Matrix metalloproteinases and their tissue inhibitors (TIMPs) in Plasmodium falciparum malaria: Serum levels of TIMP-1 are associated with disease severity

Abstract

Background. Molecular mechanisms involved in the pathogenesis of severe malaria caused by Plasmodium falciparum are not fully understood. Matrix metalloproteinases (MMPs) are enzymes that proteolytically degrade both the extracellular matrix and nonmatrix substances with various functions in the modulation of immune response. The key inhibitors of MMPs are the tissue inhibitors of metalloproteinases (TIMPs). Methods. We studied levels of MMP-8, MMP-9, TIMP-1, and TIMP-2 on admission and after 24 h, using an enzyme-linked immunosorbent assay, in serum specimens from 50 Gabonese children with severe malaria, 43 children with uncomplicated malaria, and 27 healthy control children. Results. Serum MMP-8 and TIMP-1 levels were significantly higher in the severe malaria and uncomplicated malaria groups, compared with those in the control group (P < .001). TIMP-1 levels were significantly higher in patients with severe malaria, compared with those in patients with uncomplicated malaria (P < .001). High TIMP-1 levels were significantly correlated with malaria severity, as determined by the simplified multiorgan dysfunction score (Spearman rank-correlation coefficient, 0.55; P < .001). Conclusions. TIMP-1 is associated with signs and symptoms of severe malaria. MMP-8 levels are elevated in patients with severe or uncomplicated P. falciparum malaria. MMPs and TIMPs may be relevant in the pathogenesis of severe malaria, either as proteolytic enzymes that degrade the extracellular matrix or as effectors and regulators of the immune response. © 2008 by the Infectious Diseases Society of America. All rights reserved.