Figure : Effects of novel C. sativa extracts on the levels of pro-inflammatory cytokines. To induce inflammation, human 3D EpiDermFT tissues were exposed to UV. Upon exposure, tissues were incubated with extracts or vehicle (DMSO) for 24 h. Three tissues were used for each condition. The differences between all experimental groups were examined using the likelihood ratio test (LRT) test implemented in DESeq2. The reduced model included the intercept and the full model was the experimental group (Cannabis extracts and controls). Multiple comparisons adjustment of p-values was done using Benjamini-Hochberg procedure [63]. Specific comparisons between groups were done using results() function with contrast argument specified. Genes with adjusted p-values below 0.05 were considered significant. Data are shown as log 2 fold changes as compared to UV-induced tissues. All changes shown here are statistically significant, p adj <0.05, ANOVA-like analysis and pair-wise comparison.

Anna Kovalchuk1,2* , Bo Wang1,3* , Dongping Li1,3 , Rocio Rodriguez-Juarez1,3 , Slava Ilnytskyy1,3 , Igor Kovalchuk1,3 , Olga Kovalchuk1,3

Received: May 19, 2020   Accepted: November 13, 2020    Published: January 19, 2021

Abstract

The main aspects of severe COVID-19 disease pathogenesis include hyper-induction of proinflammatory cytokines, also known as ‘cytokine storm’, that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of all cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed, that can efficiently and swiftly downregulate TNFα, IL-6, and the inflammatory cytokine cascade, in order to curb inflammation and prevent fibrosis, and lead to disease remission.

Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of novel C. sativa cultivars may be used to downregulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis.

Initially, to analyze the anti-inflammatory effects of novel C. sativa cultivars, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis cultivars. We noted that out of seven studied extracts of novel C. sativa cultivars, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of COX2, TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. These data were further confirmed in the WI-38 lung fibroblast cell line model. Most importantly, one of the tested extracts had no effect at all, and one exerted effect that may be deleterious, signifying that careful cannabis cultivar selection must be based on thorough pre-clinical studies.

The observed pronounced inhibition of TNFα and IL-6 is the most important finding, because these molecules are currently considered to be the main targets in COVID-19 cytokine storm and ARDS pathogenesis.

Novel anti-TNFα and anti-IL-6 cannabis extracts can be useful additions to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and ‘inflammaging’ – the inflammatory underpinning of aging and frailty.

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