Modulation of Neutrophil Recruitment and Inflammatory Signaling in Acute Respiratory Distress Syndrome by Leukotriene Inhibitors Montelukast and Zileuton.

Acute respiratory distress syndrome (ARDS) is characterized by excessive neutrophil-driven inflammation and remains a leading cause of mortality in critical care. Leukotriene-modifying agents, such as montelukast (a CysLTR1 antagonist) and zileuton (a 5-lipoxygenase inhibitor), are approved for chronic inflammatory lung diseases, but their role in ARDS is unclear. We investigated the effects of montelukast and zileuton in a murine model of lipopolysaccharide (LPS)-induced ARDS, supported by in vitro assays using human neutrophils. Mice were treated with either drug 1 h post-injury. Neutrophil recruitment, cytokine release, and inflammatory signaling were assessed by immunohistochemistry, flow cytometry, ELISA, and qPCR. Neutrophil chemotaxis and signaling responses were evaluated in vitro. Both montelukast and zileuton significantly reduced neutrophil infiltration into lung tissue and bronchoalveolar lavage fluid (p < 0.01), suppressed expression of adhesion molecules (PSGL-1, L-selectin, LFA-1), and decreased levels of TNF-α, CXCL2, IL-1β, and IL-6 in BAL fluid (p < 0.05). In vitro, both drugs impaired neutrophil chemotaxis and reduced CysLTR1 and ERK1/2 expression following inflammatory stimulation. These findings indicate that leukotriene pathway inhibition limits neutrophil recruitment and activation in ARDS by modulating receptor expression and ERK1/2 signaling. Montelukast and zileuton may offer a targeted strategy to attenuate hyperinflammation in ARDS.