Abstract
Pulmonary hypertension is a critical problem in infants with bronchopulmonary dysplasia. This study determined the therapeutic effects of human mesenchymal stem cells (MSCs) on pulmonary hypertension in an animal model. Pregnant Sprague–Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS, 0.5 mg/kg/day) on gestational days 20 and 21. The pups were randomly assigned to two treatment conditions: room air (RA) or an O2-enriched atmosphere. On postnatal day 5, they were intratracheally transplanted with human MSCs (3 × 105 and 1 × 106 cells) in 0.03 mL of normal saline (NS). Five study groups were examined: normal, LPS+RA+NS, LPS+O2+NS, LPS+O2+MSCs (3 × 105 cells), and LPS+O2+MSCs (1 × 106 cells). On postnatal day 14, the pup lungs and hearts were collected for histological examinations. The LPS+RA+NS and LPS+O2+NS groups exhibited a significantly higher right ventricle (RV):left ventricle (LV) thickness ratio and medial wall thickness (MWT) and higher β-myosin heavy chain (β-MHC) and toll-like receptor (TLR) 4 expression than did the normal group. Human MSC transplantation in LPS- and O2-treated rats reduced the MWT, RV:LV thickness ratio, and β-MHC and TLR4 expression to normal levels. Thus, intratracheal human MSC transplantation ameliorates pulmonary hypertension, probably by suppressing TLR4 expression in newborn rats.
Highlights
Bronchopulmonary dysplasia (BPD), a severe and common chronic lung disease in infants, is caused by interrupted alveolar and vascular growth [1, 2]
The rats exposed to prenatal lipopolysaccharide (LPS) and neonatal hyperoxia and treated with normal saline (NS) had a significantly higher right ventricle (RV):left ventricle (LV) thickness ratio than did the normal rats and those exposed to prenatal LPS (Table 1)
Human mesenchymal stem cells (MSCs) transplantation (3 × 105 and 1 × 106 cells) in the prenatal LPS- and neonatal hyperoxiatreated rats significantly reduced the RV:LV thickness ratio to that reported in the LPS+room air (RA)+NS group
Summary
Bronchopulmonary dysplasia (BPD), a severe and common chronic lung disease in infants, is caused by interrupted alveolar and vascular growth [1, 2]. Pulmonary hypertension was reported in 37% of extremely lowbirth-weight infants with severe BPD [3]. Similar to human infants with pulmonary hypertension and BPD, rat pups exposed to hyperoxia exhibit pulmonary hypertension, right ventricular hypertrophy, pulmonary vascular remodeling, and alveolar simplification [8]. The pathogenesis of pulmonary hypertension in BPD is complex and may result from interactions between antenatal risk factors, such as pregnancy-induced hypertension, intrauterine growth restriction, and infection, and postnatal risk factors, such as oxidative stress and inflammation, in preterm infants with underlying genetic susceptibility [9]. The most effective treatment for BPD-associated pulmonary hypertension remains unclear
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