3. Transcriptomic analysis revealed similarities and differences
in the mechanisms underlying the therapeutic effects of PFD and BIBF
against silicosis.
To further investigate the mechanisms underlying the therapeutic effects
of PFD and BIBF in silicosis, we conducted transcriptomic sequencing on
lung tissues from the PBS group, silica group, high-dose PFD group, and
high-dose BIBF group (Fig 4A). Firstly, our analysis revealed 5286 DEGs
between the PBS and silica groups (Fig 4B, C), including 2784
up-regulated genes and 2502 down-regulated genes. Subsequent KEGG
analysis identifies top 40 downregulated pathways such as propanoate
metabolism, citrate cycle, valine, leucine, and isoleucine degradation,
et al. in the silica group compared to PBS, signifying a close
interrelationship between perturbed metabolism of substances such as
glucose, lipids, and amino acids and the progression of pulmonary
fibrosis (Fig 4D). Additionally, consistent with previous reports, our
findings also revealed the presence of upregulated pathways, top 40
signaling pathways including primary immunodeficiency, NF-κB signaling
pathway, viral protein interaction with cytokine and cytokine receptor,
et al. in the silica group, suggesting potential implications for
complex signaling cascades, immune responses, phagocytosis, cell death
and more that contribute to the advancement of pulmonary fibrosis (Fig
4E).
Subsequently, a similar analysis was applied to PFD or BIBF group,
showing PFD elicits significant modifications in the gene expression
profiles, involving of total 1386 altered genes (Fig 4F, G) and
signaling pathways (Fig 4H) within the silica group, with notable
impacts observed in relation to steroid biosynthesis, and ribosome among
others; likewise, the administration of BIBF also elicits 305
dramatically increased DEG and 635 significantly decreased DEGs,
resulting in profound alterations in the gene expression patterns (Fig
4I, J) and signaling cascades (Fig 4K) within the silica group,
featuring significant ramifications on steroid biosynthesis, and notch
signaling pathway alongside other pathways. Ultimately, having
delineated the altered pathway profile in silicosis pathogenesis, as
well as the pathway alterations associated with PFD or BIBF treatment of
silicosis, it is now conceivable to elucidate the most effective and
pivotal pathways targeted by PFD or BIBF in silicosis therapy. The Venn
diagram depicted that PFD predominantly modulates 15 pathways in the
treatment of silicosis, whereas BIBF primarily impacts 10 pathways (Fig
4L). Notably, these two pharmacological agents share 2 common pathways,
namely antigen processing and presentation and steroid biosynthesis (Fig
4L, M), exhibiting extensive involvement in the progression of pulmonary
fibrosis.