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  • Elevated production of cysLTs in

    2021-07-23

    Elevated production of cysLTs in PD153035 hydrochloride and rhinitis in general and aspirin-sensitive disease in particular10, 11, 26, 27 has been implicated in causing epithelial cell activation and excessive mucus secretion, which characterize these diseases.2, 28 It is of particular interest, therefore, that we have been able to show for the first time that the distribution of cysLT2 in the nasal mucosa, both in health and disease, differs from that of cysLT1, with a predominance of cysLT2 on glands and epithelium (and, indeed, mucosal leukocytes in the normal controls). Presumably, separate mechanisms ultimately result in elevated expression of cysLT1 on leukocytes in aspirin-sensitive rhinosinusitis and elevated expression of cysLT2 on structural cells of the mucosa. Our findings raise intriguing implications for the treatment of rhinosinusitis, centered on the relative roles of cysLT1 and cysLT2 in disease pathogenesis. In some reports,29, 30 functional activation of key cells such as eosinophils by cysLTs seems to be blocked extensively by specific cysLT1 antagonists alone, despite the fact that these cells express both cysLT1 and cysLT2. This has led some researchers to go as far as to suggest possible redundancy of cysLT1 and cysLT2 signaling in cell types in which both receptors are expressed. Set against this is clear evidence for fundamentally different roles for cysLT1 and cysLT2 signaling. For example, in IL-4–primed cultured human mast cells, which express cysLT1 and cysLT2, a cysLT1 antagonist did not inhibit IL-8 production in response to stimulation with cysLT but did inhibit associated production of IL-5 and phosphorylation of extracellular signal-related kinase. This led the authors to suggest a possible role for cysLT2 receptor in mediating neutrophil as opposed to eosinophil infiltration. In another recent study, bleomycin-induced pulmonary fibrosis in mice was reduced by targeted ablation of LTC4 synthase, the pivotal enzyme for cysLT biosynthesis, but increased by targeted ablation of cysLT1, suggesting a role for cysLT2 in mediating airways remodeling, and a role for cysLT1 in inhibiting it. Consequently, although at first sight it is tempting to speculate from our data that combined antagonism of cysLT1 and cysLT2 or the use of 5-lipoxygenase inhibitors may offer additional therapeutic benefits over a cysLT1 antagonist used alone in these diseases,32, 33 this may not necessarily be the case if cysLT1 and cysLT2 mediate distinct, possibly antagonistic effects. Further studies will be necessary to resolve these issues.
    Introduction Adenotonsillar hypertrophy is the most frequent cause of sleep-disordered breathing (SDB) in childhood, so it is widely accepted that the first line of treatment is tonsillectomy and adenoidectomy (T&A) [1]. However, many mild patients that do not fulfill the polysomnographic criteria for surgical treatment are usually left unattended even though a significant proportion is at risk for cardiovascular, neurobehavioral, and somatic growth consequences [2], [3]. Furthermore, the effectiveness of T&A remains controversial. Persistence of abnormal polysomnographic findings after surgery is reported in approximately 20% to 75% of cases [4], [5]. The use of leukotriene (LT) modification therapy as a potential nonsurgical alternative in the management of SDB in children has been advanced by some investigators [6], [7]. However, the therapeutic mechanisms involved have not been critically delineated. Cysteinyl leukotrienes (CysLTs) are key mediators and modulators in airway inflammation [8], [9], [10], [11], exerting their actions through activation of two G-protein-coupled receptors: CysLT subtype 1 receptor (CysLT1-R) and CysLT subtype 2 receptor (CysLT2-R) [12], [13]. Goldbart et al. confirmed that increased LT level and receptor protein expression emerged in the adenotonsillar tissue of children with SDB, which may underlie signaling pathways leading to proliferation and hyperplasia of the lymphoid tissue in these children [6]. Thus, treatment with leukotriene receptor antagonists (LTRAs) may abrogate the proliferative signals, and thereby lead to progressive reductions in overall lymphoid tissue volume within the upper airway, which in turn ameliorate the respiratory disturbances during sleep.