caused by S. aureus infestation, as well as the effect of GTN on S. aureus growth. Results GTN had no effect on S. aureus growth after 240 minutes SECC. Staphylococcus aureus reduced the expression of granulocyte Fc gamma-receptor CD32 but stimulated the expression of monocyte CD32. Staphylococcus aureus stimulated expression of some leukocyte adhesion key proteins, activation marker CD66b, lipopolysaccharide-receptor CD14, and C3b-receptor CD35. Staphylococcus aureus and GTN addition induced significant increases in monocyte CD63 (lysosomal granule protein) levels. Conclusion GTN does not affect S. aureus growth during SECC and has no effect on SECC-induced leukocyte activation.

Keyword
glyceryl trinitrate, Staphylococcus aureus, simulated extracorporeal circulation, postoperative infection, cardiac surgery
National Category
Surgery Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-232653 (URN)10.1055/s-0033-1363296 (DOI)000340748500005 ()
Available from: 2014-09-24 Created: 2014-09-22 Last updated: 2016-09-09Bibliographically approved
4. Effect of simulated extracorporeal circulation and glyceryl-tri-nitrate on leukocyte activation.
Open this publication in new window or tab >>Effect of simulated extracorporeal circulation and glyceryl-tri-nitrate on leukocyte activation.
2014 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 48, no 1, 59-64 p.Article in journal (Refereed) Published
Abstract [en]

Objectives. During extracorporeal circulation (ECC), a mechanical pump and an oxygenator replace the functions of the heart and lungs. The aim of this study is to test the effect of the nitric oxide donor glyceryl-tri-nitrate on activation markers of the innate immune system during simulated ECC. Design. Whole blood concentrations of selected leukocyte adhesion molecules, complement system components and myeloperoxidase (MPO) were measured in an in vitro system of simulated ECC. Results. Simulated ECC stimulated the expression of monocyte LPS-receptor CD14 and C3b-receptor CD35. Glyceryl-tri-nitrate significantly reduced the expression of leukocyte Fcγ receptor CD32 over time, compared to control. Simulated ECC increased the concentrations of MPO, terminal complement complex, and complement component C3a. Addition of glyceryl-tri-nitrate did not significantly affect these changes. Conclusions. Simulated ECC induces the increased expression of some leukocyte markers. Glyceryl-tri-nitrate addition significantly reduces the expression of some leukocyte activation markers.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-298780 (URN)10.3109/14017431.2013.878468 (DOI)000330849500009 ()
Available from: 2016-07-07 Created: 2016-07-07 Last updated: 2017-05-18Bibliographically approved

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