Topotecan Alleviates Lipopolysaccharide-Mediated Acute Lung Injury Via the NF-κB Signaling Pathway

Background: The topoisomerase 1 (Top1) inhibitor has been reported to inhibit inflammatory genes induced by virus and protect mice from sepsis. Its role in acute lung injury (ALI) remains unknown. This study aimed to explore the effects of topotecan (TPT), a Top 1 inhibitor, in lipopolysaccharide (LPS)-ALI.

Materials and methods: THP-1 cells were stimulated with LPS and then treated with or without TPT. Inflammatory cytokines expression was measured by ELISA. In vivo, we also detected the effect of TPT in LPS-induced ALI mouse model through hematoxylin-eosin staining of lung tissue and the quantification of total protein, total cell count, and cytokines in bronchoalveolar lavage fluid. To investigate the effect of TPT on transcriptome levels, microarray analyses were performed. KEGG analysis was applied to determine potential pathways modified by TPT. Microarray results were confirmed by real-time PCR and Western blot.

Results: TPT significantly decreased the expression of TNF-α and IL-1β induced by LPS in THP-1 cells. In an LPS-induced ALI mouse model, TPT significantly attenuated lung injury and decreased the levels of total protein, total cell count, and inflammatory cytokine expression in bronchoalveolar lavage fluid. Microarray results showed that TPT significantly increased expression of 958 genes and decreased expression of 1400 genes in THP-1 cells upon LPS stimulation. KEGG analysis demonstrated that differentially expressed genes function in multiple signaling pathways, including the nuclear factor (NF)-κB signaling pathway. The downstream gene of NF-κB, including c-IAP1/2, c-FLIP, Bcl-2, IL-8, and VCAM-1, and the phosphorylation of NF-κB p105, p65, and IκB-α were significantly decreased after TPT administration in THP-1 cells.

Conclusions: In conclusion, TPT attenuates LPS-induced ALI through inhibiting the NF-κB signaling pathway, suggesting that TPT might serve as a useful therapeutic for ALI. Thus, our study has provided new insight for current ALI treatment.