Heat-killed microorganisms induce PAI-1 expression in human peritoneal mesothelial cells: Role of interleukin-1 alpha

Human peritoneal mesothelial cells (HMCs) have a critical role in maintaini ng the intraperitoneal balance between fibrinolysis and coagulation by expr essing the fibrinolytic enzyme, tissue-type plasminogen activator (WA), as well as a specific plasminogen activator inhibitor (type 1; PAI-1). During bacteria] peritonitis, the balance between intraperitoneal generation and d egradation of fibrin is disturbed. As a consequence, severe peritoneal dama ge occurs, which is one of the leading causes of patient dropout from conti nuous ambulatory peritoneal dialysis (CAPD) therapy. Cultured HMCs isolated from omental biopsy specimens were used to study the effect of heat-killed strains (2 x 10(8)/mL) of Staphylococcus aureus, Staphylococcus epidermidi s, and Escherichia coli on the synthesis of tPA and PAI-1. Conditioned medi a were obtained by incubating cells with the different bacteria[ strains. t PA and PAI-1 antigen concentrations were measured in the cell supernatants by enzyme-linked immunosorbent assay. Each of the three heat-killed microor ganisms induced a time-dependent increase in PAI-1 synthesis. After a 48-ho ur Incubation period, the strongest effect was seen in the presence of S au reus (3.5-fold versus control), followed by S epidermidis (2.5-fold versus control) and E coli (1.5-fold versus control). Under the same conditions, t PA antigen levels did not change after exposure to S aureus or E coli, wher eas the addition of S epidermidis resulted in enhanced tPA antigen producti on (2-fold versus control). The increase in PAI-1 synthesis in the presence of the heat-killed microorganisms was preceded by similar changes in inter leukin-1 alpha (IL-1 alpha) levels. Inhibiting the activity of IL-1 alpha w ith a neutralizing antibody significantly reduced bacterial-induced PAI-1 p roduction. Our results Indicate that the fibrinolytic imbalance during bact erial peritonitis depends on the bacterial species. The increase in PAI-1 s ynthesis, not the decrease in the production of tPA, alters mesothelial fib rinolytic activity. Because the increase in PAI-1 expression is significant ly quenched by blocking the activity of IL-1 alpha, the mesothelial release of this cytokine is involved in bacterial-induced changes in the fibrinoly tic system. (C) 2001 by the National Kidney Foundation, Inc.