LPS Increases Artery but Not Airway Contraction in Precision Cut Lung Slices from a Mouse Model of ARDS.

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 lipopolysaccharide (LPS), which can disrupt the pulmonary endothelium and epithelium and induce inflammation. We tested whether in vivo administration or ex vivo 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 (10μg/50μl, intranasal) or saline daily for 4d before collection of bronchoalveolar lavage fluid (BALF) or preparation of PCLS. Alternatively, PCLS from naïve mice were left untreated or treated ex vivo with LPS (10μg/mL) or tumour necrosis factor (TNF, 10ng/mL) for 18h. Contraction to endothelin-1 (ET-1), U46619 (a stable mimetic of TXA₂) or serotonin (5HT) were quantified. In vivo 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 in vivo LPS, contraction of intrapulmonary arteries in PCLS to ET-1 and U46619, but not 5HT, increased, while bronchoconstrictor responses were unchanged. In PCLS treated with LPS ex vivo, these differential effects on pulmonary artery and airway contraction were maintained. While LPS increased TNF secretion from PCLS, TNF treatment only increased U46619-induced vasoconstriction. This study demonstrates the potential contributions of LPS-induced inflammation and vascular remodelling to altered intrapulmonary artery reactivity to specific agonists with implications for ARDS-associated PH.