6. The efficacy of combination therapy surpassed that of
monotherapy in addressing inflammation and fibrosis associated with
silicosis.
Following the combined application of PFD and BIBF, the inflammatory
lesions in the lung tissue of advanced silicosis mice were reduced, and
the infiltration of inflammatory cells decreased compared to the use of
either drug alone (Fig 7A, B), indicating a stronger effect when used in
combination. Moreover, levels of crucial inflammatory factors such as
IL-1β (Fig 7C, D), IL-6 (Fig 7E, F), and TNF-α (Fig 7G) were also
found to decrease. In terms of pulmonary fibrosis, the combined
administration exhibited a more potent and effective improvement in
fibrotic conditions compared to monotherapy, leading to a reduction in
fibrotic lesions and a decrease in collagen deposition (Fig 8A, B).
Furthermore, the mRNA and protein levels of key fibrotic factors, such
as FN-1 (Fig 8C, E, F) and COL-I (Fig 8D, E, F), were reduced.
Additionally, the combined treatment effectively reduced the levels of
HYP (Fig 8G), implying an overall decrease in fibrosis. The above
results demonstrated the advantages of combined drug administration in
limiting silica-induced inflammation and fibrosis, and the effects were
consistent for both high and low doses.
Clinical reports have indicated that both PFD and BIBF have certain side
effects, including gastrointestinal reactions, skin diseases,
hepatotoxicity and so on. Therefore, we assessed the drug toxicity of
the low-dose combined therapy regimen, which is most likely to be used
in clinical settings. The results showed that compared to silica group,
low-dose combined therapy did not exhibit a significant trend of weight
loss. In fact, the rate of weight loss was even lower than that observed
with high-dose PFD or high-dose BIBF (Fig S1A). However, it is worth
noting that the combined administration increased levels of liver
function markers ALT (Fig S1B) and AST (Fig S1C) compared to silicosis
group, although the changes were not significant when compared to the
use of monotherapy. Additionally, there was no apparent structural
damage or alteration observed in liver tissue. Moreover, no conspicuous
damage to kidney tissues or small intestine tissues was observed (Fig
S1D). In conclusion, it can be inferred that the efficacy and safety of
low-dose combined administration are reasonably assured, thus
recommending its prospective utilization in future anti-fibrotic
treatments.