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The soluble urokinase receptor in inflammation ¿ with focus on HIV-infection and malaria

Sisse Rye Ostrowski  


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Accepted by: The Faculty of Health Sciences University of Copenhagen, Denmark
Defended on: March 23, 2005
Official opponents: Overlæge, dr.med, John Rømer , Overlæge, dr.med, Niels Obel , Professor, overlæge, dr.med, Jens Ole Nielsen
Tutors: Professor, overlæge, dr.med Bente Klarlund Pedersen , Afdelingslæge, ph.d., Henrik Ullum

Published in the PhD Database: March 28, 2005


English abstract
The PhD thesis consists of a review and five papers based on experiments carried out at the Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Denmark.

The blood level of the solubel urokinase receptor (suPAR) is increased in infectious and autoimmune diseases and in cancer. The aim was to investigate whether the plasma suPAR level reflected immune activation in human immunodeficiency virus (HIV)-1 infection and other diseases with inflammation.

Three-, two- and one-domain suPAR (suPAR(I-III), suPAR(II-III) and suPAR(I)) and bulk-suPAR (sum of suPAR(I-III), suPAR(II-III) and suPAR(I-III)-complexes) was measured in plasma and cell culture supernatants from HIV-1-infected patients and healthy individuals. Plasma bulk-suPAR was measured in children with acute malaria.

Untreated HIV-1-infected patients had increased plasma bulk-suPAR, suPAR(I-III), suPAR(II-III) and suPAR(I) that declined after initiation of highly active antiretroviral therapy. High blood levels of TNF-a, IL-6 and ß2-microglobulin and anaemia were independently associated with high plasma suPAR in HIV-1-infected patients whereas neutrophilia was independently associated with high plasma suPAR in healthy individuals. High plasma bulk-suPAR, suPAR(I-III) and suPAR(II-III) were independent predictors of increased mortality in HIV-1-infected patients. HIV-1-infected patients had reduced stimulated and increased spontaneous release of suPAR from whole-blood cultures.

Malaria patients had increased plasma bulk-suPAR with the highest levels in children who died or had severe malaria and high bulk-suPAR was a univariate predictor of increased mortality. Thrombocytopenia, anaemia and neutrophilia were independently associated with high plasma bulk-suPAR.

These findings indicate that high blood suPAR levels reflect inflammation and immune activation in HIV-1-infection and malaria, which may explain the negative prognostic value of suPAR in these diseases. Further understanding of the origin of the blood suPAR level in diseases with inflammation has potential clinical significance.



Danish abstract
Ph.d.-afhandlingen består af en oversigt og fem artikler og udgår fra Epidemiafd. på Rigshospitalet.
Den soluble urokinase receptor (suPAR) er forøget i blodet ved infektioner, autoimmune sygdomme og cancer. Formålet var at undersøge om plasma suPAR afspejlede immunaktivering ved human immundefekt virus (hiv)-1 infektion og andre sygdomme med inflammation.

Tre-, to- og et-domæne suPAR (suPAR(I-III), suPAR(II-III) og suPAR(I)) samt bulk-suPAR (sum af suPAR(I-III), suPAR(II-III) og suPAR(I-III)-komplekser) blev målt i plasma og cellekultur supernatanter fra hiv patienter og raske individer. Plasma bulk-suPAR blev målt hos børn med akut malaria.

Ubehandlede hiv patienter havde forhøjet plasma suPAR der faldt efter påbegyndt highly active antiretroviral therapy. Højt cirkulerende TNF-a, IL-6 og ß2-microglobulin og anæmi var uafhængigt associeret med højt suPAR hos hiv patienter. Neutrocytose var uafhængigt associeret med højt suPAR hos raske. Højt bulk-suPAR, suPAR(I-III) og suPAR(II-III) var uafhængige markører for øget mortalitet hos hiv patienter. Hiv patienter havde mindsket stimuleret og øget spontan frigivelse af suPAR fra fuldblodskulturer.

Malaria patienter havde forhøjet plasma bulk-suPAR, med de højeste niveauer hos børn der døde eller havde kliniske malaria komplikationer, og højt bulk-suPAR var en univariat markør for øget mortalitet. Trombocytopeni, anæmi og neutrocytose var uafhængigt associeret med højt bulk-suPAR.

Disse fund indikerer at højt cirkulerende suPAR afspejler inflammation og immunaktivering ved hiv-1 infektion og malaria hvilket muligvis forklarer suPAR´s negative prognostiske værdi. Yderligere forståelse af suPAR´s oprindelse i blodet ved sygdomme med inflammation har potentielt klinisk betydning.