The anti-inflammatory effects of eucalyptol in a mouse model of LPS-induced pulmonary inflammation are mediated by TRPM8

Abstract

Eucalyptol (1,8-cineol) has long been known for its anti-inflammatory properties. It interacts with Transient Receptor Potential (TRP) ion channels among other targets, but it is unclear which of these mediates its anti-inflammatory effects. In this work, the effects of eucalyptol were compared in WT and TRPM8-deficient mice in a model of pulmonary inflammation following intranasal administration of lipopolysaccharide (LPS). LPS, a component of Gram-negative bacterial cell walls, plays a major role in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). 24 hours after LPS intranasal instillation, lungs and bronchoalvelolar lavage (BAL) from eucalyptol treated and untreated TRPM8 KO and WT mice were collected and analyzed.

This study shows that eucalyptol treatment diminishes leukocyte infiltration, myeloperoxidase activity and cytokine production in the lung. Genetic deletion of TRPM8 abolishes the anti-inflammatory effects of eucalyptol in the LPS model. Eucalyptol is at least 30-fold more potent on human TRPM8 than on mouse TRPM8, and a metabolite of eucalyptol, 2-hydroxy-1,8-cineol, also activates human TRPM8. Our data show that among the pharmacological targets of eucalyptol, TRPM8 is essential for its anti-inflammatory effects.The development of more potent and selective TRPM8 agonists may yield novel anti-inflammatory pharmacological treatments with lower toxicity and adverse effects than the current available options.