Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis

Plasminogen activator inhibitor-type 1 (PAI-1) is thought to be profibrotic by inhibiting plasmin generation, thereby decreasing turnover of pathological extracellular matrix (ECM). A mutant, noninhibitory PAI-1 (PAI-1R) was recently shown by us to increase glomerular plasmin generation and reduce disease in anti-thy-1 nephritis. Here, in vitro and in vivo studies were performed to determine whether enhanced plasmin-dependent ECM degradation underlies the therapeutic effect of PAI-1R. 3H-labeled ECM was produced by rat mesangial cells (MCs). The effect of wild-type PAI-1 (wt-PAI-1) and PAI-1R on ECM degradation by newly plated MCs was measured by the release of 3H into medium. In vivo, anti-thy-1 nephritis was assessed in normal, untreated diseased and PAI-1R treated rats with or without the plasmin/plasminogen inhibitor, tranexamic acid (TA). wt-PAI-1 totally inhibited plasmin generation and reduced ECM degradation by 76% when exogenous plasminogen was added. Although PAI-1R alone had no effect, PAI-1R in the presence of wt-PAI-1 reversed the wt-PAI-1 inhibition of ECM degradation in a time- and dose-dependent manner (P<0.001). Plasmin activity and zymography were consistent with ECM degradation. Plasmin inhibitors: α2-antiplasmin, aprotinin, and TA completely blocked PAI-1R's ability to normalize ECM degradation (P<0.001). Consistent with the in vitro results, TA reversed PAI-1R-induced reductions in glomerular fibrin and ECM accumulation. Other measures of disease severity were either unaltered or partially reversed. PAI-1R reduces pathological ECM accumulation, in large part through effectively competing with native PAI-1 thereby restoring plasmin generation and increasing plasmin-dependent degradation of matrix components

Search for the Proton Decay Mode proton to neutrino K+ in Soudan 2

We have searched for the proton decay mode proton to neutrino K+ using the one-kiloton Soudan 2 high resolution calorimeter. Contained events obtained from a 3.56 kiloton-year fiducial exposure through June 1997 are examined for occurrence of a visible K+ track which decays at rest into mu+ nu or pi+ pi0. We found one candidate event consistent with background, yielding a limit, tau/B > 4.3 10^{31} years at 90% CL with no background subtraction.Comment: 13 pages, Latex, 3 tables and 3 figures, Accepted by Physics Letters