Abstract-Exposure of the neonatal lung to chronic hypoxia produces significant pulmonary vascular remodeling, right ventricular hypertrophy, and decreased lung alveolarization. Given recent data suggesting that stem cells could contribute to pulmonary vascular remodeling and right ventricular hypertrophy, we tested the hypothesis that blockade of SDF-1 (stromal cell-derived factor 1), a key stem cell mobilizer or its receptor, CXCR4 (CXC chemokine receptor 4), would attenuate and reverse hypoxia-induced cardiopulmonary remodeling in newborn mice. Neonatal mice exposed to normoxia or hypoxia were randomly assigned to receive daily intraperitoneal injections of normal saline, AMD3100, or anti-SDF-1 antibody from postnatal day 1 to 7 (preventive strategy) or postnatal day 7 to 14 (therapeutic strategy). As compared to normal saline, inhibition of the SDF-1/CXCR4 axis significantly improved lung alveolarization and decreased pulmonary hypertension, right ventricular hypertrophy, vascular remodeling, vascular cell proliferation, and lung or right ventricular stem cell expressions to near baseline values. We therefore conclude that the SDF-1/CXCR4 axis both prevents and reverses hypoxia-induced cardiopulmonary remodeling in neonatal mice, by decreasing progenitor cell recruitment to the pulmonary vasculature, as well as by decreasing pulmonary vascular cell proliferation. These data offer novel insights into the role of the SDF-1/CXCR4 axis in the pathogenesis of neonatal hypoxia-induced cardiopulmonary remodeling and have important therapeutic implications. Key Words: pulmonary hypertension Ⅲ hypoxia Ⅲ progenitor cells Ⅲ SDF-1 Ⅲ vascular remodeling D espite marked improvements in medical care, approximately 2 in 1000 neonates are perinatally exposed to intermittent or chronic periods of hypoxia. 1 Unlike that of the adult, the neonatal pulmonary vascular response to chronic hypoxic exposure is much more rapid and severe 2 and results in failure of the fetal circulation to adapt to a response that supports postnatal life. This in turn contributes to the pathogenesis of persistent pulmonary hypertension (PH) of the newborn, chronic lung disease of prematurity, and congenital heart disease. It is typically characterized by profound proliferation of smooth muscle and adventitial cells in the pulmonary vasculature and abnormal extension of smooth muscle into peripheral arteries, along with impairment in alveolar development in preterm neonates. 3,4 Although the mechanisms underlying neonatal hypoxiainduced cardiopulmonary remodeling remain unclear, recent studies have suggested that stem cells may contribute to systemic and pulmonary vascular remodeling. We therefore sought to examine the role of a key stem cell mobilizer, the chemokine SDF-1 (stromal cell-derived factor 1) and its receptor CXCR4 (CXC chemokine receptor 4) in neonatal chronic hypoxia-induced cardiopulmonary remodeling.SDF-1 or CXCL12 is a chemokine that is secreted by several tissues following exposure to hypoxia, 5,6 in turn leading to the release of p...
These data suggest that acute effects of MSC therapy in HILI are mainly paracrine mediated; however, optimum long-term improvement following HILI requires treatment with the MSCs themselves or potentially repetitive administration of CM.
Recent studies suggest that bone marrow (BM)-derived stem cells have therapeutic efficacy in neonatal hyperoxia-induced lung injury (HILI). c-kit, a tyrosine kinase receptor that regulates angiogenesis, is expressed on several populations of BM-derived cells. Preterm infants exposed to hyperoxia have decreased lung angiogenesis. Here we tested the hypothesis that administration of BM-derived c-kit+ cells would improve angiogenesis in neonatal rats with HILI. To determine whether intratracheal (IT) administration of BM-derived c-kit+ cells attenuates neonatal HILI, rat pups exposed to either normobaric normoxia (21% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to P15 were randomly assigned to receive either IT BM-derived green fluorescent protein (GFP)+ c-kit− cells (PL) or BM-derived GFP+ c-kit+ cells on P8. The effect of cell therapy on lung angiogenesis, alveolarization, pulmonary hypertension, vascular remodeling, cell proliferation, and apoptosis was determined at P15. Cell engraftment was determined by GFP immunostaining. Compared to PL, the IT administration of BM-derived c-kit+ cells to neonatal rodents with HILI improved alveolarization as evidenced by increased lung septation and decreased mean linear intercept. This was accompanied by an increase in lung vascular density, a decrease in lung apoptosis, and an increase in the secretion of proangiogenic factors. There was no difference in pulmonary vascular remodeling or the degree of pulmonary hypertension. Confocal microscopy demonstrated that 1% of total lung cells were GFP+ cells. IT administration of BM-derived c-kit+ cells improves lung alveolarization and angiogenesis in neonatal HILI, and this may be secondary to an improvement in the lung angiogenic milieu.
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