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Oxidative damage and DNA damage in lungs of an ovalbumin-induced asthmatic murine model
Yuanfang Wang1,2, Jiangtao Lin1,2, Jun Shu3
1Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China.
Background:
Asthma is characterized to chronic airway inflammation. However, the role of oxidative damage and DNA damage in the pathophysiology of asthma have rarely been studied. On the other hand, there are evidences that DNA-dependent protein kinase (DNA-PK) participates in DNA damage repair and regulates innate immune responses and proinflammatory signaling pathways.
Methods:
After ovalbumin (OVA)-induced asthmatic murine model was established, airway hyper-responsiveness (AHR), total and differential bronchoalveolar lavage fluid (BALF) cell counts. IL-4, IL-8, IL-13 and TNF-α were chosen to evaluate the airway inflammation, and oxidative damage indicators levels (8-isoprostane and 8-OhdG) in BALF were measured. Alkaline comet assay was conducted to detected DNA damage. Histological analysis was conducted after hematoxylin and eosin (HE) straining, and proteins were extracted for 3-nitrotyrosine (3-NT) detection and immunoblotting.
Results:
AHR, infiltration of inflammatory cells and pro-inflammatory cytokine levels in lungs were significantly higher in asthmatic mice. OVA challenge resulted in robust increase in 3-NT, 8-isoprostane and 8OHdG in lungs, which represented oxidative damage level. DNA damage and repair proteins levels in asthma were also increased. NU7441 aggravated the DNA damage level. However, it suppressed infiltration of lung inflammatory cells and inflammatory cytokine levels, suggesting that DNA-PK may be a potential target for treatment of allergic asthma.
Conclusions:
Our study showed that oxidative damage and DNA damage existed in the airway of asthmatic mice. NU7441 augmented DNA damage level, and moreover, it also attenuated infiltration of inflammatory cells and pro-inflammatory cytokine levels in asthmatic lungs.
Insights
Oxidative and DNA damage are present in asthma. Inhibiting DNA-dependent protein kinase (DNA-PK) with NU7441 worsened DNA damage but reduced airway inflammation, suggesting DNA-PK as a therapeutic target for allergic asthma.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Asthma involves chronic airway inflammation, with limited research on oxidative and DNA damage roles.
- DNA-dependent protein kinase (DNA-PK) is implicated in DNA repair and immune regulation.
Purpose of the Study:
- To investigate the roles of oxidative and DNA damage in asthma pathophysiology.
- To explore the therapeutic potential of targeting DNA-PK in allergic asthma.
Main Methods:
- Established an ovalbumin (OVA)-induced asthmatic mouse model.
- Assessed airway hyper-responsiveness (AHR), inflammatory cell counts, and cytokine levels (IL-4, IL-8, IL-13, TNF-α).
- Measured oxidative damage markers (8-isoprostane, 8-OhdG), DNA damage (comet assay), and DNA-PK related proteins.
Main Results:
- Asthmatic mice exhibited increased AHR, inflammatory cell infiltration, and pro-inflammatory cytokines.
- Significant increases in oxidative damage markers (3-NT, 8-isoprostane, 8-OhdG) and DNA damage/repair proteins were observed in asthmatic lungs.
- NU7441 treatment aggravated DNA damage but reduced lung inflammation and cytokine levels.
Conclusions:
- Oxidative and DNA damage are present in the airways of asthmatic mice.
- NU7441's dual effect on DNA damage and inflammation suggests DNA-PK is a potential therapeutic target for allergic asthma.
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