TY - JOUR
T1 - Sphingosine kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model
T2 - Role of s1p signaling and nox proteins
AU - Harijith, Anantha
AU - Pendyala, Srikanth
AU - Reddy, Narsa M.
AU - Bai, Tao
AU - Usatyuk, Peter V.
AU - Berdyshev, Evgeny
AU - Gorshkova, Irina
AU - Huang, Long Shuang
AU - Mohan, Vijay
AU - Garzon, Steve
AU - Kanteti, Prasad
AU - Reddy, Sekhar P.
AU - Raj, J. Usha
AU - Natarajan, Viswanathan
PY - 2013/10
Y1 - 2013/10
N2 - Bronchopulmonary dysplasia of the premature newborn is characterized by lung injury, resulting in alveolar simplification and reduced pulmonary function. Exposure of neonatal mice to hyperoxia enhanced sphingosine-1- phosphate (S1P) levels in lung tissues; however, the role of increased S1P in the pathobiological characteristics of bronchopulmonary dysplasia has not been investigated. We hypothesized that an altered S1P signaling axis, in part, is responsible for neonatal lung injury leading to bronchopulmonary dysplasia. To validate this hypothesis, newborn wild-type, sphingosine kinase1-/- (Sphk1-/-), sphingosine kinase 2-/- (Sphk2-/-), and S1P lyase+/- (Sgpl1+/-) mice were exposed to hyperoxia (75%) from postnatal day 1 to 7. Sphk1-/-, but not Sphk2-/- or Sgpl1+/-, mice offered protection against hyperoxia-induced lung injury, with improved alveolarization and alveolar integrity compared with wild type. Furthermore, SphK1 deficiency attenuated hyperoxia-induced accumulation of IL-6 in bronchoalveolar lavage fluids and NADPH oxidase (NOX) 2 and NOX4 protein expression in lung tissue. In vitro experiments using human lung microvascular endothelial cells showed that exogenous S1P stimulated intracellular reactive oxygen species (ROS) generation, whereas SphK1 siRNA, or inhibitor against SphK1, attenuated hyperoxia-induced S1P generation. Knockdown of NOX2 and NOX4, using specific siRNA, reduced both basal and S1P-induced ROS formation. These results suggest an important role for SphK1-mediated S1P signaling-regulated ROS in the development of hyperoxia-induced lung injury in a murine neonatal model of bronchopulmonary dysplasia.
AB - Bronchopulmonary dysplasia of the premature newborn is characterized by lung injury, resulting in alveolar simplification and reduced pulmonary function. Exposure of neonatal mice to hyperoxia enhanced sphingosine-1- phosphate (S1P) levels in lung tissues; however, the role of increased S1P in the pathobiological characteristics of bronchopulmonary dysplasia has not been investigated. We hypothesized that an altered S1P signaling axis, in part, is responsible for neonatal lung injury leading to bronchopulmonary dysplasia. To validate this hypothesis, newborn wild-type, sphingosine kinase1-/- (Sphk1-/-), sphingosine kinase 2-/- (Sphk2-/-), and S1P lyase+/- (Sgpl1+/-) mice were exposed to hyperoxia (75%) from postnatal day 1 to 7. Sphk1-/-, but not Sphk2-/- or Sgpl1+/-, mice offered protection against hyperoxia-induced lung injury, with improved alveolarization and alveolar integrity compared with wild type. Furthermore, SphK1 deficiency attenuated hyperoxia-induced accumulation of IL-6 in bronchoalveolar lavage fluids and NADPH oxidase (NOX) 2 and NOX4 protein expression in lung tissue. In vitro experiments using human lung microvascular endothelial cells showed that exogenous S1P stimulated intracellular reactive oxygen species (ROS) generation, whereas SphK1 siRNA, or inhibitor against SphK1, attenuated hyperoxia-induced S1P generation. Knockdown of NOX2 and NOX4, using specific siRNA, reduced both basal and S1P-induced ROS formation. These results suggest an important role for SphK1-mediated S1P signaling-regulated ROS in the development of hyperoxia-induced lung injury in a murine neonatal model of bronchopulmonary dysplasia.
UR - http://www.scopus.com/inward/record.url?scp=84884570906&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884570906&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2013.06.018
DO - 10.1016/j.ajpath.2013.06.018
M3 - Article
C2 - 23933064
AN - SCOPUS:84884570906
VL - 183
SP - 1169
EP - 1182
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 4
ER -