Am. J. Respir. Crit. Care Med., Volume 162, Number 4, October 2000, 1547-1552

Mechanisms of Endotoxin-Induced Airway and Pulmonary Vascular Hyperreactivity in Mice

HEINZ-DIETER HELD and STEFAN UHLIG

Division of Pulmonary Pharmacology, Research Center Borstel, Borstel, Germany

Endotoxin is thought to contribute to pulmonary hyperresponsiveness in byssinosis, asthma, and the acute respiratory distress syndrome (ARDS). The aim of this study was to elucidate the mechanism of this phenomenon in the isolated, blood-free perfused mouse lung. Perfusion with lipopolysaccharide (LPS) had no effect on pulmonary resistance or pulmonary artery pressure, but induced airway hyperreactivity (AHR) to methacholine (MCh) and pulmonary vascular hyperreactivity (VHR) to platelet-activating factor (PAF). Blockade of the thromboxane/endoperoxide (TP) receptor with SQ29.548 completely protected against LPS-induced AHR and VHR. Blockade of cyclooxygenase-2 (COX-2) abolished LPS-induced VHR but suppressed LPS-induced AHR only marginally. COX-2 messenger RNA was upregulated in LPS-treated lungs, and inhibition of transcription with actinomycin D or of protein biosynthesis with cycloheximide protected against LPS-induced VHR but not AHR. Pretreatment with the radical scavenger N-acetylcysteine partly protected against LPS-induced AHR. In addition, perfusion of mouse lungs with the isoprostane 8-epiprostaglandin F₂ (8-epi-PGF₂), which may be formed as a consequence of oxidative stress in the lung, elicited AHR, which was completely blocked by SQ29.548. Enzyme immunoassay did not detect either 8-epi-PGF₂ or thromboxane B₂ in perfusate samples. Our findings show that LPS induces AHR and VHR in mouse lungs via activation of the TP receptor. Although induction of VHR depends on COX-2 activity, AHR is largely mediated by a non-COX-derived TP agonist, which might be a product of radical-induced lipid peroxidation.

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