ACTIVATION OF HUMAN GRANULOCYTE TYPE 1-PROPHOSPHOLIPASE A(2)

Using an assay for measurement of released type 1-prophospholipase A(2 ). (type 1-proPLA(2)) propeptides (PROP assay), we have shown that hum an granulocytes, but not lymphocytes or macrophages, abundantly expres s this 'pancreatic' type 1-proPLA(2)-zymogen. Stimulation with tumour necrosis factor-alpha (TNF-alpha) and other cytokines results in the i mmediate release from granulocytes of a mixture of free propeptides an d type 1-proPLA(2) precursor. We also found that granulocytes contain an approximately 29 kDa trypsin-like endogenous type 1-proPLA(2) activ ator. PROP assay and TAP (trypsinogen activation peptide) assay of pla sma samples accurately predicts the segregation of acute pancreatitis into three clearly defined categories of severity-mild intermediate an d severe-at the time of first hospital admission and over the next few hours of observation. Mild and intermediate pancreatitis are associat ed with a degree of granulocyte stimulation limited to the release of the unactivated type 1-proPLA(2) precursor. Progression to severe dise ase is accompanied by the activation of granulocyte type 1-proPLA(2), apparently carried to completion. This identifies the approximately 29 kDa endogenous activator of type 1-proPLA(2) in granulocytes as a cri tical mediator at a threshold stage in acute pancreatitis, which marks the transition from uncomplicated pancreatitis to the potentially let hal disease. Specific inhibitors of this key regulatory enzyme modelle d on the P3-P1 domain of the type 1-proPLA(2) activation peptide would seem to be promising candidates for a new class of chemotherapeutic a gents.