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NO enhances basophil degranulation whereas antithrombin is primary inhibitor of FXIIa during inflammatory reaction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2005 (English)Other (Other academic)
Place, publisher, year, edition, pages
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-93396OAI: oai:DiVA.org:uu-93396DiVA: diva2:166857
Available from: 2005-09-06 Created: 2005-09-06 Last updated: 2010-11-24Bibliographically approved
In thesis
1. NO Effect on Inflammatory Reaction in Extracorporeal Circulation: Ex vivo Studies
Open this publication in new window or tab >>NO Effect on Inflammatory Reaction in Extracorporeal Circulation: Ex vivo Studies
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nitric oxide (NO) is expressed in inflammatory tissues. However, NO effects are controversial in inflammation; NO is described as acting in a dose dependent manner and possess both pro-inflammatory and anti-inflammatory properties.

The present thesis explored the role of NO in relation to white blood cell (WBC) and protein system activation by foreign surfaces in simulated extracorporeal circulation (SECC) using human whole blood from volunteer donors. Three doses of NO, 40 ppm, 80 ppm and 500 ppm, were administered and an array of markers of WBC and protein activation were studied. Neutrophil degranulation was detected with myeloperoxidase (MPO), human neutrophil lipocalin (HNL) and lactoferrin (LF); eosinophil degranulation with eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO); and basophil degranulation with histamine. Furthermore, whole blood and WBC capacity to produce reactive oxygen species (ROS) were studied and cytokine release was measured with IL-1 and IL-10. Complement activation was measured with C3a and C5b-9 complex and contact system activation with FXIIa-C1INH, FXIIa-AT, FXIa-C1INH and FXIa-AT.

NO increased neutrophil degranulation at all dose levels and 80 ppm NO increased basophil degranulation; whereas, NO exerted no effect on eosinophil degranulation, WBC subset counts, cytokine release or capacity to produce ROS. In addition, while increasing both specific and azurophil degranulation with 40 ppm, 80 ppm and 500 ppm, NO reversed the classical degranulation hierarchy with 500 ppm and azurophil degranulation became predominant. Furthermore, NO effect was greater with 500 ppm than with 80 ppm, indicating a dose response effect. The lack of iNOS mRNA expression in WBC and lack of L-NAME effect on degranulation and nitrite/nitrate production, together with absent increase in nitrite/nitrate in controls, excluded autocrine or paracrine regulation of degranulation. FXIIa-AT and FXIa-AT complexes increased and became predominant during early recirculation, whereas FXIIa-C1INH and FXIa-C1INH complexes were predominant at baseline but remained unaltered, suggesting contact system inhibition predominantly via AT. C3a and C5b-C9 increased. NO had no effect on either contact or complement system activation; however, 500 ppm NO shortened active clotting time.

In conclusion, the present data suggest that NO has a direct effect on neutrophil and basophil degranulation. Recognition of NO as an enhancer of degranulation may give access to new therapeutic tools for local and systemic inflammatory therapies; whereas, the identification of increased AT mediated inhibition of FXIIa and unchanged C1INH complexes presents new possibilities for therapeutic intervention in conditions such as hereditary angioedema and heart surgery.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 121 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 63
Medicine, Cardiac surgery, extracorporeal circulation, inflammatory reaction, NO, degranulation, neutrophil, eosinophil, basophil, complement, contact system, coagulation, Medicin
National Category
Dermatology and Venereal Diseases
Research subject
Clinical Chemistry
urn:nbn:se:uu:diva-5908 (URN)91-554-6321-5 (ISBN)
Public defence
2005-09-29, Roberg salen, Ingång 40, 4 trappor, Uppsala Akademiska Sjukhuset, Uppsala, 09:00
Available from: 2005-09-06 Created: 2005-09-06Bibliographically approved

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