Sophie P. Farooque

Leukotriene E4: Perspective on the forgotten mediator

Leukotriene (LT) E(4) mediates many of the principal features of bronchial asthma, such as bronchial constriction, hyperresponsiveness, eosinophilia, and increased vascular permeability. Furthermore, it is the most stable of the cysteinyl leukotrienes (CysLTs) and can be active at the site of release for a prolonged time after its synthesis. There might be several reasons why LTE(4) has been forgotten. LTE(4) demonstrated low affinity for CysLT(1) and CysLT(2) receptors in equilibrium competition assays. It was less potent than other CysLTs in functional assays, such as calcium flux, in cells transfected with CysLT(1) and CysLT(2). The introduction of CysLT(1) antagonists into clinical practice diverted interest into CysLT(1)-related mechanisms, which were mediated mainly by LTD(4). However, experiments with animal models and human studies have revealed that LTE(4) has unique characteristics that cannot be explained by the current knowledge of CysLT(1) and CysLT(2). These activities include its potency relative to other CysLTs to increase airway responsiveness to histamine, to enhance eosinophilic recruitment, and to increase vascular permeability. Asthmatic airways also demonstrate marked in vivo relative hyperresponsiveness to LTE(4), especially in patients with aspirin-sensitive respiratory disease. This has stimulated a search for additional LT receptors that would respond preferentially to LTE(4) stimulation.

Aspirin-Sensitive Respiratory Disease

Aspirin-sensitive respiratory disease (ASRD) is a condition characterized by persistent and often severe inflammation of the upper and lower respiratory tracts. Patients develop chronic eosinophilic rhinosinusitis, nasal polyposis, and asthma. The ingestion of aspirin and other cyclooxygenase-1 (COX-1) inhibitors induces exacerbations of airway disease that may be life-threatening. Thus, aspirin sensitivity is a phenotypic marker for the syndrome, yet nearly all affected individuals can be desensitized by the administration of graded doses of aspirin, leading to long-term clinical benefits. Patients with aspirin sensitivity are often able to tolerate selective COX-2 inhibitors. The pathogenesis of ASRD is underpinned by abnormalities in eicosanoid biosynthesis and eicosanoid receptor expression coupled with intense mast cell and eosinophilic infiltration of the entire respiratory tract. This review focuses on the molecular, cellular, and biochemical abnormalities characterizing ASRD and highlights unanswered questions in the literature and potential future areas of investigation.

1α,25-Dihydroxyvitamin D3 promotes CD200 expression by human peripheral and airway-resident T cells

Background CD200, a cell-surface immunoglobulin-like molecule expressed by immune and stromal cells, dampens the pro-inflammatory activity of tissue-resident innate cells via its receptor, CD200R. This interaction appears critical for peripheral immune tolerance, particularly in the airways where excessive inflammation is undesirable. Vitamin D contributes to pulmonary health and promotes regulatory immune pathways, therefore its influence on CD200 and CD200R was investigated. Methods CD200 and CD200R expression were assessed by qPCR and immunoreactivity of human lymphoid, myeloid and epithelial cells following 1α,25-dihydroxyvitamin D3 (1α,25VitD3) exposure in vitro and in peripheral T cells following 1α,25VitD3 oral ingestion in vivo. The effect of 1α25VitD3 was also assessed in human airway-resident cells. Results 1α25VitD3 potently upregulated CD200 on peripheral human CD4+ T cells in vitro, and in vivo there was a trend towards upregulation in healthy, but not asthmatic individuals. CD200R expression was not modulated in any cells studied. CD200 induction was observed to a lesser extent in CD8+ T cells and not in B cells or airway epithelium. T cells isolated from the human airway also responded strongly to 1α25VitD3 to upregulate CD200. Conclusions The capacity of 1α,25-dihydroxyvitamin D3 to induce CD200 expression by peripheral and respiratory tract T cells identifies an additional pathway via which vitamin D can restrain inflammation in the airways to maintain respiratory health.

T cells producing the anti-inflammatory cytokine IL-10 regulate allergen-specific Th2 responses in human airways.

