2. Academic Validation
  3. Caspase-8-driven NLRP3 inflammasome activation exacerbates bronchopulmonary dysplasia by increasing the apoptosis and pyroptosis crosstalk of alveolar epithelial cells

Caspase-8-driven NLRP3 inflammasome activation exacerbates bronchopulmonary dysplasia by increasing the apoptosis and pyroptosis crosstalk of alveolar epithelial cells

  • Int Immunopharmacol. 2025 Aug 28:161:115025. doi: 10.1016/j.intimp.2025.115025.
Dabin Huang 1,  Debo Xu 2,  Chuming You 2,  Binghui Li 2,  Lin Li 2,  Qiaohuan Yang 2,  Wei Zhou 3,  Qiong Meng 4,  Zhenyu Liang 5
Affiliations

Affiliations

  • 1 Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Department of Pediatrics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China.
  • 2 Department of Pediatrics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China.
  • 3 Department of Pediatrics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China; Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, No.9 Jinsui Road, Guangzhou 510623, China. Electronic address: zhouwei_pu002@126.com.
  • 4 Department of Pediatrics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China. Electronic address: mengqiong1969@163.com.
  • 5 Department of Pediatrics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China. Electronic address: liangzhenyu0823@163.com.
PMID: 40483833 DOI: 10.1016/j.intimp.2025.115025
Abstract

Background: The programmed cell death (PCD) of alveolar epithelial cells, which is mediated by inflammation and oxidative stress, plays an important role in the development of bronchopulmonary dysplasia (BPD). Caspase-8 is an important molecular switch that regulates PCD; however, its mechanism of mediating Pyroptosis in BPD remains unclear.

Method: We respectively established an in vitro and in vivo BPD model by stimulating human lung epithelial cells (BEAS-2B) and neonatal mice with hyperoxia exposure. These models were administered a Caspase-1 inhibitor, Caspase-8 inhibitor, or a combination to investigate the effects of Caspase-8 on BPD Pyroptosis, alveolar development, immune cell recruitment, and pulmonary vascular remodeling.

Results: The expression and activity of Caspase-8 are significantly increased in BPD mice. Caspase-8 inhibition attenuates the activation of the NLRP3 inflammasome, and reduces the expression of the pyroptosis-related proteins Caspase-1, gasdermin-D (GSDMD), and ASC. Caspase-8 inhibition reduces the recruitment of CD11b+ macrophages and the release of the interleukin-1β (IL-1β) and IL-18, as well as reducing the Apoptosis of lung epithelial cells, thereby improving alveolar development. Notably, Caspase-8 inhibition also reduced the expression of α-SMA and improved pulmonary vascular remodeling. Importantly, combination therapy increased these improvements.

Conclusion: Caspase-8 is an important molecular switch that regulates PCD in BPD. Selective targeted inhibition of Caspase-8 reduces NLRP3 inflammasome activation, resists oxidative stress-induced lung injury, reduces the crosstalk between Pyroptosis and Apoptosis in lung epithelial cells, and reduces inflammatory immune cell infiltration and abnormal vascular remodeling. As such, targeting Caspase-8 may be a potential strategy for the treatment of BPD.

Keywords

Apoptosis; Bronchopulmonary dysplasia; Caspase-8; NLRP3 inflammasome; Pyroptosis.

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