Allergy, Asthma, and Inflammation: Which Inflammatory Cell Type Is More Important?

<p/> <p>A recent review in <it>Allergy, Asthma, and Clinical Immunology </it>suggested that eosinophils play a minor role, if any, in the inflammatory spectrum of asthma and allergic inflammation. The article that dealt with mast cells suggested that the presence of these important cells within the smooth muscle layer in asthmatic airways renders this cell type primal in asthma and an obvious and important target for therapy. This article proposes that in a complex inflammatory milieu characterizing the complex syndromes we call asthma, no single cell phenotype is responsible for the condition and thus should be a sole target for therapeutic strategies. Our reductionist approach to research in asthma and related conditions has provided us with convincing evidence for multiple roles that immune, inflammatory, and structural cell types can play in complex diseases. The next stage in understanding and ameliorating these complex conditions is to move away from the simplistic notion of one cell type being more important than another. Instead, what is needed is to acquire knowledge of intricate and exquisite biological systems that regulate such conditions in both health and disease involving various cell types, mediators, pharmacologically active products, their multifaceted capacities, and their socio-biological networking.</p

Leukotriene receptor antagonists in the treatment of asthma: Implications for eosinophilic inflammation

Recent advances in the treatment and management of asthma have suggested that leukotriene (LT) receptor antagonists may be very beneficial as a second generation therapy with steroid-sparing properties and negligible side effects. These agents have shown interesting effects on peripheral blood and sputum eosinophils. A major contributor to the damage in the airway of asthmatic patients is the eosinophil, which, upon activation, releases a battery of granule-associated cytotoxic, cationic proteins, including the major basic protein and eosinophil peroxidase, and membrane-derived de novosynthesized bioactive lipid mediators, including LTC 4 , LTD 4 and LTE 4 , as well as platelet activating factor. These products have deleterious effects on the airway tissue including mucosal and smooth muscle layers. Accumulating evidence suggests that these agents may also influence the accumulation and maintenance of eosinophilic responses at the site of inflammation. This article reviews the possible anti-inflammatory mode of action of these therapies. It also discusses where there may be a gap in the knowledge regarding the potential direct and indirect effects of LT modifiers on eosinophil function and recruitment. Key Words: Asthma; Eosinophil; Inflammation; Leukotriene Les antagonistes des récepteurs des leucotriènes dans le traitement de l&apos;asthme : implications pour l&apos;inflammation éosinophile RÉSUMÉ : Les progrès récents réalisés dans le traitement et la prise en charge de l&apos;asthme laissent croire que les antagonistes des récepteurs des leucotriènes (LT) peuvent être très bénéfiques comme traitement de deuxième génération avec des propriétés permettant de réduire les stéroïdes et des effets secondaires négligeables. Ces agents ont démontré des effets intéressants sur les éosinophiles contenus dans l&apos;expectoration et dans le sang périphérique. Un des principaux responsables des dommages causés aux voies aériennes des patients asthmatiques est l&apos;éosinophile, qui, lorsqu&apos;il est activé, libère une gamme de protéines cationiques, cytotoxiques associées aux granules de l&apos;éosinophile, incluant la protéine majeure basique et la péroxidase de l&apos;éosinophile, et des médiateurs lipidiques bioactifs néoformés et dérivés de la membrane, comprenant les LTC4, LTD4 et LTE4 de même que le PAF. Ces produits ont des effets délétères sur les tissus des voies aériennes y compris sur les couches des muqueuses et du muscle lisse. Un nombre grandissant de preuves permettent de croire que ces agents pourraient aussi influer sur l&apos;accumulation et le maintien des réponses éosinophiles au site de l&apos;inflammation. Le présent article passe en revue le mode d&apos;action antiinflammatoire potentielle