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Background/aim: In acute pancreatitis, it is believed that generalized activation of pancreatic zymogens leads to autodigestion of the pancreas and if excessive to systemic organ injury. Under physiological circumstances, secretory phospholipase A(2) type I (sPLA(2)-I) is activated by trypsinogen, but the extent of this activation in acute pancreatitis is unclear. The aim of this study was to assess time course and level of activation of sPLA(2)-I and trypsinogen in acute pancreatitis, relative to severity., Methods: 246 patients were enrolled into a prospective European multicenter study. 137 patients had mild and 35 had severe acute pancreatitis, and there were 74 control patients. Urinary samples were taken on admission and at 6-hour intervals for 48 h, then every 12 h up to 72 h, and finally daily for at least 5 days for measurement of the activation peptide of sPLA(2)-I (pro-phosphatase A(2); PROP) and trypsinogen activation peptide., Results: The median maximum PROP values were significantly elevated 48 h after symptom onset in patients with severe acute pancreatitis [1.52 (95% CI 0.8-2.9) nmol/l] as compared with patients with mild acute pancreatitis [0.72 (0.55-1) nmol/l, p = 0.002] and controls [0.49 (0.22-1.2) nmol/l, p = 0.001], but not before or after this time point. The best cutoff point for urinary PROP to predict overall severity was >1 nmol/l < or =48 h after symptom onset (negative predictive value = 88%), but the PROP levels failed to predict the development of multi-organ dysfunction., Conclusions: Activation of sPLA(2)-I is associated with the early pathogenesis of acute pancreatitis, but not in the development of distant organ damage. This observation raises questions as to the theory of generalized zymogen activation being a principle mechanism involved in the pathogenesis of distant organ damage in acute pancreatitis., (Copyright 2002 S. Karger AG, Basel and IAP)

Neutrophil sequestration and activation in the pulmonary vasculature and interstitium are important in acute lung injury. Phospholipase A2 plays an important part in the production of potent inflammatory mediators in this syndrome. We used our ELISA for type 1 prophospholipase A2 activation peptides, which have the aminoacid sequence Asp-Ser-Gly-Ile-Ser-Pro-Arg (DSGISPR), to show that DSGISPR concentrations in plasma and urine are a sensitive and specific marker of acute lung injury in patients admitted to intensive care. The detection of DSGISPR in the plasma of 11 of 50 unselected patients had a sensitivity of 100% and a specificity of 93% for the presence or future development of acute lung injury.

Lipid peroxidation is one of the most important expression of oxidative stress induced by oxygen-derived free radicals. Here we evaluate the behavior of malondialdehyde (MDA) in the serum and urine from patients with chronic pancreatic diseases, with respect to patients with extra-pancreatic digestive diseases and glomerulonephritis. Serum and urinary phospholipase A2 (PLA2) activity was also determined, since this enzyme contributes to damage of plasma membranes. MDA and PLA2 levels increased in the sera from most of the patients with pancreatic and extra-pancreatic digestive diseases. In glomerulonephritis, pathological MDA levels (36%), but not PLA2 levels, were found. Serum MDA correlated with gamma-glutamyl transpeptidase (GGT), while PLA2 correlated with alanine-phosphodiesterase (ALP), GGT, alanine-aminotransferase (ALT) and creatinine. In urine, MDA and PLA2 behaved differently from the corresponding serum values. MDA increased in some patients with pancreatic cancer, extra-pancreatic diseases and glomerulonephritis. PLA2 levels did not significantly vary between groups. Urinary MDA correlated with some indicators of renal tubular damage [urinary ribonuclease, beta-2-microglobulin (B-2-M) and N-acetyl-glucosaminidase (NGA)] and with serum bilirubin. Urinary PLA2 correlated only with ribonuclease (RNase). We conclude that serum MDA increases aspecifically in pancreatic and extra-pancreatic diseases, probably reflecting an aspecific phlogistic phenomenon; PLA2, although sharing a similar pattern with MDA, seems mainly related to hepato-biliary damage. Urinary MDA reflects the presence of renal tubular damage, which may be the cause or a consequence of lipid peroxidation; little variations in PLA2 are recorded in urine, and mainly reflect the presence of impaired tubular function.

We have investigated whether human immune-mediated glomerulonephritis is associated with changes in platelet activating factor (PAF) biosynthesis. Urinary PAF, taken as a marker of its renal synthesis, was significantly higher in patients with membranous nephropathy (N = 9) than in healthy controls (N = 8). This was not due to a lower degradation of PAF since urinary acetylhydrolase activity was comparable in patients and controls. A significant positive correlation between urinary excretion of PAF and proteinuria was observed. PAF generation was comparable in polymorphonuclear cells isolated from patients with membranous nephropathy and controls. PAF levels in blood from patients with membranous nephropathy were significantly lower than in controls, suggesting that the excessive generation of PAF is confined to the kidney. The results document that signs of renal disease activity in human membranous nephropathy are associated with an excessive renal synthesis of PAF.

This study was performed to investigate the behavior of phospholipase A2 (PLA2) in serum and urine of patients with chronic pancreatic diseases and to ascertain whether any factors influenced the results. In 30 controls, 45 patients with pancreatic cancer, 54 with chronic pancreatitis, and 64 with extrapancreatic diseases, serum and urinary PLA2, pancreatic isoamylase and RNase, and urinary N-acetylglucosaminidase (NAG) were measured. Serum PLA2 levels were higher in patients with chronic pancreatitis than in all the other groups. In our patients, only occasionally was urinary PLA2 elevated, the increase occurring almost exclusively in the presence of an acute inflammatory disease, e.g., relapsed chronic pancreatitis or active inflammatory bowel disease. A correlation was found between serum PLA2 and serum RNase, an indicator of tissue damage, but not between serum PLA2 and pancreatic isoamylase. Urinary PLA2 output was correlated with its renal input and with RNase output. No correlation was found between PLA2 output and pancreatic isoamylase or NAG urinary excretion. In conclusion, (1) the determination of serum PLA2 activity may be an aspecific test of pancreatic disease; (2) PLA2 urinary excretion occasionally increases, especially in the presence of severe phlogosis, which occurs in chronic pancreatitis, in particular during relapse; and (3) irrespective of the tissue origin of urinary PLA2, its increased excretion may be accounted for in part by its increased circulating levels. It is, however, more likely the consequence of a renal tubular dysfunction, which is sometimes found in patients with pancreatic diseases.

Platelet activating factor has been demonstrated in blood and urine and has a broad range of effects on kidney function. The kidney possesses the enzymes responsible for PAF synthesis as well as the specific acetylhydrolase which deactivates PAF. We used a radioactive assay to measure PAF-acetylhydrolase activity in urine samples obtained from normal individuals and patients with various nephropathies. Activity was detected in the majority of normal urines with a mean + 2 SD = 0.70 nmol/30 min/ml. Activity exceeding this value was measured in the urines of 11 of 14 patients with diabetes mellitus, 14 of 22 with glomerulonephritis, and 5 of 16 with hypertensive renal disease. Further study is necessary to relate urine hydrolase activity to specific functional and structural abnormalities of the kidney.