Loss of CD73-mediated extracellular adenosine production exacerbates inflammation and abnormal alveolar development in newborn mice exposed to prolonged hyperoxia

BACKGROUND: Hyperoxic lung injury is characterized by cellular damage from high oxygen concentrations that lead to an inflammatory response and it disrupts normal alveolarization in the developing newborn lung. Adenosine is a signaling molecule that is generated extracellularly by ecto-5'-nucleotidase (CD73) in response to injury. Extracellular adenosine signals through cell surface receptors and has been found to have a protective role in acute injury situations; however, chronic elevations have been associated with detrimental changes in chronic lung diseases. We hypothesized that hyperoxia-induced lung injury leads to CD73-mediated increases in extracellular adenosine, which are detrimental to the newborn lung. METHODS: C57Bl/6 and CD73(-/-) mice were exposed to 95% oxygen, 70% oxygen, or room air. Adenosine concentration and markers of pulmonary inflammation and lung development were measured. RESULTS: Exposure to hyperoxia caused pulmonary inflammation and disrupted normal alveolar development in association with increased pulmonary adenosine levels. Loss of CD73-mediated extracellular adenosine production led to decreased survival with exposure to 95% oxygen, and exacerbated pulmonary inflammation and worsened lung development with 70% oxygen exposure. CONCLUSION: Exposure to hyperoxia causes lung injury associated with an increase in adenosine concentration, and loss of CD73-mediated adenosine production leads to worsening of hyperoxic lung injury.