Zebrafish as a model for investigating Klebsiella pneumoniae-driven lung injury and therapeutic targets.

Background: Lung injury induced by Klebsiella pneumoniae infection presents a significant challenge, with complex molecular mechanisms driving tissue damage and immune dysregulation. This study aimed to establish a zebrafish model of K. pneumoniae-induced lung injury to explore the underlying molecular mechanisms involved in tissue damage, immune responses, and development.

Methods: A zebrafish model was developed by injecting K. pneumoniae into the swim bladder at 96 h post-fertilization (hpf). The immune response, including neutrophil migration and cytokine secretion, was assessed through histological analysis and quantitative measures. Transcriptomic analysis was performed to evaluate gene expression changes related to lung development, immune regulation, and metabolism. The role of the TGF-β signaling pathway in immune response and tissue repair was investigated using the TGF-β inhibitor SB 431542.

Results: Infection with K. pneumoniae induced rapid neutrophil migration and the secretion of inflammatory cytokines such as IL-6, IL-1β, TNF-α, and TNF-β, similar to immune responses seen in mouse models. Transcriptomic analysis revealed significant alterations in genes involved in lung development, immune responses, and metabolic pathways, underscoring the broad impact of infection on physiological regulation. The TGF-β signaling pathway was found to play a dual role: it promoted immune cell recruitment and cytokine secretion but suppressed developmental genes, delaying tissue repair. Treatment with SB 431542 reduced neutrophil aggregation, lowered cytokine levels, and restored gene expression related to development and repair.

Conclusions: This zebrafish model effectively mimics K. pneumoniae-induced lung injury, offering valuable insights into the molecular mechanisms of tissue damage and immune dysregulation. Targeting the TGF-β signaling pathway holds therapeutic potential for reducing inflammation and promoting tissue repair, providing a foundation for the development of new treatment strategies for lung infections.