LTD4 and TGF-β1 Induce the Expression of Metalloproteinase-1 in Chronic Rhinosinusitis via a Cysteinyl Leukotriene Receptor 1-Related Mechanism

Background: Cysteinyl leukotrienes (CysLTs) play a crucial role in the pathogenesis of airway remodeling. The use of CysLTs receptor antagonists has been included in the management of asthma and rhinitis. However, despite the action of these compounds on leukotriene production has been well documented, their role in airway remodeling remains unclear. Objective: We aimed to investigate the capability of the leukotriene receptor antagonist Montelukast to inhibit MMPs release after CysLTs stimulation in nasal tissue fibroblasts. Methods: Fibroblasts were isolated from sinunasal tissue collected from five patients suffering of chronic rhinosinusitis without nasal polyposis. Cells were cultured and stimulated first with LTC4 and LTD4 (10 ́10, 10 ́8, 10 ́6 M) using as pre-stimulus 10 ng/mL of: IL-4, IL-13, or TGF-beta1 and in presence or absence of Montelukast (10 ́10, 10 ́8, 10 ́6 M). To evaluate the regulation of MMP-1 and TIMP-1 we used enzyme immunoassays and to evaluate CysLT1 receptor we used real time PCR. Results: LTD4 but not LTC4 induced production of mRNA for CysLT1 receptor in a dose dependent manner and with an additive effect when the cells where primed with TGF-β1. TNF-α, IL-4, and IL-13 did not influence the expression of the receptor. Levels of MMP-1 but not of TIMP-1 were statistically enhanced in cells primed with TGF-β1 and stimulated with LTD4. Montelukast significantly decreased Cys-LT1 receptor and MMP-1 concentrations in a dose-dependent way in cells stimulated with LTD4 and TGF-β1 separately and when they were applied together. Conclusion: The leukotriene pathway may play an important role in extra-cellular matrix formation in an inflamed environment, such as chronic sinusitis and, consequently, leukotriene receptor antagonists such as Montelukast may be of great benefit in management of this disease.