The modulation of large airway smooth muscle phenotype and effects of epidermal growth factor receptor inhibition in the repeatedly allergen-challenged rat

Abstract

Allergen challenges induce airway hyperresponsiveness (AHR) and increased airway smooth muscle (ASM) mass in the sensitized rat. Whether the remodeled ASM changes its phenotype is uncertain. We examined, in sensitized Brown Norway rats, the effects of multiple ovalbumin (Ova) challenges on ASM remodeling and phenotype and the role of the epidermal growth factor receptor (EGFR) in these processes. Rats were sensitized with Ova and challenged three times at 5-day intervals with phosphate-buffered saline or Ova and pretreated with the EGFR inhibitor AG-1478 (5 mg/kg) or its vehicle dimethyl sulfoxide. Ova challenges increased ASM mass in all-sized airways and in large airway mRNA expression of smooth muscle myosin heavy chain (sm-MHC), assessed by laser capture. Myosin light chain kinase and the fast myosin isoform SM-B mRNA expressions were not affected. Ova induced AHR to methacholine, and, based on the constant-phase model, this was largely attributable to the small airways and lung derecruitment at 48 h that recovered by 1 wk. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor (HB-EGF) were increased in bronchoalveolar lavage fluid at 48 h after Ova exposure. AG-1478 inhibited AHR and prevented ASM growth. Epithelial gene expression of EGFR, HB-EGF, matrix metalloproteinase (MMP)-9, Gro-α, and transforming growth factor-β was unaffected by Ova challenges. We conclude that EGFR drives remodeling of ASM, which results from repeated Ova challenge. Furthermore, the latter results in excessive small airway and, to a lesser degree, large airway narrowing to methacholine, and large airway gene expression of contractile protein is conserved.

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

“…Collectively, these findings indicate that epithelial DUOX1 mediates a number of critical features of allergic airway inflammation, most notably neutrophilia, mucous metaplasia, subepithelial fibrosis, and airways hyperresponsiveness. Since each of these outcomes have in previous studies been linked with enhanced epithelial activation of EGFR (12,15,16), our findings are consistent with the hypothesis that DUOX1 contributes to these phenotypes largely by promoting persistent EGFR activation within the airway epithelium.…”

“…In addition to promoting mucous metaplasia, epithelial EGFR activation has also been implicated in allergen-induced subepithelial fibrotic remodeling (15,16). In agreement with this, HDM-induced inflammation was associated with significant subepithelial collagen deposition around peripheral airways, as detected by Masson's trichrome staining ( Figure 3D) and accumulation of α-smooth muscle actin (α-SMA) ( Figure 3E), and induced lung tissue expression of the collagen genes Col1a1 and Col3a1 (Supplemental Figure 1B), and each of these outcomes was significantly reduced in Duox1 -/-mice ( Figure 3E and Supplemental Figure 1B).…”

“…in particular, it affects neutrophilic inflammation, mucous metaplasia, subepithelial fibrosis, and airway resistance (15)(16)(17). However, these findings have not been translated into clinical use of available selective EGFR tyrosine kinase inhibitors in treatment of asthma, as EGFR tyrosine kinase inhibitors are associated with adverse effects, such as enhanced skin rash and inflammation (18).…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…Previous work on families of receptor tyrosine kinases such as endothelial growth factor (EGF) receptors (171,214,270,284), insulin receptors (54,55,90,128,224,271), or plateletderived growth factor (PDGF) receptors (123) has shown a role for these receptors in airway contractility and/or remodeling. However, a number of recent studies have found that the Trk family of receptors (RTK class VII; Fig.…”

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

“…The shed HB-EGF binds to EGFR and, through autocrine signaling, suppresses ELN mRNA expression, as previously demonstrated by DiCamillo and colleagues (25) and Liu and colleagues (26) in lung fibroblasts (25,26). Levels of HB-EGF are increased in bronchoalveolar lavage fluid after allergen stimulation (27). Also, IL-13 stimulates proteolytic release of HB-EGF in airway epithelial cells (28).…”