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)-b1 and matrix metalloproteinases (MMPs). IL-13 is a key T H 2 cytokine that directs many features of airway remodeling through TGF-b1 and MMPs. Objectives: We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-b1 and MMPs in asthma compared with normal controls. Methods: Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV 1 : 90 6 3.6% pred) and 17 normal control subjects (FEV 1 : 102 6 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-b1 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-b1 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-13Ra2 was reduced in asthma compared with normal control subjects. Conclusions: IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-b1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

“…Fibroblast invasiveness may contribute to other fibrotic conditions as well, such as remodeling of the airways in asthma and remodeling of the joints in rheumatoid arthritis. Airway fibroblasts from patients with asthma are more invasive than those from control subjects (27), and fibroblast-like Figure 6. BAL from patients with idiopathic pulmonary fibrosis (IPF) induces non-cell-autonomous invasion of lung fibroblasts from patients with IPF.…”

Strategies targeting the IL-4/IL-13 axes in disease

“…IL-13 indirectly causes asthmatic airway fibroblasts to secrete collagen I via MMP-2 released TGF-b1 [120]. IL-13 also causes bronchoscopy-derived primary asthmatic lung fibroblasts to migrate through matrigel in a TGF-b-dependent fashion [121]. IL-13 induces bronchial biopsy-derived primary lung epithelial cells to release TGF-b2 in a corticosteroid-insensitive fashion [122].…”

Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13–Suppressed Elastin in Airway Fibroblasts in Asthma

“…We hypothesize that airways collapsibility associated with reduced airway elastin increases susceptibility to not only methacholine but also to other mediators known to cause bronchoconstriction, such as allergens and airway irritants. Furthermore, we have previously shown that IL-13-induced airway fibroblast invasion in asthma was inversely associated with methacholine PC 20 (12). Taken together, these data suggest that airway fibroblasts isolated from subjects with mild asthma exhibiting the most severe AHR are more susceptible to IL-13-directed signaling than those with less severe AHR, associating AHR with airway remodeling as manifested by airway wall thickening and stiffening due to increased subepithelial fibrosis and reduced elastin gene expression.…”

“…These cells, along with airway smooth muscle cells, produce elastin, alter lung architecture after injury, stimulate inflammation, and respond to cytokines relevant to asthma such as IL-4, IL-13, and transforming growth factor-b1 (10)(11)(12)(13). Specific fibroblast responses include mitogen-stimulated proliferation, invasion, and collagen production (12)(13)(14).…”

“…These cells, along with airway smooth muscle cells, produce elastin, alter lung architecture after injury, stimulate inflammation, and respond to cytokines relevant to asthma such as IL-4, IL-13, and transforming growth factor-b1 (10)(11)(12)(13). Specific fibroblast responses include mitogen-stimulated proliferation, invasion, and collagen production (12)(13)(14). IL-13, a critical effector cytokine in asthma, mediates its effects through several cells, including airway fibroblasts, and plays central roles in airway obstruction, airways hyperresponsiveness (AHR), mucus metaplasia, inflammatory cell infiltration, and fibrosis (15,16).…”