Modulation of Acute Lung Injury-Associated Systemic Inflammation by the Cannabinoid Type 2 Receptor Agonist HU-308

Abstract

Acute lung injury (ALI), clinically diagnosed as acute respiratory distress syndrome (ARDS), is a severe inflammatory syndrome characterized by pulmonary edema and refractory hypoxemia. Many patients with ARDS succumb to extrapulmonary organ dysfunction arising from dysregulated systemic inflammation. The cannabinoid type 2 receptor (CB2) is an emerging modulator of inflammation and can be targeted by CB2- specific agonists such as HU-308, which possesses low signaling bias and high target specificity. We investigated whether HU-308 could reduce systemic inflammation in lipopolysaccharide (LPS)-induced ALI. In LPS-stimulated RAW 264.7 macrophage-like cells, HU-308 reduced secretion of inflammatory cytokines. In murine LPS-induced ALI, HU-308 reduced lung injury, diminished pulmonary and systemic cytokine release, and protected against leukocyte adhesion and capillary dysfunction in the visceral microcirculation. Additionally, CB2-deficient mice showed increased lung injury and systemic cytokine release following LPS challenge. These findings suggest a potential protective role of the CB2 agonist HU-308 in ALI-associated systemic inflammation.