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Article |

Endotoxin-Induced Macrophage Gene Expression Depends on Platelet-Activating Factor

Chong-Jeh Lo, MD; H. Gill Cryer, MD, PhD; Minjuan Fu; Barbara Kim, MS
Arch Surg. 1997;132(12):1342-1347. doi:10.1001/archsurg.1997.01430360088016.
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Background:  The development of multiple organ failure in septic patients is due to a systemic inflammation orchestrated by macrophages (Mϕ). Elucidation and control of the mechanism involved in Mϕ activation in sepsis is crucial to improving survival. An early event of Mϕ 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 Mϕ gene expression depends on PAF.

Design:  Rabbit alveolar Mϕ 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, Mϕ tumor necrosis factor (TNF) messenger RNA (mRNA) expression was assessed by Northern blot analyses. The TNF production in the Mϕ supernatant was measured by L929 bioassays.

Results:  The LPS-stimulated Mϕ 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 Mϕ 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 Mϕ.

Conclusions:  Our data suggest that LPS-induced Mϕ 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 Mϕ in sepsis.Arch Surg. 1997;132:1342-1347


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