Hyperphospholipasemia A2 in human volunteers challenged with intravenous endotoxin

Abstract

Phospholipase A2 (PLA2) activity was measured in the serum of 23 individuals infused intravenously with endotoxin (EN) at a dose of 4 ng/kg body weight. A marked increase in PLA2 was noted 3 h after EN challenge (mean 828 +/- 513 units/ml), reached its maximum at 24 h after the challenge (mean 2667 +/- 2442 units/ml), and was still evident at 48 h (mean 763 +/- 366 units/ml). In contrast, TNF levels were maximal (mean 712 +/- 375 pg/ml) 90 min after the EN challenge and subsided to very low values (5 +/- 5 pg/ml) 5 h after the challenge. There was a positive correlation between the maximum response of TNF and that of PLA2 (r = 0.82, P < 0.01). Administration of ibuprofen or pentoxifylline did not alter the PLA2 response. EN challenge did not affect serum pancreatic PLA2 concentration or that of the lysosomal cationic enzyme, lysozyme. Neutralizing antibody against human recombinant (synovial type) PLA2 completely abolished PLA2 activity in the sera tested. We conclude that EN infusions cause marked intravascular release of nonpancreatic secretory PLA2 and that the magnitude of this response seems to be related to the prior generation of TNF.

Resistance of Transgenic Mice Expressing Human Group II Phospholipase A2 toEscherichia coliInfection

“…The group II PLA2 response in sera of PLA2 ϩ mice appears earlier than that observed in human patients after surgery (17). However, the increase in concentration of group II PLA2 in sera of PLA2 ϩ mice after the injection of E. coli follows the same time schedule as that seen in sera of healthy volunteers after the administration of endotoxin (27). The results suggest that bacteria and bacterial products induce a rapid systematic increase in the concentration of group II PLA2 in vivo.…”

“…coli lipopolysaccharide (LPS; endotoxin) causes an increase in the level of group II PLA2 in sera of human volunteers (27). In the present experiment, doses corresponding to the LD 70 of heat-killed E. coli did not cause clinical symptoms or deaths in mice, but live bacteria were needed for these effects.…”

A single intravenous dose of endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal volunteers

“…The reduction in total plasma phospholipid and selective decrease of phospholipid in HDL suggests that an early effect of human endoxemia is an alteration in the plasma input or clearance of HDL phospholipid. Since the decrease in HDL phospholipid occurred in all subclasses, mechanisms that shift the relative amounts of phospholipid subclasses, such as a decrease in the synthesis of PC (39), a decrease in PC and increase in LPC by secretory phospholipase A 2 (26,27,40,41), a decrease in SM by sphingomyelinase (28), or an increase in the biliary excretion of PC via the ABC membrane transporter, MDR3 P-glycoprotein (42), are less likely. Mechanisms that affect both cholesterol and phospholipid in HDL, such as an increase in the scavenger receptor class B type I scavenger receptor (43) or the ABC1 membrane transporter (44), are also less likely.…”

“…Table 2 shows that the decline in phospholipid after endotoxin treatments was due to declines in all phospholipid subclasses (PC, LPC, SM, PE, and PI-PS). A reciprocal decrease in PC and increase in LPC, as would be expected from increased activity of secretory phospholipase A2 (26,27), or a selective decrease in SM from increased activity of secretory sphingomyelinase (28), were not observed. The fatty acid compositions of PC (Table 2) and other phospholipid subclasses (not shown) showed no meaningful differences between endotoxin and saline treatments.…”

“…Six normal volunteers (three males, three females, ages [23][24][25][26][27][28][29][30][31][32][33][34][35] were admitted to The Rockefeller University Clinical Research Center in a random-order cross-over design twice for 8 days with a 6 week washout period between admissions. After a diet stabilization period, they received either a single iv dose of endotoxin or saline.…”