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Soluble Thy-1 reverses lung fibrosis via its integrin-binding motif
Chunting Tan, … , Edward Connors, James S. Hagood
Chunting Tan, … , Edward Connors, James S. Hagood
Published November 1, 2019
Citation Information: JCI Insight. 2019;4(21):e131152. https://doi.org/10.1172/jci.insight.131152.
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Categories: Research Article Pulmonology

Soluble Thy-1 reverses lung fibrosis via its integrin-binding motif

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Abstract

Loss of Thy-1 expression in fibroblasts correlates with lung fibrogenesis; however, the clinical relevance of therapeutic targeting of myofibroblasts via Thy-1–associated pathways remains to be explored. Using single (self-resolving) or repetitive (nonresolving) intratracheal administration of bleomycin in type 1 collagen-GFP reporter mice, we report that Thy-1 surface expression, but not mRNA, is reversibly diminished in activated fibroblasts and myofibroblasts in self-resolving fibrosis. However, Thy-1 mRNA expression is silenced in lung with nonresolving fibrosis following repetitive bleomycin administration, associated with persistent activation of αv integrin. Thy1-null mice showed progressive αv integrin activation and myofibroblast accumulation after a single dose of bleomycin. In vitro, targeting of αv integrin by soluble Thy-1-Fc (sThy-1), but not RLE-mutated Thy-1 or IgG, reversed TGF-β1–induced myofibroblast differentiation in a dose-dependent manner, suggesting that Thy-1’s integrin-binding RGD motif is required for the reversibility of myofibroblast differentiation. In vivo, treatment of established fibrosis induced either by single-dose bleomycin in WT mice or by induction of active TGF-β1 by doxycycline in Cc10-rtTA-tTS-Tgfb1 mice with sThy-1 (1000 ng/kg, i.v.) promoted resolution of fibrosis. Collectively, these findings demonstrate that sThy-1 therapeutically inhibits the αv integrin–driven feedback loop that amplifies and sustains fibrosis.

Authors

Chunting Tan, Min Jiang, Simon S. Wong, Celia R. Espinoza, Ceonne Kim, Xiaoping Li, Edward Connors, James S. Hagood

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Figure 3

αvβ3 Integrin is persistently activated or upregulated in mice lacking Thy-1 expression.

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αvβ3 Integrin is persistently activated or upregulated in mice lacking T...
(A) Immunofluorescence (IF) for αv integrin and αSMA in lung tissue. (B) Experimental scheme. Adult WT and Thy1–/– mice were given single-dose bleomycin (Bleo) (4 U/kg, in 100 μL saline) by orotracheal intubation (MicroSprayer). Lungs were collected at 14, 28, 42, and 56 days after Bleo instillation (n = 4–5/group). (C and D) IF quantification of active αvβ3 integrin (WOW-1) and αSMA in lung tissue. Scale bar: 100 μm. Results are presented as mean ± SEM. Two groups were compared using 2-tailed Student’s t test, *P < 0.05, **P < 0.01 versus WT group.
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