Dilip Shah1,2, Karmyodh Sandhu1, Pragnya Das1,2, Vineet Bhandari3,4. 1. Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA. 2. Neonatology Research Laboratory (Room #206), Cooper University Hospital, Camden, NJ, USA. 3. Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA. bhandari-vineet@cooperhealth.edu. 4. Neonatology Research Laboratory (Room #206), Cooper University Hospital, Camden, NJ, USA. bhandari-vineet@cooperhealth.edu.
Abstract
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common respiratory disease of preterm infants. Lower circulatory/intrapulmonary levels of the adipokine, adiponectin (APN), occur in premature and small-for-gestational-age infants and at saccular/alveolar stages of lung development in the newborn rat. However, the role of low intrapulmonary APN during hyperoxia exposure in developing lungs is unknown. METHODS: We test the hypothesis that treatment of hyperoxia-exposed newborn mice with recombinant APN protein attenuates the BPD phenotype characterized by inflammation, impaired alveolarization, and dysregulated vascularization. We used developmentally appropriate in vitro and in vivo BPD modeling systems as well as human lung tissue. RESULTS: We observed reduced levels of intrapulmonary APN in experimental BPD mice and human BPD lungs. APN-deficient (APN-/-) newborn mice exposed to moderate (60% O2) hyperoxia showed a worse BPD pulmonary phenotype (inflammation, enhanced endothelial dysfunction, impaired pulmonary vasculature, and alveolar simplification) as compared to wild-type (WT) mice. Treatment of hyperoxia-exposed newborn WT mice with recombinant APN protein attenuated the BPD phenotype (diminished inflammation, decreased pulmonary vascular injury, and improved pulmonary alveolarization) and improved pulmonary function tests. CONCLUSIONS: Low intrapulmonary APN is associated with disruption of lung development during hyperoxia exposure, while recombinant APN protein attenuates the BPD pulmonary phenotype. IMPACT: Intrapulmonary APN levels were significantly decreased in lungs of experimental BPD mice and human BPD lung tissue at various stages of BPD development. Correlative data from human lung samples with decreased APN levels were associated with increased lung adhesion markers (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin). Decreased APN levels were associated with endothelial dysfunction and moderate BPD phenotype in APN-deficient, as compared to WT, experimental BPD mice. WT experimental BPD mice treated with recombinant APN protein had an improved pulmonary structural and functional phenotype. Exogenous APN may be considered as a potential therapeutic agent to prevent BPD.
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common respiratory disease of preterm infants. Lower circulatory/intrapulmonary levels of the adipokine, adiponectin (APN), occur in premature and small-for-gestational-age infants and at saccular/alveolar stages of lung development in the newborn rat. However, the role of low intrapulmonary APN during hyperoxia exposure in developing lungs is unknown. METHODS: We test the hypothesis that treatment of hyperoxia-exposed newborn mice with recombinant APN protein attenuates the BPD phenotype characterized by inflammation, impaired alveolarization, and dysregulated vascularization. We used developmentally appropriate in vitro and in vivo BPD modeling systems as well as human lung tissue. RESULTS: We observed reduced levels of intrapulmonary APN in experimental BPD mice and human BPD lungs. APN-deficient (APN-/-) newborn mice exposed to moderate (60% O2) hyperoxia showed a worse BPD pulmonary phenotype (inflammation, enhanced endothelial dysfunction, impaired pulmonary vasculature, and alveolar simplification) as compared to wild-type (WT) mice. Treatment of hyperoxia-exposed newborn WT mice with recombinant APN protein attenuated the BPD phenotype (diminished inflammation, decreased pulmonary vascular injury, and improved pulmonary alveolarization) and improved pulmonary function tests. CONCLUSIONS: Low intrapulmonary APN is associated with disruption of lung development during hyperoxia exposure, while recombinant APN protein attenuates the BPD pulmonary phenotype. IMPACT: Intrapulmonary APN levels were significantly decreased in lungs of experimental BPD mice and human BPD lung tissue at various stages of BPD development. Correlative data from human lung samples with decreased APN levels were associated with increased lung adhesion markers (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin). Decreased APN levels were associated with endothelial dysfunction and moderate BPD phenotype in APN-deficient, as compared to WT, experimental BPD mice. WT experimental BPD mice treated with recombinant APN protein had an improved pulmonary structural and functional phenotype. Exogenous APN may be considered as a potential therapeutic agent to prevent BPD.
Authors: Jacobien B Eising; Cuno S P M Uiterwaal; Annemieke M V Evelein; Frank L J Visseren; Cornelis K van der Ent Journal: Eur Respir J Date: 2013-12-05 Impact factor: 16.671
Authors: Kathryn M Heyob; Saya Mieth; Sophia S Sugar; Amanda E Graf; Scott W Lallier; Rodney D Britt; Lynette K Rogers Journal: Am J Physiol Lung Cell Mol Physiol Date: 2019-05-01 Impact factor: 5.464
Authors: Jason M Konter; Jennifer L Parker; Elizabeth Baez; Stephanie Z Li; Barbara Ranscht; Martin Denzel; Frederic F Little; Kazuto Nakamura; Noriyuki Ouchi; Alan Fine; Kenneth Walsh; Ross S Summer Journal: J Immunol Date: 2011-12-07 Impact factor: 5.422