Associate editor: P.S. Foster
Role of cytokines and chemokines in bronchial hyperresponsiveness and airway inflammation

https://doi.org/10.1016/S0163-7258(02)00217-6Get rights and content

Abstract

Over the last decade there has been an intense interest in the potential role of cytokines and chemokines as important mediators in various atopic diseases, including asthma and the mechanisms by which these mediators regulate airway inflammation and bronchial hyperresponsiveness. This research effort has recently culminated in the publication of clinical studies that have assessed the role of interleukin (IL)-4 [Borish et al., Am J Respir Crit Care Med 160, 1816–1823 (1999)], IL-5 [Leckie et al., Lancet 356, 2144–2148 (2000)], and IL-12 [Bryan et al., Lancet 356, 2149–2153 (2000)] in allergic asthma, and the results have been disappointing. This is not surprising given the pleiotropic role cytokines play in the allergic response confirmed by numerous animal studies providing evidence of functional redundancy. The alternative view is that our current concepts in asthma pathogenesis need significant revision. This review will summarise the evidence for the role of cytokines and chemokines in various aspects of asthma pathophysiology; namely, bronchial hyperresponsiveness, eosinophil recruitment to the airways, mucus secretion, and airway remodelling.

Introduction

A hallmark feature of asthma is the presence and activation of inflammatory cells in the airways, notably eosinophils, basophils, mast cells, and T lymphocytes, and stimulation of structural/resident cells, including those of the airway epithelium, fibroblasts, smooth muscle, and fibroblasts. The potential for release of a plethora of asthma mediators acting either individually or synergistically with other mediators to stimulate a variety of cell types highlight the complexity of airway inflammation (Barnes et al., 1998). During an acute exacerbation of asthma to antigen, pre-formed and lipid mediators released from immunoglobulin (Ig)E-bearing cells have the potential to stimulate airway smooth muscle contraction, to activate neural reflexes, and to stimulate mucus secretion and bronchial wall oedema, thereby leading to the clinical manifestations of this disease; namely, cough, wheeze, chest tightness, and variability in peak expiratory flow. Similarly, antigen presentation to T helper (Th)2 memory cells leads to the generation of cytokines involved in the recruitment, activation, and maintenance of inflammatory cells in the airways and to stimulate the release of growth factors and chemokines from structural cells, e.g., epithelium. Growth factors released from various inflammatory or structural cells act in an autocrine or paracrine fashion to stimulate the proliferation of structural cells, leading to goblet cell hyperplasia, airway smooth muscle thickening, fibroblast proliferation and activation, collagen deposition beneath the basement membrane, and altered neural reflexes; collectively known as airway remodelling. Thus, cytokines have the potential not only to orchestrate the recruitment of inflammatory cells to the airways, but also to alter the structural integrity of the airways Elias et al., 1999, Fish & Peters, 1999.

An important characteristic feature of asthma is bronchial hyperresponsiveness (BHR), a term used to describe the fact that asthmatic subjects are invariably more sensitive to a variety of stimuli, including allergens, pollutants, cold air, exercise, distilled water, and nonphysiological challenges, including bradykinin, histamine, and methacholine (Fig. 1). It is generally accepted that alterations in the structure of the airways can account for the differences in airway responsiveness between asthmatic subjects and healthy individuals. This baseline hyperresponsiveness can be altered experimentally (Cockcroft & Murdock, 1987) or naturally (Sotomayor et al., 1984) following exposure of mild asthmatic subjects to airborne allergens, and these events can reverse spontaneously following removal of antigen from the environment or with glucocorticosteroid treatment. While structural remodelling is an important determinant of baseline airway responsiveness (Kips & Pauwels, 1999), the wide variability in responsivity to spasmogens in mild asthmatic subjects (Cockcroft et al., 1977) and differential expression of hyperresponsiveness to different offending stimuli (O'Connor et al., 1999) indicate that mechanisms additional to structural remodelling per se contribute toward baseline hyperresponsiveness.

