Bigh3 is essential for pulmonary fibrosis

Transforming growth factor beta (TGF- β) -induced g ene- h uman, clone 3 (BIGH3) has been implicated as a biomarker of lung fibrosis. However, it is unknown if BIGH3 plays a functional role in fibrosis pathogenesis. To address this question, we used in silico , in vitro and in vivo approaches. We found that BIGH3 / Bigh3 is upregulated in human lung fibrosis and mouse models of pulmonary fibrosis. We next generated a novel Bigh3 knockout ( Bigh3 ^−/− ) mouse and found that while these animals exhibited lung architecture and immune cellularity that is broadly equivalent to wild-type mice, they were protected from lung fibrosis in response to bleomycin administration. In silico modeling suggested that BIGH3 can bind to integrin alpha v (ITGAV). In vitro co-culture systems revealed that activated human lung fibroblasts can elicit BIGH3 expression from human monocyte-derived macrophages. Last, macrophages elicited collagen expression from lung fibroblasts in a manner that is Bigh3 -dependent. Collectively, these data suggest that Bigh3 is a product of fibroblast-macrophage interactions that is essential for the pathogenesis of lung fibrosis, possibly via interactions with ITGAV.