de ces traitements. Il discute également des endroits où il peut y avoir des failles dans les connaissances concernant les effets directs et indirects potentiels des modificateurs des LT sur la fonction et le recrutement éosinophile. A sthma is a heterogeneous and complex condition afflicting a wide range of population of varying age and sex. It is now generally recognized that the disease is caused mainly by inflammation in the airways Activated T cells and eosinophils are thought to play a major role in asthma, and the numbers of these cells correlate broadly with disease severity (1). Mucosal damage in chronic asthma is believed to be the consequence of cytotoxic and proinflammatory mediator release from activated eosinophils (2,3). These include cytotoxic granule proteins (major basic protein, eosinophil cationic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin) together with phospholipidderived, pharmacologically active mediators. Cytokines derived from T helper (Th) 2-type cells, particularly interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), are thought to regulate eosinophil activation and promote their survival (4,5). IL-5 is an obligatory terminal differentiator of eosinophil precursors (6). SULPHIDOPEPTIDE (CYSTEINYL) LEUKOTRIENES Eosinophils are a rich source of the sulphidopeptide leukotrienes (2). These are de novo-synthesized lipid mediators derived from arachidonic acid (AA) by the action of phospholipase A 2 (PLA 2 ) (7). AA is found in association with the plasma membrane as well as cytoplasmic lipid bodies in these cells (8), and is metabolized through one of two pathways, cyclo-oxygenase and lipoxygenase (9). The former leads to the generation of prostaglandins, thromboxanes and prostacyclins. The second pathway, via the 5-lipoxygenase (5-LO) enzyme acting in concert with a cofactor, 5-LO activating protein (FLAP), generates leukotrienes (LTs), including LTB 4 , LTC 4 , LTD 4 and LTE 4 (10). The 5-LO enzyme cleaves AA to form 5-hydroperoxy eicosatetranoic acid [5-HPETE] and the subsequent synthesis of an unstable intermediate epoxide (LTA 4 ), which is translocated to the perinuclear membrane (11). In turn, LTA 4 rapidly converts to either LTB 4 (via the action of LTA 4 hydrolase), or the cysteinyl LT LTC 4 (5S-hydroxy-6R,S-glutathionyl-7,9,-trans-11,14-cis-eicosatetraenoic acid) through the action of LTC 4 synthase in the nuclear membrane. This is achieved by adding the tripeptide glutathione onto LTA 4 (7). Eosinophils produce negligible amounts (6 ng/10 6 cells) of LTB 4 (5S-12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid) (12) compared with up to 200 ng/10 6 cells from neutrophils. LTB 4 is a chemotactic, priming and activating factor for leukocytes, including neutrophils (13). In contrast, human eosinophils generate relatively large quantities of LTC 4 (up to 70 ng/10 6 cells) after stimulation with the calcium ionophore A23187 (14). In general, eosinophils obtained from asthmatic subjects appear to produce more LTC 4 than those from normal healthy donors (15,16). Furthermore, co-culture of eosinophils with endothelial cells (17), or exogenous addition of cytokines, eg, IL-3, IL-5, GM-CSF and tumour necrosis factor-alpha (TNFa) was shown to result in the upregulation of ionophore-induced release of LTC 4 When LTC 4 is formed, it is transported actively out of the cell. LTD 4 and LTE 4 are produced from LTC 4 by the removal of glutamic acid (via the action of -glutamyl transpeptidase) and glycine (via the action of dipeptidase), respectively (7,9). LTC 4 , D 4 and E 4 collectively form the activity previously recognized as &apos;slow reacting substance of anaphylaxis&apos;, due to their prolonged in time spasmogenic effects on smooth muscles. Although LTD 4 and LTE 4 are rapidly degraded in the body through oxidative metabolism, small amounts of LTE 4 can be measured in the urine (21). Interestingly, in humans, the leukotriene pathway, via 5-LO, is observed only in myeloid cells, ie, mast cells, basophils, neutrophils, eosinophils and alveolar macrophages (22). Recent studies have suggested that cysteinyl LTs may also have selective eosinophilotactic activity (23,24). LT RECEPTORS Two receptors for cysteinyl LTs have been identified on smooth muscle