Hypoxia‐induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and tissue remodeling and is a leading cause of death in the United States. Increased apoptosis of pulmonary epithelial cells is thought to play a role in COPD development and progression. Identification of signaling pathways resulting in increased apoptosis in COPD can be used in the development of novel therapeutic interventions. Deoxyadenosine (dAdo) is a DNA breakdown product that amplifies lymphocyte apoptosis by being phosphorylated to deoxyadenosine triphosphate (dATP). dAdo is maintained at low levels by adenosine deaminase (ADA). This study demonstrated that mice lacking ADA developed COPD manifestations in association with elevated dAdo and dATP levels and increased apoptosis in the lung. Deoxycitidine kinase (DCK), a major enzyme for dAdo phosphorylation, was up-regulated in mouse and human airway epithelial cells in association with air-space enlargement. Hypoxia was identified as a novel regulator of DCK, and inhibition of DCK resulted in diminished dAdo-mediated apoptosis in the lungs. Our results suggest that activating the dAdo-DCK-dATP pathway directly results in increased apoptosis in the lungs of mice with air-space enlargement and suggests a novel therapeutic target for the treatment of COPD.

Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

“…This was previously observed in a mouse model of airspace enlargement, where dAdo levels accumulated because of the deficiency of adenosine deaminase (5). It was shown that activation of DCK directly correlated with the formation of dATP, accumulation of dATP pools, and the enhancement of epithelial cell apoptosis (5). Conversely, in the current study, we show that increases in DCK may play more of a role in the enhancement of proliferation in fibrosis as opposed to apoptosis in emphasemic models.…”

“…The importance of cell proliferation and apoptosis in the regulation of pulmonary fibrosis prompted us to consider DCK as a novel pathway that could influence these processes. In support of this, our recent findings demonstrate that DCK is elevated in chronic lung disease associated with alveolar airspace enlargement where it contributes to the dysregulation of apoptosis (5). Collectively, the findings of the current study demonstrate a role for DCK in pulmonary fibrosis.…”

“…However, in the presence of high levels of dAdo, which can result from excessive apoptosis, activation of DCK may be detrimental by facilitating dATP elevations that can enhance apoptosis (31). This was previously observed in a mouse model of airspace enlargement, where dAdo levels accumulated because of the deficiency of adenosine deaminase (5). It was shown that activation of DCK directly correlated with the formation of dATP, accumulation of dATP pools, and the enhancement of epithelial cell apoptosis (5).…”

“…These findings were further supported by our observation that DCK inhibition using dyC is associated with decreased fibrosis. dyC is an enzymatic inhibitor of DCK that competitively blocks the binding of DCK to other substrates and then feedback suppresses DCK activity by its phosphorylation product deoxycytidine triphosphate (5,30). Interestingly, injection of dyC was initiated on Day 20, a stage when pulmonary fibrosis is well established and results demonstrated a significantly decreased lung fibrosis, suggesting a therapeutic benefit for this treatment in halting active fibrosis.…”

“…IPF has an increasing mortality rate because of its poor prognosis and lack of effective therapies (3,5). Alveolar epithelial injury and subsequent aberrant repair processes, such as the formation of hyperplastic epithelial cells, are important in the pathogenesis of IPF (2,4).…”