Role of hyaluronan and hyaluronan-binding proteins in human asthma.

Abstract

Background

The characteristics of human asthma are chronic inflammation and airway remodeling. Hyaluronan, a major extracellular matrix component, accumulates during inflammatory lung diseases, including asthma. Hyaluronan fragments stimulate macrophages to produce inflammatory cytokines. We hypothesized that hyaluronan and its receptors would play a role in human asthma.

Objective

To investigate the role of hyaluronan and hyaluronan-binding proteins in human asthma.

Methods

Twenty-one subjects with asthma and 25 healthy control subjects underwent bronchoscopy with endobronchial biopsy and bronchoalveolar lavage. Fibroblasts were cultured, and hyaluronan and hyaluronan synthase expression was determined at baseline and after exposure to several mediators relevant to asthma pathobiology. The expression of hyaluronan-binding proteins CD44, TLR (Toll-like receptor)-2, and TLR4 on bronchoalveolar lavage macrophages was determined by flow cytometry. IL-8 production by macrophages in response to hyaluronan fragment stimulation was compared.

Results

Airway fibroblasts from patients with asthma produced significantly increased concentrations of lower-molecular-weight hyaluronan compared with those of normal fibroblasts. Hyaluronan synthase 2 mRNA was markedly increased in asthmatic fibroblasts. Asthmatic macrophages showed a decrease in cell surface CD44 expression and an increase in TLR2 and TLR4 expression. Macrophages from subjects with asthma showed an increase in responsiveness to low-molecular-weight hyaluronan stimulation, as demonstrated by increased IL-8 production.

Conclusion

Hyaluronan homeostasis is deranged in asthma, with increased production by fibroblasts and decreased CD44 expression on alveolar macrophages. Upregulation of TLR2 and TLR4 on macrophages with increased sensitivity to hyaluronan fragments suggests a novel proinflammatory mechanism by which persistence of hyaluronan fragments could contribute to chronic inflammation and airway remodeling in asthma.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1016/j.jaci.2011.04.006

Publication Info

Liang, Jiurong, Dianhua Jiang, Yoosun Jung, Ting Xie, Jennifer Ingram, Tony Church, Simone Degan, Maura Leonard, et al. (2011). Role of hyaluronan and hyaluronan-binding proteins in human asthma. The Journal of allergy and clinical immunology, 128(2). pp. 403–411.e3. 10.1016/j.jaci.2011.04.006 Retrieved from https://hdl.handle.net/10161/25442.

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Scholars@Duke

Ingram

Jennifer Leigh Ingram

Associate Professor in Medicine

Dr. Ingram's research interests focus on the study of airway remodeling in human asthma. Proliferation, migration, and invasion of airway fibroblasts are key features of airway remodeling that contribute to diminished lung function over time. Dr. Ingram uses molecular biology approaches to define the effects of interleukin-13 (IL-13), a cytokine abundantly produced in the asthmatic airway, in the human airway fibroblast. She has identified important regulatory functions of several proteins prevalent in asthma that control fibroblast growth and pro-fibrotic growth factor production in response to IL-13. By understanding these pathways and their role in human asthma and the chronic effects of airway remodeling, novel treatment strategies may be developed.

Kraft

Monica Kraft

Adjunct Professor in the Department of Medicine

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