Δ9-Tetrahydrocannabinol Prevents Mortality from Acute Respiratory Distress Syndrome through the Induction of Apoptosis in Immune Cells, Leading to Cytokine Storm Suppression

Int J Mol Sci. 2020 Aug 28;21(17):6244. doi: 10.3390/ijms21176244.

Abstract

Acute Respiratory Distress Syndrome (ARDS) causes up to 40% mortality in humans and is difficult to treat. ARDS is also one of the major triggers of mortality associated with coronavirus-induced disease (COVID-19). We used a mouse model of ARDS induced by Staphylococcal enterotoxin B (SEB), which triggers 100% mortality, to investigate the mechanisms through which Δ9-tetrahydrocannabinol (THC) attenuates ARDS. SEB was used to trigger ARDS in C3H mice. These mice were treated with THC and analyzed for survival, ARDS, cytokine storm, and metabolome. Additionally, cells isolated from the lungs were used to perform single-cell RNA sequencing and transcriptome analysis. A database analysis of human COVID-19 patients was also performed to compare the signaling pathways with SEB-mediated ARDS. The treatment of SEB-mediated ARDS mice with THC led to a 100% survival, decreased lung inflammation, and the suppression of cytokine storm. This was associated with immune cell apoptosis involving the mitochondrial pathway, as suggested by single-cell RNA sequencing. A transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following THC treatment. In addition, metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl L-carnitine in THC-treated mice. THC caused the downregulation of miR-185, which correlated with an increase in the pro-apoptotic gene targets. Interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (BALF) of human COVID-19 patients showed some similarities between cytokine and apoptotic genes with SEB-induced ARDS. Collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ARDS associated with COVID-19.

Keywords: acute respiratory distress syndrome; apoptosis; cytokine storm; staphylococcal enterotoxin B; Δ9-tetrahydrocannabinol.

MeSH terms

  • Aged
  • Animals
  • Apoptosis / drug effects*
  • Betacoronavirus / physiology*
  • Bronchoalveolar Lavage Fluid / immunology
  • Cannabinoid Receptor Agonists / therapeutic use*
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / mortality
  • Coronavirus Infections / virology
  • Cytokines / immunology*
  • Dronabinol / therapeutic use*
  • Enterotoxins / adverse effects
  • Female
  • Humans
  • Lung / immunology
  • Lung / virology
  • Male
  • Mice
  • Mice, Inbred C3H
  • MicroRNAs / genetics
  • Middle Aged
  • Pandemics
  • Pneumonia / drug therapy
  • Pneumonia / virology
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / mortality
  • Pneumonia, Viral / virology
  • Respiratory Distress Syndrome, Adult / drug therapy*
  • Respiratory Distress Syndrome, Adult / mortality
  • Respiratory Distress Syndrome, Adult / virology
  • Signal Transduction / drug effects

Substances

  • Cannabinoid Receptor Agonists
  • Cytokines
  • Enterotoxins
  • MIRN185 microRNA, human
  • MicroRNAs
  • enterotoxin B, staphylococcal
  • Dronabinol

Supplementary concepts

  • COVID-19
  • severe acute respiratory syndrome coronavirus 2