Extracellular matrix proteins modulate asthmatic airway smooth muscle cell proliferation via an autocrine mechanism

doi:10.1016/j.jaci.2003.12.312

Journal of Allergy and Clinical Immunology

Volume 113, Issue 4, April 2004, Pages 690-696

https://doi.org/10.1016/j.jaci.2003.12.312 Get rights and content

Abstract

Background

Airway remodeling is a key feature of persistent asthma and includes alterations in the extracellular matrix protein profile around the airway smooth muscle (ASM) and hyperplasia of the ASM. We have previously shown that nonasthmatic ASM cells in culture produce a range of extracellular matrix protein proteins and that asthmatic ASM cells proliferate faster than cells from nonasthmatic patients.

Objective

In this study, we compared the profile of extracellular matrix proteins produced by nonasthmatic and asthmatic ASM cells. We also examined the influence of these extracellular matrix protein proteins and conditioned medium derived from nonasthmatic or asthmatic ASM cells on the proliferation of nonasthmatic and asthmatic ASM cells.

Methods

Extracellular matrix proteins were measured by ELISA; proliferation of ASM cells was measured by tritiated thymidine incorporation.

Results

Production of perlecan and collagen I by the cells from asthmatic patients were significantly increased. In contrast, laminin α1 and collagen IV were decreased. Chondroitin sulfate was detectable only in the cells from nonasthmatic patients. Compared with nonasthmatic extracellular matrix proteins, proteins from asthmatic cells enhanced ASM cell proliferation. Conditioned medium from asthmatic ASM cells did not induce greater proliferation compared with conditioned medium from nonasthmatic cells.

Conclusions

The data show that the profile of extracellular matrix protein components is altered in asthmatic cells and that this altered profile and not soluble mediators secreted from the ASM cells has the potential to influence the proliferation of these cells. These changes are likely to contribute to the airway wall remodeling that occurs in asthma.

Section snippets

Cell culture

We obtained human ASM cells from 23 nonasthmatic (50±20 years; mean±SD) and 14 asthmatic (42±16 years; mean±SD) patients by methods adapted from those previously described.15., 16. The characteristics of the patients are listed in Table I. Approval for all experiments with human lung was provided by the Human Ethics Committee of the University of Sydney and the Central Sydney Area Health Service. ASM cell characteristics were determined by immunofluorescence and light microscopy as previously

ECM composition in ASM cells

After 7 days of growth in the presence of 10% serum, the nonasthmatic and asthmatic ASM cells produced varying amounts of the 15 ECM proteins examined. When nonasthmatic and asthmatic ASM cells were compared, a significant increase was observed in perlecan (7.9%±1.5% nonasthmatic and 12.0%±1.1% asthmatic, P<.05, n = 6 and 6, respectively, ANOVA factorial) and collagen type I (3.0%±0.5% nonasthmatic and 8.5%±0.9% asthmatic, P<.05, n = 6 and 6, respectively, ANOVA factorial) (Fig 1). In contrast, a

Discussion

In this study, we have shown that when ASM cells from asthmatic and nonasthmatic patients are compared, cells from asthmatic patients produce increased relative amounts of the structural protein collagen I, the basement membrane protein perlecan, and decreased amounts of the structural protein collagen IV, the glycosaminoglycan chondroitin sulfate, and the basement membrane protein laminin α1. These changes in ECM production are the result of posttranscriptional effects, as there were no

Acknowledgements

We acknowledge the collaborative effort of the cardiopulmonary transplant team and pathologists at St Vincent's Hospital, Sydney. We thank Dr Greg King from the Woolcock Institute of Medical Research,³ Royal Prince Alfred Hospital, Sydney, Australia, for the supply of lung biopsy specimens.

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^☆: Supported by the NHMRC, Australia, and Astra Zeneca, Switzerland, and the Rebecca L. Cooper Foundation. Drs Johnson and Burgess contributed equally to this work.

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Mechanisms of allergyExtracellular matrix proteins modulate asthmatic airway smooth muscle cell proliferation via an autocrine mechanism☆

Abstract

Background

Objective

Methods

Results

Conclusions

Section snippets

Cell culture

ECM composition in ASM cells

Discussion

Acknowledgements

J Allergy Clin Immunol

Lancet

Atherosclerosis

Chest

Chest

Regul Pept

Arch Biochem Biophys

The effect of age and duration of disease on airway structure in fatal asthma

Am J Respir Crit Care Med

Cellular hypertrophy and hyperplasia of airway smooth muscle underlying bronchial asthma

Am Rev Respir Dis

The mechanics of airway narrowing in asthma

Am Rev Respir Dis

The functional consequences of airway remodeling in asthma

Monaldi Arch Chest Dis

Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid

Am J Respir Crit Care Med

Remodelling of the extracellular matrix in asthma: proteoglycan synthesis and degradation

Can Respir J

Asthma: a disease remodeling the airways

Allergy

Mechanisms of allergy
Extracellular matrix proteins modulate asthmatic airway smooth muscle cell proliferation via an autocrine mechanism☆