Effect of heparin and related glycosaminoglycan on PDGF-induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity.

Masahiro Sasaki,Takanobu Shioya,Akiko Watanabe,Manabu Kagaya,Takefumi Ito,Masaaki Sano,Mamoru Miura,Masayuki Kashima

doi:10.1080/096293500411541

Masahiro Sasaki, Takanobu Shioya + Show 6 more

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https://doi.org/10.1080/096293500411541

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Journal: Mediators of inflammation	Publication Date: Jan 1, 2000
Citations: 23	License type: CC BY 3.0

Affiliation: Akita University

Abstract

Fibroblast migration, proliferation, extracellular matrix protein synthesis and degradation are the key events in various biological and pathological processes in pulmonary fibrosis. In addition, biopsy specimens from the lungs of patients with pulmonary fibrosis show increased numbers of mast cells which have metachromatic granules containing heparin, histamine and proteases. Little is known about how these products influence pulmonary fibrosis. In the present study, we investigated the effect of heparin and related glycosaminoglycans on PDGF-induced lung fibroblast proliferation and chemotactic response in vitro. In addition, we examined the effect of heparin on both the induction of matrix metalloproteinases (MMPs) and MMPs activity in lung fibroblasts in vitro. Heparin, de-N-sulphated heparin but not heparan sulphate inhibited PDGF-induced lung fibroblast proliferation. In contrast, only heparin inhibited PDGF-stimulated human lung fibroblast chemotaxis. Negatively charged poly-L-glutamic acid had no effect on either fibroblast proliferation or chemotaxis. Thus the negative charge alone cannot account for the ant-proliferative and anti-chemotactic effects of heparin. Furthermore, heparin and heparan sulphate also had no inhibitory effect on induction of MMPS, including MMP-1 (interstitial collagenase), MMP-2 (gelatinase A) and MMP-9 (gelatinase B). Only heparin inhibited both MMP-1 and MMP-2/MMP-9 activity. Additionally, tissue inhibitor of metalloproteinase type 1 (TIMP-1) and type 2 (TIMP-2) inhibited PDGF-stimulated human lung fibroblast chemotaxis. The ability of heparin to inhibit fibroblast chemotaxis may account for the inhibitory effect of heparin on MMP activity. The above results suggested that heparin and related glycosaminoglycans differentially regulate PDGF-induced lung fibroblast proliferation, chemotaxis and MMPs activity and further that these effects may have a key role in extracellular matrix remodeling in inflammatory lung disease.

Highlights

Biopsy sp ecimens from the lungs of patients w ith plumonary fibrosis show inc re ased numbe rs of mast ce lls[1,2,3] w hic h have me tachromatic granules containing heparin, histamine and prote ase s
Plate let-de rive d grow th factor (PDGF), w hich is one of the most important mitogens derived from various ce lls including alveolar macrophage s and platelets, may implic ate the ex trace llular matrix prote ins and matrix metallop rote inases (MMPs )[6] in w ound he aling
We demonstrate d the ability of PDGF to modulate the induc tion of MMPs and the activity of MMPs in the present study

Summary

Introduction

Biopsy sp ecimens from the lungs of patients w ith plumonary fibrosis show inc re ased numbe rs of mast ce lls[1,2,3] w hic h have me tachromatic granules containing heparin, histamine and prote ase s. Plate let-de rive d grow th factor (PDGF), w hich is one of the most important mitogens derived from various ce lls including alveolar macrophage s and platelets, may implic ate the ex trace llular matrix prote ins and matrix metallop rote inases (MMPs )[6] in w ound he aling. The role of PDGF in inf lammatory lung dise ase s is consis te nt w ith the observation of PDGF-like prote ins localised to mac rophages and epithe lial c ells associated w ith tissue repair of patients w ith idiopathic pulmonary fibrosis .7,8.

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