The pathological destruction of collagen plays a key role in the development of inflammatory disease states affecting every organ system in the human body. Neutrophils localized at inflammatory sites can potentially degrade collagen by releasing a metalloenzyme, collagenase, which is stored in a latent inactive form. Triggered human neutrophils were shown to release and simultaneously activate their latent collagenase. The activation of the latent enzyme was coupled to an oxidative process that required the generation of a highly reactive oxygen metabolite, hypochlorous acid. Oxidative regulation of latent collagenase activity may be important in the pathogenesis of connective tissue damage in vivo.

Triggered human neutrophils degraded denatured type I collagen (gelatin) by releasing and activating the latent metalloenzyme, gelatinase. The ability of the neutrophil to activate this enzyme was significantly, but not completely, inhibited by agents known to inhibit or scavenge chlorinated oxidants generated by the H202/myeloperoxidase/chloride system. A direct role for chlorinated oxidants in this process was confirmed by the ability of reagent HOCI to activate the latent enzyme in either the cell-free supernatant or in a highly purified state. Gelatinase activity was also expressed by triggered neutrophils isolated from patients with chronic granulomatous disease. The amount of gelatinolytic activity expressed by the patients' cells was similar to that released by normal neutrophils that were triggered in the presence of antioxidants. Thus, human neutrophils have the ability to activate gelatinase by either an HOCl-dependent process or an uncharacterized oxygen-independent process. The ability of the neutrophil to directly regulate this enzyme suggests an important role for the metalloproteinase in physiologic and pathophysiologic connective tissue metabolism.Human neutrophils can be triggered to release the collagenolytic metalloenzyme, gelatinase, which is stored in a unique secretory particle compartment (1, 2). The purified enzyme has been shown to directly attack denatured collagens (i.e., gelatin), to solubilize native type IV and type V collagens, as well as to potentiate the activity of neutrophil interstitial collagenase (3-6). Based on the substrate specificity of the isolated enzyme, an increasing number of studies have postulated potential roles for gelatinase in diapedesis, chemotaxis, inflammation, and wound repair (1-4). However, neutrophil gelatinase, like many other collagenolytic metalloenzymes, is synthesized in a latent form and must be activated before it can catalyze substrate degradation (3)(4)(5)(6). At present, it is clear that neutrophils can release latent gelatinase (1, 2), but the potential significance of the enzyme's action in vivo is blunted by the fact that the ability of the phagocyte to activate gelatinase is unknown.In addition to gelatinase, neutrophils contain a second latent metalloenzyme, collagenase, whose substrate specificity is limited to the interstitial collagens-i.e., types I, II, and III collagens (3,4). Recently, we demonstrated that latent collagenase is activated by triggered neutrophils via an unusual process dependent on the cell's ability to generate the highly reactive oxygen metabolite, hypochlorous acid (HOCl; ref. 7). Despite the fact that both collagenase and gelatinase are latent metalloenzymes, the proteinases are structurally distinct, can be released independently, and possess little or no overlap in substrate specificity (1-6). In this study, we demonstrate that triggered neutrophils are able to activate a portion of their released latent gelatinase, but by two distinct processes; one that is directly mediated by HOCI and a second that ...

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