Characterization of a novel model incorporating airway epithelial damage and related fibrosis to the pathogenesis of asthma

Abstract

Asthma develops from injury to the airways/lungs, stemming from airway inflammation (AI) and airway remodeling (AWR), both contributing to airway hyperresponsiveness (AHR). Airway epithelial damage has been identified as a new etiology of asthma but is not targeted by current treatments. Furthermore, it is poorly studied in currently used animal models of AI and AWR. Therefore, this study aimed to incorporate epithelial damage/repair with the well-established ovalbumin (OVA)-induced model of chronic allergic airway disease (AAD), which presents with AI, AWR, and AHR, mimicking several features of human asthma. A 3-day naphthalene (NA)-induced model of epithelial damage/repair was superimposed onto the 9-week OVA-induced model of chronic AAD, before 6 weeks of OVA nebulization (NA þ OVA group), during the second last OVA nebulization period (OVA/NA group) or 1 day after the 6-week OVA nebulization period (OVA þ NA group), using 6-8-week-old female Balb/c mice (n ¼ 6-12/group). Mice subjected to the 9-week OVA model, 3-day NA model or respective vehicle treatments (saline and corn oil) were used as appropriate controls. OVA alone significantly increased epithelial thickness and apoptosis, goblet cell metaplasia, TGF-b1, subepithelial collagen (assessed by morphometric analyses of various histological stains), total lung collagen (hydroxyproline analysis), and AHR (invasive plethysmography) compared with that in saline-treated mice (all Po0.05 vs saline treatment). NA alone caused a significant increase in epithelial denudation and apoptosis, TGF-b1, subepithelial, and total lung collagen compared with respective measurements from corn oil-treated controls (all Po0.01 vs corn oil treatment). All three combined models underwent varying degrees of epithelial damage and AWR, with the OVA þ NA model demonstrating the greatest increase in subepithelial/total lung collagen and AHR (all Po0.05 vs OVA alone or NA alone). These combined models of airway epithelial damage/AAD demonstrated that epithelial damage is a key contributor to AWR, fibrosis and related AHR, and augments the effects of AI on these parameters.

Dual role of RACK1 in airway epithelial mesenchymal transition and apoptosis

“…Accumulating evidence has suggested TGF‐β1‐related airway epithelial apoptosis process is the major morphological feature leading to epithelial cell injury . Moreover, repeated airway epithelial cell damage and repair is a key cause of airway remodelling, because of enhancing activation of the epithelial mesenchymal trophic unit and leading to subepithelial airway fibrosis . Notably, some recent studies indicate that as a potent pleiotropic cytokine, TGF‐β1 even simultaneously induces the apoptosis and EMT in certain epithelial cells, such as renal tubular epithelial cells, mammary epithelial cells and lens epithelial cells .…”

Combining an epithelial repair factor and anti‐fibrotic with a corticosteroid offers optimal treatment for allergic airways disease

“…Mice were subjected to the 9.5 week OVA‐induced model of chronic AAD incorporating epithelial damage, as described previously (Royce et al ., ). Briefly, mice ( n = 48) were sensitized with two i.p.…”

“…To address this limitation and the fact that currently used mainstay in asthma therapy, including corticosteroids (which primarily act to suppress AI) and/or short‐ and long‐acting β‐agonists (which suppress AHR independently of regulating the pathogenesis of AI or AWR) do not target epithelial damage or the ensuing AWR, we recently superimposed naphthalene (NA)‐induced epithelial damage onto the well‐established ovalbumin (OVA)‐induced murine model of chronic AAD, which presented with the three central components of asthma pathogenesis (Royce et al ., ). Although human asthma is not typically induced by injurious stimuli such as OVA or NA per se , which even in combination would probably not cause the myriad of allergic, chemical and genetic factors associated with disease progression in humans, the strength of combining these agents in mice is that they create a model that allows investigation and therapeutic targeting of the contribution of epithelial damage to several morphological and functional processes that typify the human disease, without any confounding alveolitis (Kumar et al ., ).…”

“…Although human asthma is not typically induced by injurious stimuli such as OVA or NA per se , which even in combination would probably not cause the myriad of allergic, chemical and genetic factors associated with disease progression in humans, the strength of combining these agents in mice is that they create a model that allows investigation and therapeutic targeting of the contribution of epithelial damage to several morphological and functional processes that typify the human disease, without any confounding alveolitis (Kumar et al ., ). The induction of epithelial damage in the OVA + NA model was found to contribute to AWR, fibrosis and related AHR and exacerbate the effects of AI on these parameters (Royce et al ., ).…”

Serelaxin enhances the therapeutic effects of human amnion epithelial cell‐derived exosomes in experimental models of lung disease

“…Fibrosis (scar tissue accumulation) results from a failed wound healing response to tissue injury, where extracellular matrix (ECM) synthesis is ongoing and further exacerbates tissue damage in a self‐perpetuating cycle (Eming, Wynn, & Martin, ; Wynn & Ramalingam, ). This depends largely on the activation of ECM‐producing myofibroblasts (activated fibroblasts), which in turn are influenced by several mediators, particularly transforming growth factor (TGF)‐β1 (Royce, Patel, & Samuel, ). Additionally, newly‐secreted ECM components can be remodelled and reorganised by several proteases (Afratis, Selman, Pardo, & Sagi, ).…”