Human neutrophils secrete gelatinase B in vitro and in vivo in response toendotoxin and proinflammatory mediators

Bacterial sepsis is characterized by a systemic inflammatory state, with ac tivation of numerous cell types. Phagocytes participate in this phenomenon by secreting various proinflammatory cytokines and enzymes. Matrix metallop roteinases (MMPs) such as gelatinases are produced by phagocytes and are th ought to play an important role in processes of cell transmigration and tis sue remodeling. In this work, we show that endotoxin (lipopolysaccharide [L PS]) and other inflammatory mediators, such as tumor necrosis factor (TNF), interleukin-8, and granulocyte colony-stimulating factor, induce a rapid ( within 20 min) release of gelatinase-B (MMP-9) zymogen in whole human blood , as determined by gelatin zymography. The polymorphonuclear neutrophil was identified as the cell responsible for this rapid secretion. as a result o f the release of preformed enzymes stored in granules. Normal human subject s given LPS intravenously showed a similar pattern of proMMP-9 secretion, w ith maximum plasma levels reached 1.5 to 3 h after LPS administration (P = 0.0009). Prior administration of TNF receptor:Fc, a potent TNF antagonist, to subjects given LPS, only partially blunted the release of proMMP-9 (P = 0.033). Ibuprofen. a cyclooxygenase inhibitor, did not alter this pattern o f release. Increased levels of proMMP-9 and proMMP-2, as well as activated forms of MMP-9, were found in plasma from two patients with gram-negative s epsis. The levers of MMPs paralleled die severity of clinical condition and a marker of the severity of sepsis, plasma procalcitonin. These data indic ate that MMPs are released in whole blood in response to various inflammato ry mediators and that they could serve as sensitive and early markers for c ell activation during the course of bacterial sepsis.