Authorship J E has conducted the literature search and designed the outline of this article. He has also written and revised the article.
Conflicts of interest This article forms part of a supplement sponsored by GlaxoSmithKline. The author (JE) has no conflicts of interest.
Jonas S. Erjefält, PhD, Unit of Airway Inflammation, Department of Experimental Medical Science, BMC D12, Lund University, SE-221 84 Lund, Sweden. Tel: +46 46 2220960 Fax: +46 46 2223098 email: email@example.com
Introduction: Asthma is a complex, heterogeneous and mutifactorial disease and represents a major health problem in Westernised countries. The airway epithelium, with its direct physical contact with luminal triggers, has a major role in determining the nature of inflammation that develops in asthmatic airways.
Objective: The present review aims to provide a brief overview of the numerous ways the airway epithelium can affect and influence the histopathological picture in asthma.
Results and Conclusion: The ways the epithelium aggravates inflammation range from acute responses to luminal triggers such as allergens and infections to the multipathogenic events occurring as a consequence of repeated epithelial damage–repair responses. The airway epithelium also facilitates the selective migration of leukocytes into the airway lumen, a process that is important in regulating inflammatory cell homeostasis. The fact that only some of the important leukocyte subtypes participate in this process cause translational problems and difficulties in the interpretation of luminal samples. To further reveal the nature of the multifaceted involvement of the airway epithelium in inflamed asthmatic airways emerges as a promising goal for identifying new therapeutic strategies.
Please cite this paper as: Erjefält JS. The airway epithelium as regulator of inflammation patterns in asthma. Clin Respir J 2010; 4 (Suppl. 1): 9–14.
Asthma is a chronic inflammatory airway disease and represents a major health problem in Westernised countries. Along with the paramount medical problem and need for more effective treatment, especially in steroid-resistant and severe asthma, there is also a significant cost of medical expenditures. The development of improved therapies is currently slowed down by lack of knowledge about the processes that cause functional disturbances and symptoms in the affected tissues. Although the progress is hampered by the complex nature of chronic tissue inflammation (1–3), it has become much clearer that the airway epithelium has a central role in orchestrating the inflammation in asthma. The aim with this review is to first describe the complexity of an asthma-associated inflammation and then illustrate how the airway epithelium may have multiple roles in determining both acute and more long-term/chronic aspects of the inflammation [the basic features of histopathological changes in asthma has previously been presented in numerous excellent reviews (e.g. (4–8)) and are outside the scope of this review].
The complexity of epithelial-induced inflammation in asthma
Asthma is a common inflammatory disease where the airways are infiltrated by large numbers of immune cells (6, 9). The inflammation is foremost localised to central airways, although more peripheral regions may be involved to a variable extent. Harmful processes caused by tissue leukocytes and structural cells are thought to play a central role in disease aetiology and progression (6). This view is derived from more than a century of examinations of airway tissues or luminal samples (10, 11). In the current era of molecular-based genomic and proteomic approaches, it is, however, easy to oversee the fact that several fundamental questions regarding asthma histopathology remain. The scientific community still argues about which cell types are pathogenic culprits (12–14) and which structural alterations contribute most to symptoms (9, 15). From the wealth of new data produced on asthma-associated inflammation, a double-edged sword emerges. The new findings undoubtedly contribute important pieces of understanding disease but also expose an almost overwhelming complexity of the inflammation present in asthmatic airways. This forwards the possibility that the epithelium is an even more important player for orchestrating inflammation than previously thought.
Historically, linear models have been used to explain the development of pathological changes in asthmatic patients. By this traditional view, primary triggers (e.g. allergen in atopic asthma) are believed to lead initiate a linear chain of events: leukocyte activation, tissue pathology and symptoms. However, it seems that linear models are not particularly good in describing complex inflammatory diseases such as asthma. It has been argued that the disease progression in inflammatory airway diseases should rather be described by a gradually evolving pathology driven by multiple parallel networks of cellular and physiological responses (16–18). Applying this reasoning to asthma, the inflammatory pattern inside the tissue is under constant influence from both primary and confounding secondary environmental or internal factors (Fig. 1). Importantly, as the chronic inflammation evolves, the epithelial responses evoked by the luminal triggers change as a reflection of altered inflammatory status, ongoing damage/repair processes and irreversible structural alterations. In this context, the airway epithelium, with its direct physical contact with luminal triggers, has a major role in determining the nature of inflammation that develops in asthmatics. Indeed, when provoked by luminal stimuli, the airway epithelium swiftly releases a variety of pro-inflammatory and chemotactic mediators (19) that have a profound effect on the way the inflammation develops. The airway epithelium may also contribute to inflammation in more indirect ways, for example, in cases when the epithelium is subjected to damage.
