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 a,-antitrypsin (a,AT) and a,-antichymotrypsin (a,ACT), the two major inhibitors of the neutrophilic serine proteinases, in synovial fluid (SF) from patients with inflammatory arthropathies (n = 71) and osteoarthritis (OA) (n = ll), and related the results to neutrophil activation in SF.Results. The ratio of functional to antigenic levels of q A T in SF of patients with inflammatory joint diseases was similar to that of alAT in normal plasma, whereas that of a,ACT was significantly decreased. Patients with inflammatory arthropathies had significantly higher levels of inactivated a,AT (ialAT) and inactivated a,ACT (ia,ACT) 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 a,AT and ia,ACT levels corresponded to 0.341% and 3-99%, respectively, of the total amount of these inhibitors in SF. Most

The cell biology of leukocyte-mediated proteolysis

“…Oxidatively and proteolytically inactivated proteinase inhibitors have been detected in vivo in lung secretions from patients with cystic fibrosis [105,110], and in synovial fluid from patients with inflammatory arthritides [111][112][113][114]. Thus it is clear that, during infection and inflammation, oxidants and proteinases released from activated leukocytes and/or bacteria may act synergistically to create microenvironments in which extracellular proteolysis by leukocyte proteinases is facilitated via the inactivation of proteinase inhibitors.…”

Tissue injury in neutrophilic inflammation

“…In fact, oxidized and proteolyzed, i.e. inactive, AT together with free and active elastase and MPO, is present in fluids recovered from a variety of inflamed tissue sites characterized by the local extravascular recruitment of circulating neutrophils [81,82]. Finally, lobar pneumonias due to pneumococcal type I strains are characterized by a neutrophilic alveolitis, which resolves without permanent lung destruction [80].…”

Proteins of rat serum V: Adjuvant arthritis and its modulation by nonsteroidal anti-inflammatory drugs

“…Matrix metallo)proteinases and their inhibitors in synovial Inhibition of gelatinase B by D-penicillamine[86] Proteolytic inactivation of a 1 -AT and a 1 -antichymotrypsin by neutrophils in arthritic joints[87] 1-DE and 2-DE to identify autoantigens Nucleolar fibrillar component (HeLa cells)[88] Rat oesophagus epithelium antigens (`antikeratin antibodies')[89] HLA class II b-chain[90] Detection of rheumatoid factors belonging to the IgM or IgA classes by transfer of serum proteins separated by electrophoresis onto NC membranes precoated with human polyclonal IgG, followed by revelation with anti-m or anti-a antisera[91] …”