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Chong-Jeh Lo, MD; H. Gill Cryer, MD, PhD; Minjuan Fu; Barbara Kim, MS

Arch Surg. 1997;132(12):1342-1347.

Abstract
Background
The development of multiple organ failure in septic patients is due to a systemic inflammation orchestrated by macrophages (M). Elucidation and control of the mechanism involved in M activation in sepsis is crucial to improving survival. An early event of M activation involves the hydrolysis of membrane phospholipid by phospholipase A₂ (PLA₂) and subsequent generation of platelet-activating factor (PAF).

Objective
We designed this study to test the hypothesis that M gene expression depends on PAF.

Design
Rabbit alveolar M were obtained by bronchoalveolar lavage and were stimulated with 10 ng/mL of Escherichia coli endotoxin lipopolysaccharide (LPS), PAF (1 µmol/L), LPS±CV3988 (10 µmol/L), a PAF receptor antagonist, or LPS±PLA₂ inhibitors: AACOCF₃ (50 µmol/L) or manoalide (10 µmol/L). After 4 hours of incubation, M tumor necrosis factor (TNF) messenger RNA (mRNA) expression was assessed by Northern blot analyses. The TNF production in the M supernatant was measured by L929 bioassays.

Results
The LPS-stimulated M expressed increased levels of TNF mRNA and produced an enormous amount of TNF. CV3988, a PAF antagonist, inhibited LPS-induced TNF mRNA. Furthermore, inhibiting PAF production with AACOCF₃, or manoalide, also inhibited LPS-induced M TNF mRNA expression. The effect of PAF depends on changes in intracellular calcium concentration. Inhibitors of calcium flux attenuated the PAF effects on LPS-stimulated M.

Conclusions
Our data suggest that LPS-induced M gene expression is mediated by PAF. It is likely that modulation of PAF production or activity may be beneficial in down-regulating the overactivity of M in sepsis.

Arch Surg. 1997;132:1342-1347

Author Affiliations
From the Department of Surgery, University of California, Los Angeles.

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