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Inhibition of DNA methylation attenuates lung ischemia-reperfusion injury after lung transplantation

Objective: DNA methylation plays an important role in inflammation and oxidative stress. This study aimed to investigate the effect of inhibiting DNA methylation on lung ischemia-reperfusion injury (LIRI).

Methods: We adopted a completely random design for our study. Thirty-two rats were randomized into the sham, LIRI, azathioprine (AZA), and pluripotin (SC1) groups. The rats in the LIRI, AZA, and SC1 groups received left lung transplantation and intravenous injection of saline, AZA, and SC1, respectively. After 24 hours of reperfusion, histological injury, the arterial oxygen partial pressure to fractional inspired oxygen ratio, the wet/dry weight ratio, protein and cytokine concentrations in lung tissue, and DNA methylation in lung tissue were evaluated. The pulmonary endothelium that underwent hypoxemia and reoxygenation was treated with AZA or SC1. Endothelial apoptosis, chemokines, reactive oxygen species, nuclear factor-κB, and apoptotic proteins in the endothelium were studied.

Results: Inhibition of DNA methylation by AZA attenuated lung injury, inflammation, and the oxidative stress response, but SC1 aggravated LIRI injury. AZA significantly improved endothelial function, suppressed apoptosis and necrosis, reduced chemokines, and inhibited nuclear factor-κB.

Conclusions: Inhibition of DNA methylation ameliorates LIRI and apoptosis and improves pulmonary function via the regulation of inflammation and oxidative stress.

 

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Title: **Inhibition of DNA Methylation Alleviates Lung Ischemia-Reperfusion Injury and Endothelial Dysfunction**

**Abstract:** Lung ischemia-reperfusion injury (LIRI) is a significant complication of lung transplantation, characterized by inflammation, oxidative stress, and endothelial dysfunction. This study aimed to investigate the impact of inhibiting DNA methylation on LIRI using a rat model. Rats were randomly assigned to sham, LIRI, azathioprine (AZA), and pluripotin (SC1) groups. Rats in the LIRI, AZA, and SC1 groups underwent left lung transplantation and were treated with saline, AZA, and SC1, respectively. After 24 hours of reperfusion, various parameters including histological injury, oxygenation, lung water content, protein and cytokine levels, and DNA methylation were assessed.

**Methods:**

- **Study Design:** Completely random design.
- **Experimental Groups:** Sham, LIRI, AZA, SC1.
- **Interventions:**
  - LIRI, AZA, and SC1 groups underwent left lung transplantation.
  - LIRI group received intravenous saline.
  - AZA group received azathioprine treatment.
  - SC1 group received pluripotin treatment.
- **Evaluation Parameters:**
  - Histological injury assessment.
  - Arterial oxygen partial pressure to fractional inspired oxygen ratio measurement.
  - Wet/dry weight ratio determination.
  - Protein and cytokine concentrations in lung tissue analysis.
  - DNA methylation analysis in lung tissue.
  - Treatment of pulmonary endothelium with AZA or SC1.
  - Evaluation of endothelial apoptosis, chemokines, reactive oxygen species, nuclear factor-κB, and apoptotic proteins.

**Results:**

- Inhibition of DNA methylation by AZA attenuated LIRI, inflammation, and oxidative stress.

- AZA significantly improved endothelial function, suppressed apoptosis and necrosis, reduced chemokines, and inhibited nuclear factor-κB.

- SC1 aggravated LIRI injury and oxidative stress response.

**Conclusions:** Inhibition of DNA methylation, specifically through azathioprine treatment, ameliorates lung ischemia-reperfusion injury. This intervention not only reduces inflammation and oxidative stress but also preserves endothelial function. These findings suggest that modulating DNA methylation holds therapeutic potential in mitigating complications associated with lung transplantation and ischemia-reperfusion injury. Further research is needed to explore the underlying mechanisms and optimize the application of DNA methylation inhibitors in clinical settings.

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