Nicotinamide Although elevated production of cysLTs is chara
Although elevated production of cysLTs is characteristic of rhinosinusitis of diverse etiology, patients with aspirin-sensitive rhinosinusitis show even higher levels of cysLTs in the nasal mucosa, which are further enhanced by aspirin challenge., Elevated production of cysLTs in these patients may reflect enhanced activity of key synthetic enzymes, which may in part be genetically determined. Alternatively, or in addition, it may reflect unique sensitivity of LT-producing cells, particularly mast Nicotinamide and eosinophils, to the direct stimulatory reflects of aspirin and related salicylates. In a recent study, we showed that the percentages of inflammatory leukocytes expressing cysLT were significantly elevated in the nasal mucosa of patients with aspirin-sensitive compared with aspirin-tolerant chronic rhinosinusitis. This may be one mechanism for increased target organ responsiveness to cysLTs in aspirin-sensitive rhinosinusitis, as we have previously observed in aspirin-sensitive asthma. Clearly, altered cysLT expression could also influence such responsiveness.
Our aim was to extend our previous study by comparing the expression of cysLT and cysLT on inflammatory cells, epithelium, and mucus glands in the nasal mucosa of a group of patients with chronic rhinosinusitis, both aspirin-sensitive and aspirin-tolerant, as well as a group of healthy controls. We hypothesized that cysLT as well as cysLT expression is upregulated in nasal mucosal inflammatory and structural cells in patients with chronic rhinosinusitis compared with controls, and further upregulated in aspirin-sensitive compared with aspirin-tolerant patients.
Discussion We have shown in this study that elevated expression of cysLT1 on nasal mucosal inflammatory leukocytes is a phenomenon confined to aspirin-sensitive patients with rhinosinusitis. In contrast, these same cells showed no evidence of upregulation of cysLT2 in patients with rhinosinusitis, whether aspirin-sensitive or aspirin-tolerant, compared with controls. These data considerably extend our previous study. The data in this and our previous study confirm that subsets of leukocytes of all phenotypes express both cysLT1 and cysLT2 in chronic rhinosinusitis. This is in accord with a recent study on leukocytes obtained by nasal lavage of patients with seasonal allergic rhinitis, in which it was shown that subsets of macrophages, mast cells, eosinophils, and neutrophils expressed both receptors. The mechanisms of preferential upregulation of cysLT1 compared with cysLT2 expression on leukocytes in aspirin-sensitive rhinosinusitis remain obscure. Proinflammatory cytokines such as IL-5, IL-4, and IL-13 have been shown to upregulate cysLT1 expression on an eosinophilic cell line and monocyte/macrophages19, 22 and cysLT2 expression on cultured human mast cells, and the expression of such cytokines is increased in the target mucosa of patients with aspirin-sensitive rhinosinusitis and asthma compared with aspirin-tolerant patients of comparable disease severity.24, 25 Aspirin and other COX-1 inhibitors, as well as endogenous salicylates, might also activate granulocytes directly in these patients, thereby altering cysLT receptor expression. For example, we have provided evidence that endobronchial aspirin challenge of aspirin-sensitive patients with asthma directly activates mast cells, and that desensitization of patients with aspirin-sensitive rhinosinusitis with repeated topical application of lysine aspirin downregulates cysLT1 expression. As far as we are aware, the hypothesis that aspirin directly alters expression of cysLT1 and cysLT2 on cells such as mast cells and eosinophils in aspirin-sensitive subjects has never been investigated. Selective recruitment of leukocytes expressing cysLT1 to the nasal mucosa of aspirin-sensitive subjects is also a possibility that has been postulated on the basis of discrepancies in receptor expression on blood and nasal mucosal leukocytes in patients with rhinitis. Although the mechanism of this selective recruitment is unclear, it is possible that local elaboration of cysLTs in the inflamed tissues selectively promotes chemotaxis and/or survival of cells bearing the highest concentrations of cysLT receptors.