JZL184 modulates lung injury via occludin and TNF-α in two distinct ARDS models

English (OpenAlex)

Aim: Acute respiratory distress syndrome (ARDS) is a severe condition with high morbidity and mortality, currently treated with limited therapeutic options. Recent studies indicate that cannabinoids could play a protective role in preventing tissue damage, particularly in pulmonary disorders. While their benefits in lung pathologies are established, the specific role of cannabinoids in ARDS mechanisms remains underexplored. This study aims to investigate the protective effects of cannabinoids, particularly through occludin and TNF-α regulation, in two ARDS models with distinct pathophysiological mechanisms. Materials and Methods: Rats were treated with LPS for the direct ARDS model or ANTU for the indirect ARDS model. The inhibitor of MAGL, the enzyme that degrades the endocannabinoid 2-AG, JZL184, was administered 30 minutes prior to the administration of LPS or ANTU. Lung tissue samples were collected 24 hours post-LPS and 4 hours post-ANTU administration. Biochemical analyses, including MDA, SOD and catalase, as well as immunohistochemical evaluations of occludin and TNF-α, were conducted on lung tissue samples. Results: Biochemical analysis showed that MDA levels decreased in the ANTU and LPS groups, but increased in the ANTU+JZL184 group and decreased in the LPS+JZL184 group, reflecting paradoxical effects. SOD and catalase levels were higher in the ANTU group and lower in the ANTU+JZL184 group. Immunohistochemical analysis demonstrated the restoration of occludin expression in both endothelial and bronchiolar cells and a reduction in TNF-α levels following JZL184 treatment. Conclusion: JZL184 attenuates inflammation and restores occludin expression in both ARDS models, indicating its possible use as a therapeutic strategy for ARDS.