Epithelial damage and repair aggravate inflammation in asthma
As a consequence of an ongoing inflammation or inadequate repair capacity (20–22), the epithelium in asthmatics are frequently subjected to damage and shedding of epithelial cells into the airway lumen (19, 23, 24). Indeed, epithelial damage is a hallmark of asthma and occurs not only in adults but also in children (25). The epithelial disturbances in asthma may have several causes. Among the common mechanisms are accidental release of cytotoxic agents from infiltrating leukocytes and increased fragility of epithelial cell-to-cell contracts (i.e. desmosomes, hemidesmosomes and tight junctions). Also, viral infections are important, especially during asthma exacerbations. Regardless of the nature of epithelial insult, epithelial damage and repair processes result in powerful tissue responses, many of which aggravate the inflammation (18, 26). For example, carefully conducted in vivo studies show that gentle removal of small restricted tracheal epithelial sheets in naïve (or sensitised) animals, without disturbing the basement membrane, leads to several hallmarks of asthma such as plasma extravasation, activation of resident eosinophils (27), hyper-secretion, recruitment of neutrophils and macrophages as well as subepithelial proliferation and remodelling (18, 26–28). Recently, it has been proposed that the epithelial damage in intrinsic asthma may also expose intracellular epithelial epitopes, an event that could lead to activation of an autoimmune component in this type of asthmatics (29, 30).
Taking the available data together, it is clear that the multiple consequences of epithelial damage in a profound way worsen the inflammation and alter the way the airways respond to subsequent allergen and infectious triggers. Hence, to further identify the mechanisms involved in the responses to epithelial damage emerges as highly warranted.
Role of the airway epithelium in cellular homeostasis
It is well established that the airway epithelium has the capacity to regulate a local inflammation in several ways. Thus, apart from being a physical barrier, the epithelium in asthmatics expresses and releases multiple mediators that participate in the recruitment activation, and survival of leukocytes (31–34). Taken together, these actions of the epithelium have an important role to establish the leukocyte infiltration patterns observed in asthmatic airways. The epithelium not only promotes cellular infiltration but also participates in the clearance of senescent leukocytes. The research on leukocyte clearance from inflamed tissues has traditionally been on elimination through apoptosis (35, 36). However, more recent data suggest that in the respiratory tract, transepithelial migration into the airway lumen is an alternative and powerful physiological mode of leukocyte elimination (37, 38). Clues to this hypothesis come from observations in patients and animal models of allergic airway inflammation. For example, after steroid treatment of an allergic inflammation, the resulting decline in tissue eosinophilia occurs without any signs of apoptosis, while there is an uncompromised, or even increased, influx of eosinophils into the airway lumen (39). Additional data show that leukocyte elimination through transepithelial migration fulfil the criteria of a physiological elimination mode: it has a remarkable kinetic capacity (40, 41); it occurs in an active and non-injurious fashion (37, 42); and it occurs during both natural or drug-induced resolution of airway inflammation.
Importantly, in the same way the endothelial cells promote leukocyte traffic from blood vessels into inflamed tissues, the airway epithelium takes an active role in the influx of leukocytes into the airway lumen. This is carried out by a polarised release of chemoattractant molecules from the epithelium, provisional loosening of epithelial junctions and a regulated interaction between epithelial and leukocyte adhesion molecules (37, 43, 44). Indeed, an active facilitation of a non-injurious transepithelial passage of selected leukocytes into the lumen seems to be a general feature of airway epithelial cells (37, 45). The airway epithelium thus acts as a critical determinant for both recruitment and elimination of leukocytes.
