Combined therapy with pirfenidone and nintedanib counteracts fibrotic silicosis in mice

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.