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ARTICLE |

Endotoxin-Induced Nitric Oxide Production in Pulmonary Artery Endothelial Cells Is Regulated by Cytokines

Juan C. Cendan, MD; Lyle L. Moldawer, PhD; Wiley W. Souba, MD, ScD; Edward M. Copeland III, MD; D. Scott Lind, MD
Arch Surg. 1994;129(12):1296-1300. doi:10.1001/archsurg.1994.01420360086011.
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Background:  L-Arginine is the sole precursor of nitric oxide (NO). Bacterial lipopolysaccharide (endotoxin) (LPS) stimulates carrier-mediated L-arginine transport in porcine pulmonary artery endothelial cells (PAECs) through an autocrine pathway that involves interleukin-1α (IL-1α) and tumor necrosis factor α (TNF-α).

Objectives:  To determine if Escherichia coli LPS stimulates NO synthesis in PAECs and, if so, if LPS stimulation of NO production is also mediated by autocrine secretion of IL-1α and TNF-α.

Design:  Monolayers of PAECs were incubated with various concentrations of LPS, recombinant human TNF-α, or IL-1α, and total nitrate-nitrite accumulation was measured at different time points with the Greiss reagent following cadmium reduction. Release of TNF-α and IL-1α release by LPS-stimulated PAECs were measured using the WEHI (for TNF-α) and A375.S2 (for IL-α) bioassays. The PAECs were then incubated with saline solution or LPS in the presence or absence of either a polyclonal antibody to human TNF or IL-1 receptor antagonist, and nitratenitrite accumulation was measured at 48 hours.

Results:  Production of NO by PAECs was increased 230% by LPS (1 μg/mL), 350% by TNF-α (1000 U/mL), and 240% by IL-1α (1000 U/mL) (P<.05 vs control). The LPS-stimulated NO production was inhibited by IL-1 receptor antagonist (100 μg/mL) or antibody to TNF (10 μg/mL) to control levels (P<.05 vs LPS; difference vs saline solution was not significant). The LPS-stimulated TNF-α secretion by PAECs and TNF-α activity were maximal at 6 hours (400±42 pg/mL). The IL-1α activity was not detectable in LPS-stimulated PAECs by the A375.S2 bioassay.

Conclusions:  Endotoxin, TNF-α, and IL-1α stimulated NO synthesis in PAECs. Endotoxin-stimulated NO synthesis through an autocrine pathway involving the cytokines TNF-α and IL-1α.(Arch Surg. 1994;129:1296-1300)

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