Airway fibroblasts in asthma manifest an invasive phenotype.

Abstract

RATIONALE:

Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor (TGF)-β1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-β1 and MMPs.

OBJECTIVES:

We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-β1 and MMPs in asthma compared with normal controls.

METHODS:

Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV(1): 90 ± 3.6% pred) and 17 normal control subjects (FEV(1): 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-β1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels.

MEASUREMENTS AND MAIN RESULTS:

IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-β1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared with normal control subjects.

CONCLUSIONS:

IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-β1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.

• Authors: Jennifer L Ingram, Molly J Huggins, Tony D Church, Yuejuan Li, Dave C Francisco, Simone Degan, Rafael Firszt, Denise M Beaver, Njira L Lugogo, Ying Wang, Mary E Sunday, Paul W Noble, Monica Kraft
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 183 Issue 12 Pg. 1625-32 (Jun 15 2011) ISSN: 1535-4970 [Electronic] United States
• PMID: 21471104 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-13
• Receptors, Interleukin-13
• Transforming Growth Factor beta1
• Matrix Metalloproteinases

Topics

• Adult
• Airway Remodeling (physiology)
• Asthma (pathology)
• Bronchi (pathology)
• Cells, Cultured
• Female
• Fibroblasts (physiology)
• Flow Cytometry
• Humans
• Immunohistochemistry
• Interleukin-13 (physiology)
• Male
• Matrix Metalloproteinases (physiology)
• Receptors, Interleukin-13 (analysis)
• Transforming Growth Factor beta1 (physiology)