Sphingosine kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model: Role of s1p signaling and nox proteins

Anantha Harijith*, Srikanth Pendyala, Narsa M. Reddy, Tao Bai, Peter V. Usatyuk, Evgeny Berdyshev, Irina Gorshkova, Long Shuang Huang, Vijay Mohan, Steve Garzon, Prasad Kanteti, Sekhar P. Reddy, J. Usha Raj, Viswanathan Natarajan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1169-1182
Number of pages14
JournalAmerican Journal of Pathology
Volume183
Issue number4
DOIs
StatePublished - Oct 2013

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint

Dive into the research topics of 'Sphingosine kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model: Role of s1p signaling and nox proteins'. Together they form a unique fingerprint.

Cite this