Human airway trypsin‐like protease exerts potent, antifibrotic action in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by the deposition of excessive extracellular matrix and the destruction of lung parenchyma, resulting from an aberrant wound-healing response. Although IPF is often associated with an imbalance in protease activity, the mechanisms underlying the sustained repair mechanisms are not fully understood. Here, we addressed the role of the recently identified, membrane-anchored serine protease human airway trypsin-like protease (HAT). In the present study, we show that both HAT expression and activity were up-regulated in human IPF specimens. Next, adenoviral overexpression of HAT before bleomycin challenge attenuated lung injury as well as extracellular matrix deposition in the bleomycin-induced pulmonary fibrosis model. In vitro, HAT prevented specific fibrosis-associated responses in primary human pulmonary fibroblasts and induced the expression of mediators associated with the prostaglandin E2 pathway. Altogether, our findings suggested that HAT could have a protective role in IPF and other fibrotic lung disorders.-Menou, A., Flajolet, P., Duitmen, J., Justet, A., Moog, S., Jaillet, M., Tabèze, L., Solhonne, B., Garnier, M., Mal, H., Mordant, P., Castier, Y., Cazes, A., Sallenave, J.-M., Mailleux, A. A., Crestani, B. Human airway trypsin-like protease exerts potent, antifibrotic action in pulmonary fibrosis.

Iterative, multiplexed CRISPR-mediated gene editing for functional analysis of complex protease gene clusters

“…In the context of cancer, individual HAT/DESC proteases (DESC1, HAT, and HAT-like 5) have been identified as either promotors of human tumorigenesis (24 -26) or as putative tumor suppressors (DESC1, HAT, HAT-like 5, and TMPRSS11A) (27)(28)(29)(30). HAT has been proposed to promote chronic airway disease through its ability to induce inflammatory cytokine and mucin production (31,32) but also to ameliorate bleomycin-induced pulmonary fibrosis by suppressing several pro-inflammatory pathways (33). Additionally, HAT was reported to exacerbate psoriasis vulgaris symptoms via induction of cytokine release (34).…”

SARS-CoV-2 infection of human lung epithelial cells induces TMPRSS-mediated acute fibrin deposition

“…The protease domains of ST14 and TMPRSS11D are referred to as matriptase and human airway trypsin-like protease (HAT) 49,50 , respectively. ST14 and TMPRSS11D are known to be upregulated in idiopathic pulmonary fibrosis 51,52 . The mouse homolog of ST14, epithin, was shown to be shed by ADAM17 in response to inflammatory stimulation and human matriptase activation required proteolytic cleavage [53][54][55][56] .…”