Selective CB2 Receptor Agonist, HU-308, Reduces Systemic Inflammation in Endotoxin Model of Pneumonia-Induced Acute Lung Injury

Abstract

Acute respiratory distress syndrome (ARDS) and sepsis are risk factors contributing to mortality in patients with pneumonia. In ARDS, also termed acute lung injury (ALI), pulmonary immune responses lead to excessive pro-inflammatory cytokine release and aberrant alveolar neutrophil infiltration. Systemic spread of cytokines is associated with systemic complications including sepsis, multi-organ failure, and death. Thus, dampening pro-inflammatory cytokine release is a viable strategy to improve outcome. Activation of cannabinoid type II receptor (CB2) has been shown to reduce cytokine release in various in vivo and in vitro studies. Herein, we investigated the effect of HU-308, a specific CB2 agonist, on systemic and pulmonary inflammation in a model of pneumonia-induced ALI. C57Bl/6 mice received intranasal endotoxin or saline, followed by intravenous HU-308, dexamethasone, or vehicle. ALI was scored by histology and plasma levels of select inflammatory mediators were assessed by Luminex assay. Intravital microscopy (IVM) was performed to assess leukocyte adhesion and capillary perfusion in intestinal and pulmonary microcirculation. HU-308 and dexamethasone attenuated LPS-induced cytokine release and intestinal microcirculatory impairment. HU-308 modestly reduced ALI score, while dexamethasone abolished it. These results suggest administration of HU-308 can reduce systemic inflammation without suppressing pulmonary immune response in pneumonia-induced ALI and systemic inflammation.

Intravital Microscopy of Lipopolysaccharide-Induced Inflammatory Changes in Different Organ Systems—A Scoping Review

“…Although LPS administration can induce sepsis pathophysiology in experimental animals and trigger various inflammatory pathways in vivo, it does not mimic the clinical course of the condition; it can only generate hyperinflammation [35]. Future research should use a more clinically relevant model of sepsis, where an infection is present.…”

“…The exposed intestines are bathed in a continuous flow of warm saline to mimic physiological conditions. Some researchers administer isoproterenol in a drop-wise manner to reduce peristaltic movement [35].…”

“…LPS increased leukocyte adhesion and decreased FCD. [35] Wistar Kyoto rats LPS (E. coli), (2 mg/kg); i.v. FCD of the muscle layer LPS had no significant difference in FCD.…”

Enantiomeric Agonists of the Type 2 Cannabinoid Receptor Reduce Retinal Damage during Proliferative Vitreoretinopathy and Inhibit Hyperactive Microglia In Vitro

“…HU-308 is a synthetic structural analog of cannabidiol with greater than 440-fold selectivity for CB 2 over CB 1 . HU-308 is a relatively unbiased CB 2 agonist with a record of therapeutic use in a variety of animal and cellular models of inflammation. ,− Notably, HU-308 was reported to suppress inflammation and improve parameters of retinal tissue histopathology in an in vivo mouse PVR model, effects that underscore the potential of HU-308 and similar CB 2 -selective ligands for further development as clinical candidates . As HU-308 is synthesized from chiral starting material, its production yields a racemic mixture rather than a pure product .…”

Cell Death in Acute Organ Injury and Fibrosis

“…example, the inhibition of pyroptosis of bladder epithelial cells improves neurogenic bladder fibrosis, lung overexpression of matrix metalloproteinase-2 has been shown to mitigate lung fibrosis by blocking apoptosis of lung epithelial cells, and selective cannabinoid type II receptors, which are known to block apoptosis, protect against inflammatory response in endotoxin-induced acute lung injury and hepatic ischemic/reperfusion injury [21][22][23][24][25].…”