cells, namely, Cys-LT1 and Cys-LT2. Cys-LT1 is now recognized as the probable regulating receptor for bronchial smooth muscle contraction and, thus, may be directly relevant to asthma treatment (25). Cys-LT2, on the other hand, appears to be mainly involved in pulmonary vein contraction (26). In addition to LTD 4 , both LTC 4 and LTE 4 bind to Cys-LT1, although LTE 4 exhibits a greatly reduced binding capacity (25). There is, however, no evidence available in the literature to suggest that eosinophils express either of these two receptors for LTs. One exception is the observation that HL-60 cells, which were differentiated into eosinophils, in vitro, expressed a very low affinity LTD 4 receptor (Kd 41.91 nM) (27). However, these cells may not reflect fully all the properties and the biological profile of circulating mature eosinophils. EVIDENCE FOR A BIOLOGICAL ROLE FOR LTS IN ASTHMA Evidence has accumulated to suggest that, in vivo, LTs are among the most potent constrictors of airway smooth muscle and are, thus, major players in the complex picture of asthmatic inflammation. A substantial amount of the published literature shows that LTs are critical elements in the development, progression and chronicity of the inflammatory response associated with various clinical presentations of asthma (28-30). For instance, both LTC 4 and LTD 4 , when inhaled, are an order of magnitude greater in pharmacological potency than histamine in inducing airflow obstruction in normal subjects, and their effects lasted longer. In these studies, asthmatic airways appeared to be more sensitive (100 to 1000 times) to inhaled cysteinyl LTs than those of nonasthmatic subjects. These patients also demonstrated increased bronchial hyperresponsiveness to methacholine or histamine following inhalation of LTC 4 and LTD 4 (31). 454 Can Respir J Vol 6 No 5 September/October 1999 Moqbel LT MODIFIERS The potential contribution of the sulphidopeptide LTs in bronchoconstriction has been identified by recent developments in the field of LT-modifying therapies Two new strategies aimed at blocking the effects of the LT pathway have recently gained rapid momentum and provided hope for better and more efficient treatment for asthma. The first area relates to the development of LT synthesis inhibitors, such as zileuton and BAYx1005. These were shown to produce significant reductions in LT generation levels, including both LTB 4 and the cysteinyl LTs (34,35). Zileuton inhibits the 5-LO and, thus, prevents the synthesis of LTA 4 (34). In contrast, BAYx1005 is an antagonist of FLAP, which prevents the translocation of 5-LO and blocks the formation of LTA 4 (35). This area of FLAP inhibition is currently under intensive development because it will determine the role of other products of 5-LO metabolic pathway in asthmatic inflammation. More recently, second generation LTD 4 receptor antagonists have been introduced. These new agents have the potential to inhibit the biological activities of LTD 4 and the other members of the cysteinyl LT family by competing for their receptors on smooth muscle cells (36). These include montelukast (Singulair [Merck Frosst Canada Inc, Kirkland, Quebec]), zafirlukast (Accolate [Zeneca Pharma Inc, Mississauga, Ontario]), and pranlukast (Ultair, SmithKline Beecham, United Kingdom), which, when used in inhalation challenge studies, in vivo, have demonstrated a greater potency in blocking LT effects and a better safety record (37-40). LT MODIFIERS AND THE EOSINOPHIL IN ASTHMA The clinical effects of LT receptor antagonists (including montelukast and zafirlukast) on dampening the pathophysiological sequelae of inflammation in asthma have been amply reviewed previously (37-41). These reports show clearly that these agents have significant efficacy in controlling asthma symptoms in a large percentage of patients. The present paper concentrates on the as yet unanswered question of whether LT receptor antagonists are anti-inflammatory drugs, potent bronchodilators or both. In particular, the issue of the biological relevance and efficacy of LT receptor antagonists from the perspective of their effect on the eosinophil is addressed. As stated earlier, the latter is a highly relevant inflammatory cell type in asthmatic airway mucosal tissu