Regulation of matrix metalloproteinases and their inhibitor genes in lipopolysaccharide-induced endotoxemia in mice

An imbalance between matrix metalloproteinases (MMPs) and inhibitors of MMP s (TIMPS) may contribute to tissue destruction that is found in various inf lammatory disorders, To determine in an in vivo experimental setting whethe r the inflammatory reaction in the course of lipopolysaccharide (LPS)-induc ed endotoxemia causes an altered balance In the MMP/TIMP system, we analyze d the expression of a number of MMP and TIMP genes as well as MMP enzymatic activity in the liver, kidney, spleen, and brain at various time points af ter systemic infection of different doses of LPS in mice, injection of subl ethal doses of LPS led to an organ- and time-specific pattern of up-regulat ion of several MMP genes and the TIMP-1 gene in the liver, spleen, and kidn ey, whereas in the brain only TIMP-1 was induced. Injection of a lethal dos e of LPS caused similar but more prolonged expression of these MMP genes as well as the induction of additional MMP genes in all organs. In LPS-treate d mice fit situ hybridization revealed collagenase 3 gene Induction In cell s resembling macrophages whereas TIMP-1 RNA was detected predominantly in p arenchymal cells. Finally, gelatin zymography revealed increased gelatinoly tic activity ill all organs after LPS treatment. These observations highlig ht a dramatic shift In favor of increased expression of the MMP genes over the TIMP genes during LPS-induced endotoxemia, and suggest that MMPs may co ntribute to the development of organ damage in endotoxemia.