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The Specific Connexin 43-Inhibiting Peptide Gap26 Improved Alveolar Development of Neonatal Rats With Hyperoxia
Cai Qing1, Zhao Xinyi1, Yu Xuefei1
1Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.
Frontiers in Pharmacology
|July 22, 2021
Summary
Oxidative stress in bronchopulmonary dysplasia (BPD) increases connexin 43 (Cx43) gap junctions, amplifying apoptosis. The Cx43 inhibitor Gap26 improved alveolar development in a rat model, suggesting a novel therapeutic strategy for BPD.
Area of Science:
- Pulmonary Medicine
- Neonatology
- Cell Biology
- Pathophysiology
Background:
- Bronchopulmonary dysplasia (BPD) is a severe complication in preterm infants, characterized by alveolar maldevelopment.
- Oxidative stress and excessive apoptosis are key pathological features of BPD.
- Gap junction (GJ)-mediated intercellular communication, particularly involving connexin 43 (Cx43), can propagate cellular injury.
Purpose of the Study:
- To investigate the role of Cx43-GJ in BPD-related alveolar maldevelopment.
- To determine if Cx43-GJ amplifies oxidative stress signaling and induces apoptosis in BPD.
- To evaluate the therapeutic potential of Gap26, a Cx43-GJ inhibitor, in a neonatal hyperoxia model.
Main Methods:
- Neonatal Sprague Dawley rats were exposed to normoxia or hyperoxia (85% O2) from postnatal day 1 to 14, with or without Gap26 treatment.
- Rat lung epithelial (RLE-6TN) cells were cultured in vitro under normoxia or hyperoxia and treated with N-acetyl cysteine (NAC) or Gap26.
- Evaluated Cx43 expression, reactive oxygen species (ROS) production, ASK1-JNK/p38 signaling pathway activity, apoptosis, and GJ intercellular communication (dye-coupling assay).
Main Results:
- In vitro, hyperoxia increased ROS, Cx43 expression, and GJ communication; Gap26 reduced ROS, inhibited ASK1-JNK/p38 signaling, and decreased apoptosis.
- In vivo, hyperoxia exposure led to increased ROS, Cx43 expression, activated ASK1-JNK/p38 signaling, and excessive apoptosis.
- Gap26 treatment reversed hyperoxia-induced changes, improving alveolar development in neonatal rats.
Conclusions:
- Oxidative stress upregulates Cx43 expression and enhances Cx43-GJ-mediated intercellular communication.
- Cx43-GJ signaling amplifies oxidative stress, promoting apoptosis via the ASK1-JNK/p38 pathway.
- Gap26 demonstrates potential as a novel therapeutic agent to mitigate alveolar developmental defects in BPD.
