Article

Early growth response-1 suppresses epidermal growth factor receptor-mediated airway hyperresponsiveness and lung remodeling in mice.

Section of Neonatology, Perinatal & Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 4.11). 03/2009; 41(4):415-25. DOI: 10.1165/rcmb.2008-0470OC
Source: PubMed

ABSTRACT Transforming growth factor (TGF)-alpha and its receptor, the epidermal growth factor receptor, are induced after lung injury and are associated with remodeling in chronic pulmonary diseases, such as pulmonary fibrosis and asthma. Expression of TGF-alpha in the lungs of adult mice causes fibrosis, pleural thickening, and pulmonary hypertension, in addition to increased expression of a transcription factor, early growth response-1 (Egr-1). Egr-1 was increased in airway smooth muscle (ASM) and the vascular adventitia in the lungs of mice conditionally expressing TGF-alpha in airway epithelium (Clara cell secretory protein-rtTA(+/-)/[tetO](7)-TGF-alpha(+/-)). The goal of this study was to determine the role of Egr-1 in TGF-alpha-induced lung disease. To accomplish this, TGF-alpha-transgenic mice were crossed to Egr-1 knockout (Egr-1(ko/ko)) mice. The lack of Egr-1 markedly increased the severity of TGF-alpha-induced pulmonary disease, dramatically enhancing airway muscularization, increasing pulmonary fibrosis, and causing greater airway hyperresponsiveness to methacholine. Smooth muscle hyperplasia, not hypertrophy, caused the ASM thickening in the absence of Egr-1. No detectable increases in pulmonary inflammation were found. In addition to the airway remodeling disease, vascular remodeling and pulmonary hypertension were also more severe in Egr-1(ko/ko) mice. Thus, Egr-1 acts to suppress epidermal growth factor receptor-mediated airway and vascular muscularization, fibrosis, and airway hyperresponsiveness in the absence of inflammation. This provides a unique model to study the processes causing pulmonary fibrosis and ASM thickening without the complicating effects of inflammation.

Download full-text

Full-text

Available from: Timothy D Le Cras, Jun 30, 2015
0 Followers
 · 
97 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: As the most ancient extant metazoans, glass sponges (Hexactinellida) have attracted recent attention in the areas of molecular evolution and the evolution of conduction systems but they are also interesting because of their unique histology: the greater part of their soft tissue consists of a single, multinucleate syncytium that ramifies throughout the sponge. This trabecular syncytium serves both for transport and as a pathway for propagation of action potentials that trigger flagellar arrests in the flagellated chambers. The present chapter is the first comprehensive modern account of this group and covers work going back to the earliest work dealing with taxonomy, gross morphology and histology as well as dealing with more recent studies. The structure of cellular and syncytial tissues and the formation of specialised intercellular junctions are described. Experimental work on reaggregation of dissociated tissues is also covered, a process during which histocompatibility, fusion and syncytialisation have been investigated, and where the role of the cytoskeleton in tissue architecture and transport processes has been studied in depth. The siliceous skeleton is given special attention, with an account of discrete spicules and fused silica networks, their diversity and distribution, their importance as taxonomic features and the process of silication. Studies on particle capture, transport of internalised food objects and disposal of indigestible wastes are reviewed, along with production and control of the feeding current. The electrophysiology of the conduction system coordinating flagellar arrests is described. The review covers salient features of hexactinellid ecology, including an account of habitats, distribution, abundance, growth, seasonal regression, predation, mortality, regeneration, recruitment and symbiotic associations with other organisms. Work on the recently discovered hexactinellid reefs of Canada's western continental shelf, analogues of long-extinct Jurassic sponge reefs, is given special attention. Reproductive biology is another area that has benefited from recent investigations. Seasonality, gametogenesis, embryogenesis, differentiation and larval biology are now understood in broad outline, at least for some species. The process whereby the cellular early larva becomes syncytial is described. A final section deals with the classification of recent and fossil glass sponges, phylogenetic relationships within the Hexactinellida and the phylogenetic position of the group within the Porifera. Palaeontological aspects are covered in so far as they are relevant to these topics.
    Advances in Marine Biology 02/2007; 52:1-145. DOI:10.1016/S0065-2881(06)52001-2 · 5.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The early growth response gene (Egr-1) codes for a zinc finger transcription factor that has important roles in the regulation of cell growth, differentiation, and survival. Aberrant Egr-1 expression is implicated in carcinogenesis, inflammation, atherosclerosis, and ischemic injury. We reported previously that normal fibroblasts stimulated by transforming growth factor-ss showed rapid and transient induction of Egr-1. Moreover, we observed that tissue expression of Egr-1 was elevated in patients with scleroderma, which suggests that Egr-1 may be involved in tissue repair and fibrosis. Here, we investigated matrix remodeling and wound healing in mice harboring gain of function or loss of function mutations of Egr-1. Using the model of bleomycin-induced scleroderma, we found that the early influx of inflammatory cells into the skin and lungs, and the subsequent development of fibrosis in these organs, were markedly attenuated in Egr-1 null mice. Furthermore, full-thickness incisional skin wound healing was impaired, and skin fibroblasts lacking Egr-1 showed reduced migration and myofibroblast transdifferentiation in vitro. In contrast, transgenic mice with fibroblast-specific Egr-1 overexpression showed exuberant tissue repair, with enhanced collagen accumulation and increased tensile strength of incisional wounds. Together, these results point to the fundamental role that Egr-1 plays in the regulation of transforming growth factor-ss-dependent physiological and pathological matrix remodeling.
    American Journal Of Pathology 09/2009; 175(3):1041-55. DOI:10.2353/ajpath.2009.090241 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increases in the epidermal growth factor receptor (EGFR) have been associated with the severity of airway thickening in chronic asthmatic subjects, and EGFR signaling is induced by asthma-related cytokines and inflammation. The goal of this study was to determine the role of EGFR signaling in a chronic allergic model of asthma and specifically in epithelial cells, which are increasingly recognized as playing an important role in asthma. EGFR activation was assessed in mice treated with intranasal house dust mite (HDM) for 3 wk. EGFR signaling was inhibited in mice treated with HDM for 6 wk, by using either the drug erlotinib or a genetic approach that utilizes transgenic mice expressing a mutant dominant negative epidermal growth factor receptor in the lung epithelium (EGFR-M mice). Airway hyperreactivity (AHR) was assessed by use of a flexiVent system after increasing doses of nebulized methacholine. Airway smooth muscle (ASM) thickening was measured by morphometric analysis. Sensitization to HDM (IgG and IgE), inflammatory cells, and goblet cell changes were also assessed. Increased EGFR activation was detected in HDM-treated mice, including in bronchiolar epithelial cells. In mice exposed to HDM for 6 wk, AHR and ASM thickening were reduced after erlotinib treatment and in EGFR-M mice. Sensitization to HDM and inflammatory cell counts were similar in all groups, except neutrophil counts, which were lower in the EGFR-M mice. Goblet cell metaplasia with HDM treatment was reduced by erlotinib, but not in EGFR-M transgenic mice. This study demonstrates that EGFR signaling, especially in the airway epithelium, plays an important role in mediating AHR and remodeling in a chronic allergic asthma model.
    AJP Lung Cellular and Molecular Physiology 12/2010; 300(3):L414-21. DOI:10.1152/ajplung.00346.2010 · 4.04 Impact Factor