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Infection and Immunity, March 2005, p. 1764-1770, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1764-1770.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Plasmodium falciparum Malaria: Reduction of Endothelial Cell Apoptosis In Vitro

Christoph Josef Hemmer,1* Hans Anton Lehr,2 Kathi Westphal,1 Marcus Unverricht,1 Manja Kratzius,1 and Emil Christian Reisinger1

Division of Tropical Medicine and Infectious Diseases, Department of Medicine, University of Rostock Medical School, Rostock,1 Department of Pathology, University of Mainz Medical School, Mainz, Germany2

Received 7 June 2004/ Returned for modification 13 July 2004/ Accepted 1 October 2004

Organ failure in Plasmodium falciparum malaria is associated with neutrophil activation and endothelial damage. This study investigates whether neutrophil-induced endothelial damage involves apoptosis and whether it can be prevented by neutralization of neutrophil secretory products. Endothelial cells from human umbilical veins were coincubated with neutrophils from healthy donors and with sera from eight patients with P. falciparum malaria, three patients with P. vivax malaria, and three healthy controls. Endothelial apoptosis was demonstrated by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and annexin V staining. The rate of apoptosis of cells was markedly increased after incubation with patient serum compared to that with control serum. Apoptosis was most pronounced after incubation with sera from two patients with fatal cases of P. falciparum malaria, followed by sera of survivors with severe P. falciparum malaria and, finally, by sera of patients with mild P. falciparum and P. vivax malaria. Ascorbic acid, tocopherol, and ulinastatin reduced the apoptosis rate, but gabexate mesilate and pentoxifylline did not. Furthermore, in fatal P. falciparum malaria, apoptotic endothelial cells were identified in renal and pulmonary tissue by TUNEL staining. These findings show that apoptosis caused by neutrophil secretory products plays a major role in endothelial cell damage in malaria. The antioxidants ascorbic acid and tocopherol and the protease inhibitor ulinastatin can reduce malaria-associated endothelial apoptosis in vitro.

* Corresponding author. Mailing address: University of Rostock Medical School, Division of Tropical Medicine and Infectious Diseases, Department of Medicine, Ernst-Heydemann-Strasse 6, 18057 Rostock, Germany. Phone: 49 381 494.7414. Fax: 49 381 494.7509. E-mail: Christoph_Hemmer{at}med.uni-rostock.de.

Editor: W. A. Petri, Jr.

Infection and Immunity, March 2005, p. 1764-1770, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1764-1770.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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