Effect of long-acting β-agonists/glucocorticoids on human airway epithelial cell cytokine, transcriptomic and oxidative stress responses to cannabis smoke

Abstract

Cannabis is one of the most widely consumed drugs in the world, with an estimated 180 million annual users globally [1]. Recent trends of legalisation of medicinal and/or recreational cannabis have led to increased access to cannabis products that will likely lead to increased use over the coming years. Inhalation of combusted cannabis is by far the most prevalent form of cannabis use, reported by 89% of users in the 2018 Canadian Cannabis Survey [2]. Chemically, cannabis smoke includes pharmacologically active components such as tetrahydrocannabinol (THC), cannabidiol (CBD) and polycyclic aromatic hydrocarbons [3]. Many studies have investigated the psychoactive and immunomodulatory properties of THC and CBD respectively, and examined the potential use of cannabis as an intervention for chronic pain, immune disorders and neurological disorders [4, 5]. Despite this body of knowledge and recent rise of systematic reviews on these topics, the effects of inhaled cannabis smoke on the respiratory mucosal immune responses are less clear [6]. Like tobacco smoke, repeated exposure to cannabis smoke has been associated with cough and shortness of breath [7]. However, few studies have examined the effects of cannabis smoke on the respiratory mucosa, the primary physical and immunological barrier to the environment [8]. Tobacco smoke induces oxidative stress and cytokine production while disrupting epithelial barrier function, impacting chronic lung disease pathology and exacerbations [9]. To manage chronic lung diseases, an individual may be prescribed a broad, anti-inflammatory long-acting β-agonist (LABA)/glucocorticoid (GC) combination treatment [10], a therapy that may be compromised by tobacco smoke exposure [11, 12]. Given the similarities between tobacco and cannabis smoke [8], we examined whether cannabis smoke exposure similarly attenuates LABA/GC transcriptomic responses and inflammatory mediator release in human airway epithelial cells. Cannabis smoke extract (CSE)-and tobacco smoke extract (TSE)-conditioned media were prepared according to previously published methods [12]. TSE was generated from Kentucky Research Grade Cigarettes with an intact filter (lot 3R4F), and CSE from cannabis rolled with cardboard filters and sourced from Jonathan Page (University of British Columbia, Vancouver, Canada) (13% (w/w) tetrahydrocannabinolic acid strain with 0.18% THC, 0.35% tetrahydrocannabivarinic acid and 0.18% cannabigerolic acid; ∼0.7 g dried cannabis). Extracts were prepared by bubbling cannabis or tobacco smoke through 4 mL HEPES-buffered Eagle's minimal essential medium, filtering (0.22 μm) and diluting with fresh medium (10% dilution, optical density at 260 nm 0.04045). Calu-3 lung epithelial cells on Transwells (Corning Inc., Corning, NY, USA) were apically exposed to 10% of either CSE or TSE with and @ERSpublications LABA/GC intervention in airway epithelial cells exposed to cannabis smoke reduces levels of pro-inflammatory (CXCL8) and antiviral (CXCL10) mediators, while transcriptomic signatures of neutrophil-...

Expression of endocannabinoid system components in human airway epithelial cells: impact of sex and chronic respiratory disease status

“…Airway epithelial cells carry out a number of functions such as providing a physical barrier against microbial infiltration, maintaining the inflammatory microenvironment, and releasing immune mediators to recruit leukocytes to the site of insult. It has been demonstrated that the inhalation of air pollution, tobacco smoke, and cannabis smoke can compromise airway epithelial function [30][31][32]. Notably, recent findings show that cannabis smoke exposure can lead to impaired airway epithelium barrier integrity, attenuated antiviral capacity, and exacerbated inflammatory response to immune challenges [31,32].…”

“…It has been demonstrated that the inhalation of air pollution, tobacco smoke, and cannabis smoke can compromise airway epithelial function [30][31][32]. Notably, recent findings show that cannabis smoke exposure can lead to impaired airway epithelium barrier integrity, attenuated antiviral capacity, and exacerbated inflammatory response to immune challenges [31,32]. However, the contribution of the endocannabinoid system to these observations has not been defined.…”

Expression of the endocannabinoid system in the human airway epithelial cells – Impact of sex and chronic respiratory disease status

“…Inhaled cannabis smoke travels through the upper and lower airways, with airway epithelial cells being a major site of first contact. We have demonstrated with an in vitro model of airway epithelial cell culture that cannabis smoke induces a concentration-dependent reduction in airway epithelial cell viability, barrier function, while promoting pro-inflammatory cytokine secretion (31, 32). Complementary profiling of human epithelial cells isolated via bronchial brushings has demonstrated cannabis consumption-dependent elevations in TLR5, TLR6, and TLR9 gene expression(101).…”

“…Airway epithelial cells carry out a number of functions such as providing a physical barrier against microbial infiltration, maintaining the inflammatory microenvironment, and releasing immune mediators to recruit leukocytes to the site of insult. It has been demonstrated that the inhalation of air pollution, tobacco smoke, and cannabis smoke can compromise airway epithelial function(30-32). Notably, recent findings show that cannabis smoke exposure can lead to impaired airway epithelium barrier integrity, attenuated antiviral capacity, and exacerbated inflammatory response to immune challenges(31, 32).…”

“…It has been demonstrated that the inhalation of air pollution, tobacco smoke, and cannabis smoke can compromise airway epithelial function(30-32). Notably, recent findings show that cannabis smoke exposure can lead to impaired airway epithelium barrier integrity, attenuated antiviral capacity, and exacerbated inflammatory response to immune challenges(31, 32). However, the contribution of the endocannabinoid system to these observations has not been defined.…”