Matrix Metalloproteinases and Their Tissue Inhibitors (TIMPs) in Plasmodium falciparum Malaria: Serum Levels of TIMP-1 Are Associated with Disease Severity

Background. Molecular mechanisms involved in the pathogenesis of severe malaria caused by Plasmodium fal-ciparum are not fully understood. Matrix metalloproteinases (MMPs) are enzymes that proteolytically degrade both the extracellularmatrix andnonmatrix substanceswith various functions in themodulation 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 chil-dren 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 uncomplicatedmalaria (P .001). High TIMP-1 levelswere significantly correlatedwithmalaria severity, as determined by the simplifiedmultiorgandysfunction 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. falciparummalaria. 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 o