Epithelial Injury and Repair in Airways Diseases

doi:10.1378/chest.12-1944

Chest

Volume 144, Issue 6, December 2013, Pages 1906-1912

https://doi.org/10.1378/chest.12-1944 Get rights and content

Asthma is a common chronic disease characterized by variable respiratory distress with underlying airway inflammation and airflow obstruction. The incidence of asthma has risen inexorably over the past 50 years, suggesting that environmental factors are important in its etiology. All inhaled environmental stimuli interact with the lung at the respiratory epithelium, and it is a testament to the effectiveness of the airway innate defenses that the majority of inhaled substances are cleared without the need to elicit an inflammatory response. However, once this barrier is breached, effective communication with immune and inflammatory cells is required to protect the internal milieu of the lung. In asthma, the respiratory epithelium is known to be structurally and functionally abnormal. Structurally, the epithelium shows evidence of damage and has more mucus-producing cells than normal airways. Functionally, the airway epithelial barrier can be more permeable and more sensitive to oxidants and show a deficient innate immune response to respiratory virus infection compared with that in normal individuals. The potential of a susceptible epithelium and the underlying mesenchyme to create a microenvironment that enables deviation of immune and inflammatory responses to external stimuli may be crucial in the development and progression of asthma. In this review, we consider three important groups of environmental stimuli on the epithelium in asthma: oxidants, such as environmental pollution and acetaminophen; viruses, including rhinovirus; and agents that cause barrier disruption, such as house dust mite allergens. The pathology associated with each stimulus is considered, and potential future treatments arising from research on their effects are presented.

Section snippets

Epithelial Phenotype

The airway epithelium from trachea to small bronchi is pseudostratified and columnar, comprising mostly ciliated epithelial cells that possess approximately 200 cilia per cell, each extending into the epithelial surface liquid, powering the mucociliary escalator. Other cells include mucus-secreting goblet cells, which are more prevalent in the larger airways, and surfactant-secreting club cells (Clara), which are found peripherally and, hence, are usually absent from bronchoscopic biopsy

The Epithelial Mesenchymal Trophic Unit

The epithelium and the underlying attenuated fibroblast sheath have been referred to as the epithelial mesenchymal trophic unit (EMTU).¹³ Within the EMTU, these airway structural cells work in concert to control the airway microenvironment during key processes, including tissue injury and repair, recapitulating responses, and signaling pathways that contributed to lung growth and development during embryogenesis. In asthma, it is postulated that the EMTU is dysregulated, leading to abnormal

Bronchial Epithelial Repair

Normal repair in the airway epithelium is highly regulated, and as shown in Figure 1, it involves a series of temporally regulated steps. Initially, epithelial cells at the edges of the wound dedifferentiate and adopt a repair phenotype by undergoing epithelial-to-mesenchymal transition. These mesenchymal-like cells migrate into the wound and lay down a provisional matrix to rapidly restore some barrier protection. Despite the epithelial cells becoming migratory, they remain within the

The Dysregulated EMTU in Asthma

In asthma, there is evidence of epithelial injury and repair with loss of columnar epithelial cells and increased expression of the epidermal growth factor receptor (EGFR) in biopsy specimens from adults¹⁸ and children.¹⁹ Activation of the EGFR controls cell migration and proliferation, and upregulation of its expression is a normal response to injury.¹⁵ However, the repair response in asthma appears to be impeded, as evidenced by increased expression of the cell cycle inhibitor p21^waf1, which

Triggers and Potential Treatment of Epithelial Damage

Asthmatic epithelium not only repairs abnormally but also is more susceptible to inhaled insults than normal. Although a wide range of inhaled substances can cause epithelial damage, here we address three of the most common groups: oxidant stressors, viral infections, and mediators of tight junction damage.

Summary

Epithelial vulnerability to environmental agents and impaired injury and repair responses are increasingly being considered as primary drivers in the initiation, exacerbation, and treatment of asthma. Although current approaches to treating what may be fundamental abnormalities are in their infancy, future treatment of asthma may target specific therapies to the protection and maintenance of the respiratory epithelium.

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Davies is a cofounder of Synairgen Research Ltd and holds shares in Synairgen plc. Synairgen is currently developing inhaled IFN-β for treatment of virus-induced asthma exacerbations. Dr Grainge has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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Airway epithelial cells are connected by TJ proteins, which form the first barrier against external pathogens, including bacteria, viruses, chemicals and allergens [19,20]. Airway epithelial cells can coordinate the immune defence of the body, transmit external signals to immune cells to clear the external pathogens in the respiratory tract and avoid causing inflammation [21]. Allergens containing proteases and environmental contaminants promote the paracellular transport of epithelial cells by destroying the TJ proteins of the epithelial barrier, resulting in the transmission of allergens to the subcortical layer [22].
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MYN repairs the nasal mucosal epithelial barrier by upregulating the transcription of claudin-1 and reduces nasal inflammatory infiltration.
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The loss of epithelial integrity increases the transepithelial permeation of toxic compounds and pathogens, e.g. cigarette smoke [86]. As consequence of loosened tight junctions between epithelial cells, the wounded regions undergo EMT [87]. This de-differentiation of the epithelium appears in COPD leading to peribronchial fibrosis and airflow limitations.
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Chest

Translating Basic Research into Clinical PracticeEpithelial Injury and Repair in Airways Diseases

Section snippets

Epithelial Phenotype

The Epithelial Mesenchymal Trophic Unit

Bronchial Epithelial Repair

The Dysregulated EMTU in Asthma

Triggers and Potential Treatment of Epithelial Damage

Summary

Acknowledgments

Respir Med

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunity

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Clin Nutr

J Allergy Clin Immunol

Chest

Curr Opin Immunol

Gene

J Allergy Clin Immunol

J Allergy Clin Immunol

Mucosal Immunol

J Allergy Clin Immunol

Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease

Proc Am Thorac Soc

Prevalence and severity of self-reported asthma in young adults, 1976-2004

Eur Respir J

Upper and Lower Respiratory Disease (Lung Biology in Health and Disease)

Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling

Dis Model Mech

Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression

Am J Respir Crit Care Med

Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus

J Exp Med

Asthmatic bronchial epithelium is more susceptible to oxidant-induced apoptosis

Am J Respir Cell Mol Biol

A large-scale, consortium-based genomewide association study of asthma

N Engl J Med

The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit

Am J Respir Cell Mol Biol

Knowledge translation: airway epithelial cell migration and respiratory diseases

Cell Mol Life Sci

Lung epithelial wound healing in health and disease

Expert Rev Respir Med

Epithelial repair mechanisms in the lung

Am J Physiol Lung Cell Mol Physiol

Translating Basic Research into Clinical Practice
Epithelial Injury and Repair in Airways Diseases