Bigh3 is essential for pulmonary fibrosis

Buechler, M. B.; Altieri, A.; Aghazadeh Habashi, Y.; Chung, Y.; McCartney, E. E.; Schuster, R.; Abovsky, M.; Abdullah, F. S.; Hakim, S.; Cooper, S.; Jurisica, I.; Hinz, B.

doi:10.1101/2025.09.02.673852

bioRxiv · 10.1101/2025.09.02.673852

Bigh3 is essential for pulmonary fibrosis

Buechler, M. B.·Altieri, A.·Aghazadeh Habashi, Y.·Chung, Y.·McCartney, E. E.·Schuster, R.·Abovsky, M.·Abdullah, F. S.·Hakim, S.·Cooper, S.·Jurisica, I.·Hinz, B.

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Abstract

Transforming growth factor beta (TGF-{beta})-induced gene-human, 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.

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Buechler, M. B., Altieri, A., Aghazadeh Habashi, Y., Chung, Y., McCartney, E. E., Schuster, R., Abovsky, M., Abdullah, F. S., Hakim, S., Cooper, S., Jurisica, I., Hinz, B.. 2025-09-07. Bigh3 is essential for pulmonary fibrosis. https://doi.org/10.1101/2025.09.02.673852

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