Combined therapy with pirfenidone and nintedanib counteracts fibrotic
silicosis in mice
Abstract
Abstract Background and Purpose Pneumoconiosis, especially silicosis has
emerged as a prominent occupational disease with remarkable global
implications with no definitive cure available. While pirfenidone and
nintedanib have been approved in treating idiopathic pulmonary fibrosis,
their potential efficacy as anti-fibrotic agents in advanced silicosis
warrants further investigation. Thus, we aimed to assess the individual
and combined effects of pirfenidone and nintedanib in treating advanced
silicosis mice and further elucidate the underlying mechanisms involved
in their therapeutic actions. Experimental Approach We administrated
monotherapy or combination therapy of pirfenidone and nintedanib with
low and high doses in silicosis mouse models established after 6 weeks
and then evaluated lung function, inflammatory responses, and fibrotic
status. Moreover, we employed transcriptomic and metabolomic analyses to
unravel the mechanisms underlying different therapeutic strategies. Key
Results Both pirfenidone and nintedanib were demonstrated to be
effective for advanced silicosis, with superior outcomes when used in
combination. Transcriptomic and metabolomic analyses revealed that
pirfenidone and nintedanib primarily exerted their therapeutic effects
through modulation of immune responses, signaling cascades, circadian
rhythm, and metabolic processes of substances including lipid, amino
acids, nucleotides, and carbohydrates. Conclusion and Implications In
conclusion, pirfenidone and nintedanib, either administered individually
or in combination, exhibit remarkable potential in advanced silicosis
mouse models. Further, combined therapy outperformed monotherapy even at
a half dose. These therapeutic benefits are attributed to their
influence on diverse signaling pathways and metabolic processes.
Keywords: silicosis, pulmonary fibrosis, pirfenidone, nintedanib,
multi-omics.