Murine models suggest a critical functional role for the anti‐inflammatory cytokine IL‐10 in local regulation of allergic airways inflammation. There is little corresponding information on human airway cells. This study aimed to investigate whether local IL‐10 production regulates responses by respiratory mucosal leucocytes isolated from nasal polyps.

Mechanisms of Aspirin-Sensitive Respiratory Disease – A Two-Compartment Model

Cysteinyl LTs The hallmark of ASRD is excessive cysteinyl (Cys) LT production both in the steady state and for several hours after aspirin challenge [6] . Urinary LTE 4 levels, as a measure of the total body production of CysLTs, are a mean 6-fold higher in patients with ASRD and still increasing 4-fold higher after aspirin challenge [7] . To date, the question of whether ASRD is associated with a fundamental, predetermined abnormality in the production of CysLTs or whether it is simply a consequence of greater numbers and the activation of granulocytes, such as eosinophils and mast cells [8, 9] , remains unanswered – although these possibilities are not mutually exclusive. It has been reported that the numbers of cells immunoreactive for LTC 4 synthase are significantly elevated a priori in the bronchial mucosa of aspirin-sensitive patients, as compared with aspirin-tolerant patients [10] . The expression of LTC 4 synthase in aspirin-sensitive patients correlated with the patients’ bronchial response In August of 1897 Felix Hoffmann, working at the Bayer factory in Germany, developed aspirin. He synthesised the acetylated form of salicylic acid as a treatment for his father’s arthritis and since then aspirin has become the most widely used medicine of all time [1] . Around 35 years later, the French physician Widal first described the association of aspirin sensitivity, asthma and nasal polyps [2] , a phenomenon further popularized by Samter and Beer [3] in 1968. Aspirin-sensitive respiratory disease (ASRD) is a phenotype of asthma that may be aggressive and refractory to treatment. Patients with ASRD are over-represented in the severe asthma group and 50% of the patients with aspirin sensitivity are steroid dependent [4] . ASRD affects women more frequently than men. Rhinorrhoea and nasal congestion are usually the first symptoms. Furthermore, the condition is rare in childhood with the peak age of onset in the early 30s. It is a condition that progresses from the upper to the lower respiratory tract and asthma manifests around 1–5 years after the onset of rhinitis [5] . The aetiology of ASRD is complex but most investigators are agreed that the reaction to aspirin is not mediated by allergic mechanisms. Most evidence points towards an abnormality of arachidonic acid (AA) metabolism. AA is a substrate for both the production of Published online: October 2, 2006

Aspirin sensitivity and eicosanoids

Aspirin sensitive respiratory disease (ASRD) was first described in 1922 by the French physician Widal.1 It is characterised by asthma, chronic rhinosinusitis and nasal polyps on a background of aspirin sensitivity. The condition is a distinct, often aggressive, clinical syndrome, and it is rare in childhood with a peak age of onset in the early 30s.2 Rhinorrhoea and nasal congestion are typically the first symptoms with asthma usually manifesting 1–5 years after the onset of rhinitis.3 Once the disease is established, ingestion of aspirin induces the release of critical mediators that provoke an acute exacerbation of rhinosinusitis and asthma. It is estimated that 5–10% of all patients with asthma are aspirin sensitive.4 Often poorly responsive to treatment, patients with aspirin sensitivity are over-represented in the severe asthma group and 50% are steroid dependent.5 The aetiology of ASRD is complex, but most investigators are agreed that the reaction to aspirin is not mediated by allergic mechanisms. Most evidence points towards an abnormality of arachidonic acid (AA) metabolism. AA is a substrate for both the production of leucotrienes (via the 5-lipoxygenase (5-LO) pathway) and prostanoids (via the cyclooxygenase (COX) pathway). ASRD is characterised by excessive cysteinyl leucotriene (CysLT) production both in the steady state and for several hours after aspirin challenge.6 Urinary leucotriene E4 (LTE4) levels, as a measure of total body production of CysLTs, are a mean sixfold higher in patients with ASRD, increasing fourfold higher still after aspirin challenge.7 To date, the question of whether ASRD is associated with a fundamental predetermined abnormality in the production of CysLT8 or whether …