The In Vivo Fibrotic Role of FIZZ1 in Pulmonary Fibrosis

Tianju Liu,Matthew Ullenbruch,Hong Jin,Hongfeng Yu,Zhe Wu,Jianhua Liu,Toshihiro Ito,Sem H Phan,Jian Fu

doi:10.1371/journal.pone.0088362

Tianju Liu, Matthew Ullenbruch + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0088362

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Journal: PloS one	Publication Date: Feb 6, 2014
Citations: 55	License type: CC BY 4.0

Affiliation: University of Michigan–Ann Arbor, Michigan United

Abstract

FIZZ (found in inflammatory zone) 1, a member of a cysteine-rich secreted protein family, is highly induced in lung allergic inflammation and bleomycin induced lung fibrosis, and primarily expressed by airway and type II alveolar epithelial cells. This novel mediator is known to stimulate α-smooth muscle actin and collagen expression in lung fibroblasts. The objective of this study was to investigate the in vivo effects of FIZZ1 on the development of lung fibrosis by evaluating bleomycin-induced pulmonary fibrosis in FIZZ1 deficient mice. FIZZ1 knockout mice exhibited no detectable abnormality. When these mice were treated with bleomycin they exhibited significantly impaired pulmonary fibrosis relative to wild type mice, along with impaired proinflammatory cytokine/chemokine expression. Deficient lung fibroblast activation was also noted in the FIZZ1 knockout mice. Moreover, recruitment of bone marrow-derived cells to injured lung was deficient in FIZZ1 knockout mice. Interestingly in vitro FIZZ1 was shown to have chemoattractant activity for bone marrow cells, including bone marrow-derived dendritic cells. Finally, overexpression of FIZZ1 exacerbated fibrosis. These findings suggested that FIZZ1 exhibited profibrogenic properties essential for bleomycin induced pulmonary fibrosis, as reflected by its ability to induce myofibroblast differentiation and recruit bone marrow-derived cells.

Highlights

Found in inflammatory zone (FIZZ1), initially identified in lung allergic inflammation, belongs to a class of cysteine-rich secreted proteins known as the FIZZ/RELM family [1,2,3]
There was no significant difference between KO and Wild type (WT) littermates in their body weights, major organ weights, blood cell counts, as well as some serum chemistries tested including glucose, triglycerides, insulin, lipase, albumin, etc
Significant BLM-induced increases in type I collagen and a-smooth muscle actin (a-SMA) expression in WT mice were significantly reduced in KO mice after BLM injection, consistent with the reduced fibrosis noted on the basis of lung HYP content

Summary

Introduction

Found in inflammatory zone (FIZZ1), initially identified in lung allergic inflammation, belongs to a class of cysteine-rich secreted proteins known as the FIZZ/RELM (resistin-like molecules) family [1,2,3]. The FIZZ/RELM family consists four known members, FIZZ1/RELMa, FIZZ2/RELMb, FIZZ3/resistin, and RELMc, characterized by their conserved 10-cysteine residue motif, with 2 members, FIZZ2/RELMb and FIZZ3/resistin, having an additional cysteine residue in the highly variable N-terminus [1,2,3,4] This family has a unique tissue expression pattern. FIZZ1 is first reported to inhibit the nerve growth factor-mediated gene expression in dorsal root ganglion neurons [1]. It has an inhibitory effect on 3T3-L1 preadipocyte differentiation into adipocytes, but does not affect cell proliferation [5]. In the gut it is reported to activate IL-17 pathogenic responses and inflammation [19]

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