Inflammatory cells, including CD4+ T lymphocytes (Romagnani, 2000) and eosinophils (Gleich, 2000), are thought to play important roles in the pathogenesis of asthma. The role of eosinophils is central to our current thinking concerning this disease, and while there are numerous reports supporting this view, this is not a universal finding (Smith & McFadden, 1995). A similar discrepancy has also been demonstrated in various murine models of allergic inflammation. Thus, numerous reports support a role for eosinophils in the ‘asthma’ response Hogan et al., 1998c, Cieslewicz et al., 1999. However, under different experimental conditions, BHR can be documented independently of the presence of eosinophils Mathur et al., 1999a, Tournoy et al., 2000b, a finding that is not restricted to murine models and recently has been documented in trials investigating the clinical efficacy of anti-interleukin (IL)-5 and IL-12 Bryan et al., 2000, Leckie et al., 2000. A characteristic feature of eosinophils recruited to the airways in asthma is the degranulation of these cells and deposition of cationic proteins, including major basic protein (MBP). These proteins and MBP, in particular, are thought to play an important role in asthma pathogenesis (Gleich, 2000). Interestingly, there is some debate as to whether murine eosinophils degranulate once recruited to the airways following an inflammatory insult. In some studies, there is a demonstrable lack of evidence for deposition of extracellular granule products in the airways, despite the presence of BHR Eum et al., 1995, Lee et al., 1997, Persson & Erjefalt, 1997, Stelts et al., 1998, Malm-Erjefalt et al., 2001, although this is disputed Hogan et al., 1998c, Hamelmann et al., 1999a, Mould et al., 2000. Whether this discrepancy is related to the different antigen protocols used in these studies and, hence, to the degree of eosinophil activation is unclear. However, it recently has been shown that mice deficient in MBP (Denzler et al., 2000) or eosinophil peroxidase (Denzler et al., 2001) still retain the capacity to develop BHR. Hence, it is clear that eosinophil-independent mechanisms can contribute toward BHR, and it is self evident that multiple pathways are likely to operate in asthma to account for this physiological phenomenon Callard et al., 1999, Hyland, 1999. Hence, in this review, eosinophil recruitment and BHR will be treated separately.

Section snippets

Role of T lymphocytes in allergic inflammation

Different T lymphocyte functions (cytolysis, induction of apoptosis, B-cell help, and inflammatory cell recruitment) are mediated by different T lymphocyte subsets that can be identified by the effector molecules (cytokines) they secrete (Mosmann et al., 1986). CD4+ T lymphocytes are classified as Thl cells, which provide immunity to pathogens such as Mycobacterium tuberculosis and as Th2 cells, which give rise to allergic inflammation. Thl lymphocytes secrete interferon (IFN)-γ, IL-2, and

Dale's criteria for mediator identification

In the 1930s, Dale enunciated a number of criteria that had to be met before a substance was accorded the status of neurotransmitter (Dale, 1933) and these criteria often have been used in order to determine whether an endogenous substance has features characteristic of an inflammatory mediator. These criteria include (1) evidence for the generation or release of substance within the tissue, (2) the functional effects of the endogenous substance should be mimicked in vitro and in vivo, (3) the

Cytokine expression in the airways

The first criterion proposed by Dale is that the mediator in question must occur naturally and should be present at the relevant site, in this case, human airways. However, it is clear that for many cytokines, their documentation within the lungs is dependent upon the recruitment of inflammatory cells.

Using a variety of techniques, ranging from quantification of protein levels to in situ hybridisation techniques, a number of studies have assessed the presence of many cytokines in BAL fluid and

Chemokines

Chemokines are a group of small molecular mass peptides (8–10 kDa) that have a number of biological effects, including chemotaxis, immunoregulation, and cell growth, and that are classified into families of either N-terminal cysteine (C) residues, which can be separated by any amino acid (X); namely, CXC, CC, and C Alam, 1997, Mantovani, 1999. Of particular interest is the role of CC chemokines, including eotaxin-1, eotaxin-2, eotaxin-3, regulated on activation normal T-cell expressed and

Conclusion

It is abundantly clear that Th2-like cytokines and chemokines are constituents of animal and human airways, and there has been adequate demonstration that acute exposure or overexpression of some cytokines and chemokines can increase airway responsiveness to spasmogens (Table 1). Similarly, during an inflammatory insult, the release of these mediators can be documented and is associated with BHR. In contrast, removal of these substances or their signalling processes can impair the development

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