Journal of Allergy and Clinical Immunology
Inflammatory cells in asthma: Mechanisms and implications for therapy☆
Section snippets
Inflammatory cells in asthma
Asthma is a chronic airway inflammatory disease characterized by infiltration of the airway T cells. In both normal and asthmatic airway mucosa, the prominent cells are the T lymphocytes, which are activated in response to antigen stimulation, or during acute asthma exacerbations, and produce high levels of cytokines. They are subdivided into two broad subsets according to their surface cell markers and distinct functions: the CD4+ (T helper) and the CD8+ (T cytotoxic) cells. CD4+ cells are
Cytokines
The initial indication for cytokine involvement in the pathogenesis of asthma came from studies performed in the early 1990s showing that atopic asthma was associated with local TH2 cytokine expression. IL-3, IL-4, IL-5, and GM-CSF were upregulated in asthmatic patients relative to control subjects. These cytokines were significantly upregulated after antigen challenge, and their receptors were identified locally on the surface of inflammatory cells.6 Studies have confirmed the existence of the
Leukotrienes
Although not cytokines, the CysLTs have emerged as important mediators in asthma and as modulators of cytokine function. Leukotrienes are lipid mediators resulting from the catabolism of the arachidonic acid (AA) released from the cell membrane by phospholipase A2 after cell activation. After its release, AA is metabolized either by the cyclooxygenase pathway, generating prostaglandins and thromboxanes, or by the 5-lipoxy-genase (5-LO) pathway, which in association with 5-LO-activating protein
Mast cells
Mast cells make up a small proportion of cells recovered by BAL, but within the airway tissue as many as 20% of inflammatory cells are mast cells.34, 35 In BAL specimens, normal mast cell numbers range from 0.02% to 0.48%.36, 37 Normal mast cell numbers36, 38, 39, 40, 41 or increases of 2- to 6-fold, have been reported in patients with atopic34, 37, 42, 43, 44, 45, 46, 47 as well as nonatopic asthma.48 On the airway surface and in the submucosa, mast cells are mostly the mucosal type,
Basophils
Basophils possess high levels of the FcϵRI receptor and are capable of an immediate response to allergen. Although basophils are not present in healthy airways, they are present in the airways of asthmatic persons under a variety of circumstances. Basophils have been reported in the sputum of patients with symptomatic asthma,62 and recent studies have demonstrated basophil infiltration of airways in cases of fatal asthma63, 64 and in bronchial biopsy specimens from patients with asthma.65, 66
Macrophages
Macrophages are the predominant cell recovered by BAL in both nonasthmatic and asthmatic persons. Although most macrophages are recovered from alveoli, small volume lavage or lavage of isolated airway segments72 supports macrophage predominance in conducting airways as well as alveoli. Thus, macrophages are well positioned to respond to and regulate inflammation along the airway. Although the prominence of macrophages along the airway surface and their diverse functions strongly implicate
Anti-IgE
In the pathogenesis of allergic disease, IgE plays a central role. Mast cells and basophils are the primary cells that bear the high-affinity IgE receptor, and a critical role for these cells is supported by the effect of anti-IgE therapy on the airway response to allergen bronchoprovocation. Omalizumab is a humanized murine monoclonal antibody (rhuMAb-E25) that binds to the same portion of IgE as the high-affinity IgE receptor. Because the anti-IgE antibody and the cell surface receptor
SAC
The cellular, mediator, and cytokine responses underlying the physiologic response to allergen exposure have been examined with the SAC model, in which allergen is instilled directly into an airway segment during bronchoscopy and events occurring within minutes, hours, or days can be examined, generally by BAL. This model also has been used to examine the effects of prednisone and leukotriene modifier therapy on inflammatory changes. Cellular effects of these asthma medications on BAL cells
Eosinophils
Activated T cells and eosinophils are important pathophysiologic elements in asthma (Fig 4).
Cyslts
Eosinophils are a rich source of CysLTs103 that are derived from native AA by the action of phospholipase A2.107 Human eosinophils synthesize and release relatively large concentrations of LTC4 (as much as 70 ng/106 cells) after stimulation with the calcium ionophore A23187.108 In general, eosinophils obtained from asthmatic subjects appear to produce more LTC4 than do those from healthy control donors.109, 110 Experimentally, coculture of eosinophils with endothelial cells111 or exogenous
Leukotriene modifiers
The contribution of the CysLTs in bronchoconstriction has been inferred from recent developments in the field of leukotriene-modifying therapies.33, 119, 120 LTD4 receptor antagonists (montelukast, zafirlukast, and pranlukast) inhibit the biologic activities of LTD4 and the other members of the CysLT family by competing for their receptors on smooth muscle cells.121 Clinical trials of LTRAs, including montelukast and zafirlukast,122, 123, 124, 125, 126 have significantly controlled asthma
Conclusions
The sensitized reaction to an allergen includes responses from T cells, mast cells, basophils, macrophages, and eosinophils. In the case of asthma and allergic rhinitis, the mediators released from these cells perpetuate the asthmatic inflammatory response, and the CysLTs have emerged as one of the important mediators.
In human beings, the 5-LO pathway is expressed only in myeloid cells, including mast cells, basophils, neutrophils, eosinophils, and alveolar macrophages. Eosinophils from
Questions and discussion
Marc Peters-Golden: Qutayba, is the epithelium capable of differentiating into mesenchymal-like cells, as they appear to do in the kidney? Could the smooth muscle cells that appear to be pushing up into the epithelial layer actually be the basal epithelial cells that are differentiating into smooth muscle cells instead?
Qutayba Hamid: We did not see any evidence that epithelial cells go to something that is not a cytocuritin-positive cell or what would probably look like a smooth muscle.
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Reprint requests: Qutayba Hamid, MD, PhD, Professor of Medicine, Meakins-Christie Laboratories, McGill University, 3626 St-Urbain St, Montreal, Quebec, Canada H2X 2P2.