TY - JOUR
T1 - Detrimental Effects of an Inhaled Phosphodiesterase-4 Inhibitor on Lung Inflammation in Ventilated Preterm Lambs Exposed to Chorioamnionitis Are Dose Dependent
AU - Huetten, Matthias C.
AU - Fehrholz, Markus
AU - Konrad, Franziska M.
AU - Ophelders, Daan
AU - Kleintjes, Clementine
AU - Ottensmeier, Barbara
AU - Spiller, Owen Brad
AU - Glaser, Kirsten
AU - Kramer, Boris W.
AU - Kunzmann, Steffen
N1 - Funding Information:
The study was supported by Deutsche Forschungs-gemeinschaft (DFG, project no. Ku 1403/6-1). Surfactant (Curosurf®) was a kind gift of Chiesi Pharmaceuticals (Parma, Italy).
Publisher Copyright:
© 2019, Mary Ann Liebert, Inc.
PY - 2019/12
Y1 - 2019/12
N2 - Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 mu g/kg) or low dose (1 mu g/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population.
AB - Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 mu g/kg) or low dose (1 mu g/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population.
KW - bronchopulmonary dysplasia
KW - lung injury
KW - mechanical ventilation of neonates
KW - PDE4 inhibitors
KW - prematurity
KW - BRONCHOPULMONARY DYSPLASIA
KW - NEBULIZED PENTOXIFYLLINE
KW - PULMONARY-DISEASE
KW - PDE4 INHIBITOR
KW - INJURY
KW - COLONIZATION
KW - MECHANISMS
KW - EXPRESSION
KW - TOXICITY
KW - INFANTS
U2 - 10.1089/jamp.2019.1528
DO - 10.1089/jamp.2019.1528
M3 - Article
C2 - 31573405
SN - 1941-2711
VL - 32
SP - 396
EP - 404
JO - Journal of Aerosol Medicine and Pulmonary Drug Delivery
JF - Journal of Aerosol Medicine and Pulmonary Drug Delivery
IS - 6
ER -