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Ecto-5'-nucleotidase (CD73)-mediated adenosine production is tissue protective in a model of bleomycin-induced lung
Jonathan B Volmer1, Linda F Thompson, Michael R Blackburn
1Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Medical School, Houston, 77030, USA.
Abstract:
Adenosine signaling has diverse actions on inflammation and tissue injury. Levels of adenosine are rapidly elevated in response to tissue injury; however, the mechanisms responsible for adenosine production in response to injury are not well understood. In this study, we found that adenosine levels are elevated in the lungs of mice injured by the drug bleomycin. In addition, increased activity of ecto-5'-nucleotidase (CD73) was found in the lungs in conjunction with adenosine elevations. To determine the contribution of CD73 to the generation of adenosine in the lung, CD73(-/-) mice were subjected to bleomycin challenges. Results demonstrated that CD73(-/-) mice challenged with bleomycin no longer accumulated adenosine in their lungs, suggesting that the primary means of adenosine production following bleomycin injury resulted from the release and subsequent dephosphorylation of adenine nucleotides. CD73(-/-) mice challenged with bleomycin exhibited enhanced pulmonary inflammation and fibrosis as well as exaggerated expression of proinflammatory and profibrotic mediators in the lung. Intranasal instillations of exogenous nucleotidase restored the ability of lungs of CD73(-/-) mice to accumulate adenosine following bleomycin challenge. Furthermore, these treatments were associated with a decrease in pulmonary inflammation and fibrosis. CD73(+/+) animals challenged with bleomycin and supplemented with exogenous nucleotidase also exhibited reduced inflammation. Together, these findings suggest that CD73-dependent adenosine production contributes to anti-inflammatory pathways in bleomycin-induced lung injury.
Insights
Ecto-5'-nucleotidase (CD73) generates adenosine, reducing inflammation and fibrosis in bleomycin-induced lung injury. Restoring CD73 activity in mice lessened lung damage, highlighting its protective role.
Area of Science:
- Biochemistry
- Immunology
- Pulmonary Medicine
Background:
- Adenosine signaling plays a critical role in regulating inflammation and tissue injury.
- Mechanisms of adenosine production during tissue injury are not fully understood.
- Adenosine levels increase rapidly following tissue damage.
Purpose of the Study:
- To investigate the role of ecto-5 omino-nucleotidase (CD73) in adenosine production during bleomycin-induced lung injury.
- To determine the contribution of CD73 to pulmonary inflammation and fibrosis.
- To assess the therapeutic potential of CD73-dependent adenosine production.
Main Methods:
- Bleomycin-induced lung injury model in wild-type and CD73 knockout mice.
- Measurement of adenosine levels and CD73 activity in lung tissue.
- Assessment of pulmonary inflammation and fibrosis markers.
- Treatment with exogenous nucleotidase in vivo.
Main Results:
- Bleomycin challenge elevated adenosine levels and CD73 activity in mouse lungs.
- CD73 knockout mice showed impaired adenosine accumulation and exacerbated lung inflammation and fibrosis.
- Exogenous nucleotidase administration restored adenosine levels and reduced lung injury in CD73 knockout mice.
- Supplementation with exogenous nucleotidase also reduced inflammation in wild-type mice.
Conclusions:
- CD73-dependent adenosine production is a primary mechanism for generating adenosine in bleomycin-induced lung injury.
- CD73 plays a protective role by mitigating pulmonary inflammation and fibrosis.
- Targeting CD73-mediated adenosine production represents a potential therapeutic strategy for lung injury.
