Aims: Pulmonary fibrosis (PF) is a chronic interstitial lung disease with an increasing incidence following the COVID-19 outbreak. Pirfenidone (Pirf), an FDA-approved pulmonary anti-fibrotic drug, is poorly tolerated and exhibits limited efficacy. Trigonelline (Trig) is a natural plant alkaloid with diverse pharmacological actions. We investigated the underlying prophylactic and therapeutic mechanisms of Trig in ameliorating bleomycin (BLM)-induced PF and the possible synergistic antifibrotic activity of Pirf via its combination with Trig.
Materials and methods: A single dose of BLM was administered intratracheally to male Sprague-Dawley rats for PF induction. In the prophylactic study, Trig was given orally 3 days before BLM and then for 28 days. In the therapeutic study, Trig and/or Pirf were given orally from day 8 after BLM until the 28th day. Biochemical assay, histopathology, qRT-PCR, ELISA, and immunohistochemistry were performed on lung tissues.
Key findings: Trig prophylactically and therapeutically mitigated the inflammatory process via targeting NF-κB/NLRP3/IL-1β signaling. Trig activated the autophagy process which in turn attenuated alveolar epithelial cells apoptosis and senescence. Remarkably, Trig attenuated lung SPHK1/S1P axis and its downstream Hippo targets, YAP-1, and TAZ, with a parallel decrease in YAP/TAZ profibrotic genes. Interestingly, Trig upregulated lung miR-375 and miR-27a expression. Consequently, epithelial-mesenchymal transition in lung tissues was reversed upon Trig administration. These results were simultaneously associated with profound improvement in lung histological alterations.
Significance: The current study verifies Trig's prophylactic and antifibrotic effects against BLM-induced PF via targeting multiple signaling. Trig and Pirf combination may be a promising approach to synergize Pirf antifibrotic effect.
Keywords: MicroRNAs; NLRP3; Pulmonary fibrosis; Sphingosine/Hippo; Trigonelline; Trigonelline/pirfenidone combination.
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