Inflammation and Airway Remodeling

Asthma has been defined as a chronic inflammatory disease of the airways characterized by airway obstruction which is at least partially reversible with or without medication, and increased bronchial responsiveness to a variety of stimuli.1 Today, the primary emphasis in treatment is on the reduction of inflammation. Inflammation is the body's response to injury or infection, and its function is to both destroy the invader and lay the groundwork for tissue repair.

Inflammation is caused by both resident and recruited cells. Resident cells are the mast cells, epithelial cells and alveolar macrophages. The recruited inflammatory cells include the eosinophils, neutrophils, basophils, and lymphocytes. T-cells are also important contributors to inflammation. The inflammatory cascade begins with degranulation of the mast cells. Mast cell degranulation releases both pre-formed and synthesized mediators that include histamine, bradykinin, leukotrienes, prostaglandins, thromboxane, chemotactic factors and platelet activating factor (PAF). PAF is a major contributor to inflammation2

The epithelium of the airway does not act solely as a protective barrier for the underlying tissue. It too plays a role in the inflammatory process with both production and recruitment of inflammatory agents. It produces cytokines and mediators as well as the adhesion molecules that trap the intruding inflammatory cells. The recruited cells continue the process of inflammation begun by the resident cells. They release and synthesize bronchoconstrictors, cytokines and chemokines (a name derived from chemotactic and cytokine). These cells help clear the area of irritants and remove damaged cells quickly and efficiently. Inflammation causes damage to the lining of the airways. This initially results in epithelial cell edema, muscle constriction, mucus hyper-secretion and vascular leakage. As the inflammation progresses, epithelial cells are sloughed exposing nerves, cilia are lost and the number of glandular cells increases.

A variety of causes result in inflammation. Among the known causes of systemic inflammation are nicotine and stress.3 A recent study showed a “direct link” between nicotine and inflammation.4 Age too has an effect on inflammation. The changing differences in airway inflamation between young and aged individuals with asthma may contribute to increased morbidity in the elderly from this chronic disease.5

Repair and regeneration follow inflammation. Collagen deposition in the sub-basement membrane increases as does muscle mass. Vascular enlargement occurs.1 Connective tissue is replaced and in time matures into scar tissue.6 Thus reconstruction and repair of damaged airways leads to remodelling, a term used to describe the healing process whereby changes inthe structure of the airways occur. This is characteristic of asthma.

Structural changes in the airways affect lung function. These structural changes include hyperplasia or hypertrophy of the goblet cells, the submucosal cells, blood vessel cells and smooth muscle cells. Changes also occur in the epithelium and sub-epithelium. Further, the basement membrane thickens, collagen deposition increases in the extra cellular matrix and there is propagation of both connective tissue cells and smooth muscle. This affects air flow by decreasing the size of the lumen while in an exacerbation, theincreased mucus secretions and inflammatory exudate further reduce the airways and also increase the surface tension that encourages closure of the airways.7

The clinical consequences of remodelling include:

  • increase in smooth muscle mass, resulting in increased bronchospasm severity during exacerbations
  • poor response to bronchodilation
  • reduction in elasticity of the airways
  • accelerated decline in FEV1
  • increase in mucous glands which results in

∙    increased mucus secretions
∙    persistent inflammatory cells that sustain the inflammatory process, and
∙    increased collagen deposition in the basement membrane and the cellular matrix.

For a time it was supposed that airway remodelling occurred only in patients with severe asthma. To date, there is no data that shows that remodelling is dependent on severity.8 The injury-repair process is seen as the cause for the development of irreversible airway obstruction,9 especially in patients with long-standing asthma, despite optimal therapy.10

A study by Chetta and others11 showed that remodelling as a result of airway scarring occurs even in mild asthma. Thus this concept has important implications for both understanding of the pathophysiology and treatment of asthma.12

Inflammation plays a role in several deadly diseases including cancer, diabetes, obesity, Alzheimer’s and atherosclerosis, to name a few. A brief increase in inflammation is an essential part of wound healing. Unfortunately, too much inflammation can cause damage to healthy tissue including muscles, blood vessels, bones and joints and as such, too much inflammation has been called the juice of death. Preventing and reducing inflammation should then be the prime consideration in dealing with asthma and other chronic diseases..

References

  1. The Allergy Report, Volume 2. The American Academy of Allergy, Asthma & Immunology, Inc. 2000.
  2. Spector SL. Airway inflammation in upper and lower airways. Ann Allergy, Asthma Immunol 1999; 83:435-444
  3. Slavich GM. Life, stress and health: A review of conceptual issues and recent findings. Teach Psychol. 2016 Oct;43(4):346-355 Doi:  10.1177/0098628316662768
  4. Hosseinzadeh A, Thompson PR, et al. Nicotine induces neutrophil extracellular traps. J Leukocyte Biology, 2016; 100 (5): 1105 DOI: 10.1189/jlb.3AB0815-379RR
  5. Busse PJ, Birmingham JM et al. The effect of aging on sputum inflammation and asthma control. J Allergy Clin Immunol. 2016 Oct 7. pii: S0091-6749(16)31115-0. doi: 10.1016/j.jaci.2016.09.015. [Abstract]
  6. Vignola AM, Kips J, Bousquet J. Tissue remodeling as a feature of persistent asthma. J Allergy Clin Immunol 2000; 106:1041-53
  7. Vignola AM et al. Structural consequences of airway inflammation in asthma. J Allergy Clin Immunol 2000; 105: S514-S517
  8. Bento AM, Henderson MB. Airway remodeling: potential contributions of subepithelial fibrosis and airway smooth muscle hypertrophy/hyperplasia to airway narrowing in asthma. Allergy Asthma Proc. 1998; 19:353-8
  9. Busse W. The science of airway remodeling. Presentation at American College of Allergy, Asthma & Immunology Conference. Seattle. November 2000.
  10. Fish JE, Peters SP. Airway remodeling and persistent airway obstruction in asthma. J Allergy Clin Immunol. 1999; 104:509-16
  11. Chetta A et al. Airway remodeling is airway scarring: an issue even in mild asthma. Chest 1997;111:852-857
  12. Djukanovic R. Asthma: A disease of inflammation and repair. J Allergy Clin Immunol. 2000; 105:S522-6