Role of hyaluronan and hyaluronan-binding proteins in human asthma

doi:10.1016/j.jaci.2011.04.006

Journal of Allergy and Clinical Immunology

Volume 128, Issue 2, August 2011, Pages 403-411.e3

https://doi.org/10.1016/j.jaci.2011.04.006 Get rights and content

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.

Section snippets

Study population

Subjects age 18 to 60 years were recruited by advertisement. Samples used for this study are from a total of 21 patients with asthma and 25 healthy control subjects. Not all studies were performed on all subjects; numbers studied in each experiment are denoted in the Results section. Subjects were of mild severity per National Asthma Education and Prevention Program criteria³⁵ and used no controller medications. Healthy subjects demonstrated normal lung function, had no history of asthma, and

Hyaluronan accumulates in asthmatic lung tissue

To determine the role of hyaluronan in human asthma, we first assessed hyaluronan accumulation in human lung tissues. Lung sections from patients with asthma and healthy control subjects were stained by using a bHABP-based protocol. A significant increase in hyaluronan immunohistochemical staining was observed in bronchial sections of patients with asthma (Fig 1, D and E) compared with that of bronchial sections from healthy subjects (Fig 1, A and B). Quantitative analysis of hyaluronan stained

Discussion

In this study, we have explored the roles of hyaluronan and hyaluronan-binding proteins in human asthma. Hyaluronan has been shown to accumulate in the BALF of patients with asthma and may correlate with persistence of asthma symptoms.33, 34 Our data show that asthmatic airway fibroblasts produce constitutively higher concentrations of lower-molecular-weight hyaluronan with increased HAS2 gene expression compared with airway fibroblasts from healthy controls. In addition, alveolar macrophages

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: Supported by NIH grants AI052201, HL06539, P50-HL084917, HL77291 (P.W.N.), and P50-HL084917 (M.K.).

: Disclosure of potential conflict of interest: J. Ingram receives research support from the NIH-NHLBI and the Parker B. Francis Family Foundation. M. Kraft receives research support from GlaxoSmithKline, Merck, Genentech, Novartis, and GE Healthcare and is vice president of the American Thoracic Society. P. W. Noble receives research support from the NIH. The rest of the authors have declared that they have no conflict of interest.

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Mechanisms of allergy and clinical immunologyRole of hyaluronan and hyaluronan-binding proteins in human asthma

Background

Objective

Methods

Results

Conclusion

Section snippets

Study population

Hyaluronan accumulates in asthmatic lung tissue

Discussion

Int J Biochem Cell Biol

Chest

Matrix Biol

J Biol Chem

Exp Cell Res

J Biol Chem

J Pediatr Surg

J Biol Chem

J Allergy Clin Immunol

J Allergy Clin Immunol

Arch Biochem Biophys

J Biol Chem

Free Radic Biol Med

J Biol Chem

J Biol Chem

Cell

Remodeling in asthma and chronic obstructive lung disease

Am J Respir Crit Care Med

Airway remodeling in asthma

J Clin Invest

Pharmacotherapy and airway remodelling in asthma?

Thorax

Hyaluronan as an immune regulator in human diseases

Physiol Rev

Resolution of lung inflammation by CD44

Science

Matrix regulation of lung injury, inflammation, and repair: the role of innate immunity

Proc Am Thorac Soc

High levels of hyaluronan in idiopathic pulmonary arterial hypertension

Am J Physiol Lung Cell Mol Physiol

Hyaluronan fragments activate an NF-kappa B/I-kappa B alpha autoregulatory loop in murine macrophages

J Exp Med

Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages: the role of HA size and CD44

J Clin Invest

Regulation of hyaluronan-induced chemokine gene expression by IL-10 and IFN-gamma in mouse macrophages

J Immunol

Regulation of lung injury and repair by Toll-like receptors and hyaluronan

Nat Med

Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4

J Exp Med

Mechanisms of allergy and clinical immunology
Role of hyaluronan and hyaluronan-binding proteins in human asthma