Iloprost attenuates hyperoxia-mediated impairment of lung development in newborn mice

Abstract

Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O) or hyperoxia (85% O) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 µg·kg·day, nimesulide (selective COX-2 antagonist) 100 mg·kg·day, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1β and TNF-α) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.

Effects of hyperoxia on alveolar and pulmonary vascular development in germ-free mice

“…The right ventricle (RV)-to-left ventricle (LV) free wall thickness ratio was used to estimate right ventricular hypertrophy. Measurement of the RV and LV free wall thickness was done just inferior to the mitral leaflet attachment, as described previously (2,4,23). This measurement is more accurate than the conventional Fulton index of RV/(LV ϩ Septum) weight ratio in newborn mice, as the Fulton index is technically challenging in extremely small newborn mouse hearts.…”

Different contributions from lungs and chest wall to respiratory mechanics in mice, rats, and rabbits

“…More importantly, the chest wall contributes significantly to the dissipative and elastic properties of the respiratory tissues (11,31). Notwithstanding, the interpretation of the changes in lung mechanics is often inferred from global respiratory measures, whereas a potentially confounding influence of the chest wall is neglected (19,25,26,28).…”

Anti-Tn Monoclonal Antibody Attenuates Hyperoxia-Induced Lung Injury by Inhibiting Oxidative Stress and Inflammation in Neonatal Mice

“…The improvement of lung development was associated with a reduction in oxidative stress, NF- κ B expression, and cytokine expression. Previous studies also revealed that caffeine and iloprost improves hyperoxia-induced lung injury through reduction of oxidative stress and inflammation and attenuation of the endoplasmic reticulum stress and mitochondrial dysfunction ( Teng et al., 2017 ; Olave et al., 2018 ; Endesfelder et al., 2019 ). Therefore, we propose that anti-Tn monoclonal antibody improves hyperoxia-induced lung injury in neonatal mice through the suppression of oxidative stress and inflammation, suggesting that anti-Tn antibody may be a promising treatment modality against hyperoxia-induced lung injury.…”