Background: Given that severe inflammatory reaction is an important manifestation of asthma, it would be helpful to understand the pathological mechanism of asthma to determine the endogenous anti-inflammatory events of asthma. Recent studies have found that energy metabolites in the body are related to some inflammatory diseases, but little is known about their role in asthma. Method: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene–knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5’-(α, β-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. Result: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic destruction of CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. Conclusion: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.

As a potent target for cancer therapy, ATR mainly regulates homologous recombination (HR)-mediated DNA damage repair. Our previous study first identified that ATR binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, most important lncRNAs, as critical factors for ATR activation, are largely unknown. In the present study, scaRNA2, the most enriched ATR-binding lncRNA, was identified and well characterized. ScaRNA2 was found to be essential for HR-mediated DNA damage repair. Furthermore, scaRNA2 knockdown abrogated the mobilization of ATR and its substrates in response to DNA damage. Mechanistically, scaRNA2 was observed to be necessary for Exo1-mediated DNA end resection and bridged the MRN complex to ATR activation. Using cancer cells and a cell-derived xenograft model, we demonstrated that lentivirus-based knockdown of scaRNA2 effectively increases sensitivity to multiple kinds of chemoradiotherapy. Preclinically, knockdown of scaRNA2 improved the therapeutic effects of radiotherapy on patient-derived organoids and xenograft models. Finally, upregulation of scaRNA2 colocalized with ATR was also found in clinical patients who are resistant to radiotherapy based on tumor regression grades. In conclusion, we identified scaRNA2 as the most abundant lncRNA bound to ATR and uncovered its mechanism in bridging DNA end resection to ATR activation, which could be applied as a potent target for combined cancer treatments with chemoradiotherapy.

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