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Abstract

Objective. In vitro, activated neutrophils create a microenvironment in which proteinase inhibitors are inactivated through the coordinate action of reactive oxygen species and released elastase. We investigated whether such a mechanism may contribute to the destruction of the joint tissues in arthritis.

Methods. We analyzed the state of α1-antitrypsin (α1AT) and α1-antichymotrypsin (α1ACT), the two major inhibitors of the neutrophilic serine proteinases, in synovial fluid (SF) from patients with inflammatory arthropathies (n = 71) and osteoarthritis (OA) (n = 11), and related the results to neutrophil activation in SF.

Results. The ratio of functional to antigenic levels of α1AT in SF of patients with inflammatory joint diseases was similar to that of α1AT in normal plasma, whereas that of α1ACT was significantly decreased. Patients with inflammatory arthropathies had significantly higher levels of inactivated α1AT (iα1AT) and inactivated α1ACT (iα1ACT) in SF (as determined with monoclonal antibodies specific for the inactivated [i.e., proteolytically inactivated and/or complexed] forms of these inhibitors) than patients with OA (P < 0.005). Inactivated α1AT and iα1ACT levels corresponded to 0.3–11% and 3–99%, respectively, of the total amount of these inhibitors in SF. Most of the iα1AT in SF had a lower Mr than that of native α1AT. Inactivated α1ACT in SF had an Mr identical to that of nonfunctional α1ACT in plasma treated with chymotrypsin. Levels of both iα1AT and iα1ACT correlated significantly with lactoferrin and elastase levels.

Conclusion. These results suggest that α1AT and α1ACT in arthritic joints are inactivated in part by activated neutrophils, suggesting a role for these cells in impairment of the local balance between proteinases and their inhibitors in arthritis.