Consequences of transepithelial leukocyte migration
The cooperation between leukocytes and epithelial cells in selected elimination of certain leukocytes through luminal egression raises important questions regarding the interpretations of bronchoalveolar lavage (BAL) and sputum samples from asthmatics. Analysis of luminal cells has, since the turn of the century, been used to diagnose airway diseases (46–49). Despite the widespread use of luminal samples, the biological function of luminal cells has remained largely unexplored. As suggested for most hollow organs, one function is as a first-line defence system: ‘neutralize the enemy at the surface before they enter the host tissue’(43, 50, 51). Alternatively, as outlined earlier, luminal influx of leukocytes may also function as a natural cell elimination of old senescent tissue cells (37, 38, 52, 53). Thus, the mode by which leukocytes enter the airway lumen has significant bearings for our interpretation of sputum and BAL data.
If many worn out and senescent leukocytes enter the lumen as part of their natural elimination, do luminal samples then give a representative picture of the active inflammation in the tissue? We recently explored this issue in small airways of chronic obstructive pulmonary disease (COPD) patients. In 10 patients with mild COPD (Global Initiative for Chronic Obstructive Lung Disease stages I and II), small airways were identified in surgical resections and stained for leukocyte populations: T-lymphocytes (CD4+,CD8+,CD3+), B lymphocytes (CD20+), monocytes/macrophages (CD68+), neutrophils (MPO+) and eosinophils (ECP+). Using consecutive sections from >100 individual small airways, each cell population was quantified in the airway wall and lumen. In summary, while the tissue infiltration was dominated by lymphocytes and mast cells, the luminal content in the same airways was characterised by a marked dominance of macrophages and neutrophils (54). These data highlight the difficulty in assessing, e.g. small airway inflammation through luminal sampling. Naturally, the lumen–tissue correlation varies greatly between cell types and clinical settings from very good, as for neutrophils in cystic fibrosis (55), to poor, as for mast cells that rarely leave the tissue and are thus ‘invisible’ in most luminal samples. It is therefore not surprising that luminal sampling and tissue analysis frequently yield a different picture of the airway inflammation (54, 56, 57). More detailed work seems needed to identify luminal mediators/parameters that also reflect the activity of the tissue-dwelling cells that are not represented in standard BAL and sputum samples.
Under normal conditions, the removal of luminal leukocytes occurs efficiently without causing inflammation. In pathogenic situations, the epithelial mucociliary clearance, transepithelial migration or phagocyte system may, however, be dysfunctional or disturbed. Formation of airway plugs, which frequently occurs in inflamed airways, efficiently prevents the mucociliary transport. In such cases, luminal cells are doomed to undergo either primary or secondary necrosis. There is ample clinical evidence that luminal necrosis occurs to a large extent in inflammatory airway conditions including asthma (38,55,58). Indeed, airway plugs from asthmatics are, apart from their mucus content, characteristically rich in disintegrating cells and cell debris that are in direct contact with the underlying epithelium. To what extent this actually affects the epithelial cells is currently not known. However, the potential importance of such an interaction is highlighted by observations that neutrophils undergoing secondary necrosis have the capacity to damage airway epithelial cells (59, 60) and thus, triggering the potent epithelial damage–repair processes discussed earlier.
Taken together, the examples earlier illustrate the critical role of the airway epithelium in regulating airway inflammation in asthmatic airways. The ways the epithelium aggravate inflammation range from acute responses to luminal triggers such as allergens and infections to the multipathogenic events occurring as a consequence of repeated epithelial damage-repair responses. The highly selective transepithelial migration of leukocytes into the airway lumen limits luminal assessments in asthmatic patients. Although approaches such as BAL and induced sputum are valuable and irreplaceable tools in today's research, there are thus significant shortcomings in the translation of luminal data to events inside the inflamed tissue. Hence, ideally, the complexity of chronic airway diseases should be explored by combining methodological approaches that together explores both the luminal and the histological aspects of the inflammation. Considering the amount of intertwined inflammatory pathways operating during an epithelium-driven inflammation, it seems that increased research efforts are needed to reveal the true and complex nature of epithelial involvements in asthma pathology.