2. Pirfenidone outperformed nintedanib in ameliorating lung
inflammation and fibrosis in silicosis mice.
The administration of varying doses (low and high dose) of PFD or BIBF
to the silicosis mice resulted in notable reductions in inflammatory
cell infiltration as well as a mitigated inflammatory response (Fig 2A).
Strikingly, the anti-inflammatory efficacy of PFD surpassed that of
BIBF, showcasing an impressive ability to curb inflammation.
Furthermore, both high doses of these pharmacological agents almost
exhibited a conspicuous superiority over their low-dose counterparts,
highlighting the dose-dependent nature of their therapeutic effects. In
relation to crucial inflammatory mediators, both PFD and BIBF
demonstrated remarkable efficacy in inhibiting the mRNA and protein
expressions of IL-1β (Fig 2B, C) and IL-6 (Fig 2D, E), as well as
the mRNA levels of Tnf-α (Fig 2F), thereby providing compelling
evidence for the therapeutic impact of PFD and BIBF in mitigating the
inflammatory response associated with silicosis.
In the context of the obstinate fibrotic milieu, microscopic examination
through Masson’s staining revealed a discernible regression in fibrotic
lesions and a conspicuous attenuation of collagen deposition following
pharmacological intervention (Fig 3A). Remarkably, paralleling its
anti-inflammatory prowess, PFD demonstrated a superior inhibitory effect
on fibrogenesis when compared to BIBF, with higher dosages presenting a
dose-dependent enhancement of therapeutic efficacy. Mechanistically, PFD
exerted a profound influence by effectively curtailing the mRNA and
protein levels of prominent fibrotic mediators, including FN-1 (Fig 3B,
D, E) and COL-I (Fig 3C, D, F). Administration of BIBF at a
subtherapeutic dose resulted in robust downregulation of both the mRNA
and protein levels of FN-1 (Fig 3B, D, E). In contrast, the mRNA levels
of Col-I were minimally affected, yet its protein levels remained
significantly altered (Fig 3C, D, F). Furthermore, both PFD and BIBF
exhibited a substantial reduction in HYP content, substantiating their
comprehensive remedial potential (Fig 3G). Collectively, these insights
underscore the therapeutic value of PFD and BIBF in ameliorating the
concurrent inflammatory and fibrotic sequelae associated with silicosis,
with PFD emerging as a therapeutically favorable candidate over BIBF,
particularly when administered at higher dosages in monotherapy
settings.