Proteolytic inactivation of α1‐antitrypsin and α1‐antichymotrypsin by neutrophils in arthritic joints

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 M_r than that of native α₁AT. Inactivated α₁ACT in SF had an M_r 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.