LPS Increases Artery but Not Airway Contraction in Precision-Cut Lung Slices from a Mouse Model of Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) results in decreased quality of life, including increased risk of pulmonary hypertension (PH). In animal models, ARDS can be induced by LPS, which can disrupt the pulmonary endothelium and epithelium and induce inflammation. We tested whether <i>in vivo</i> administration or <i>ex vivo</i> treatment with LPS alters the reactivity of intrapulmonary arteries and airways to constrictors relevant to both ARDS and PH, using the precision-cut lung slice (PCLS) technique. Mice were administered LPS (10 μg/50 μl, intranasal) or saline daily for 4 days before collection of BAL fluid or preparation of PCLSs. Alternatively, PCLSs from naive mice were left untreated or treated <i>ex vivo</i> with LPS (10 μg/ml) or TNF (10 ng/ml) for 18 hours. Contraction to endothelin-1, U46619 (a stable mimetic of thromboxane A₂), or serotonin was quantified. <i>In vivo</i> LPS administration increased BAL total inflammatory cells 5-fold, neutrophils 125-fold, and protein 2-fold, as well as the thickness of the pulmonary arterial smooth muscle layer. After <i>in vivo</i> LPS, contraction of intrapulmonary arteries in PCLSs to endothelin-1 and U46619, but not serotonin, increased, whereas bronchoconstrictor responses were unchanged. In PCLSs treated with LPS <i>ex vivo</i>, these differential effects on pulmonary artery and airway contraction were maintained<i>.</i> Although LPS increased TNF secretion from PCLSs, TNF treatment only increased U46619-induced vasoconstriction. This study demonstrates the potential contributions of LPS-induced inflammation and vascular remodeling to altered intrapulmonary artery reactivity to specific agonists, with implications for ARDS-associated PH.