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cbd and lung disease

These showed that the tumour was progressively shrinking, reducing in size from 41 mm in June 2018 to 10 mm by February 2021, equal to an overall 76% reduction in maximum diameter, averaging 2.4% a month, say the report authors.

The body’s own endocannabinoids are involved in various processes, including nerve function, emotion, energy metabolism, pain and inflammation, sleep and immune function.

The supplier had advised that the main active ingredients were Δ9-­tetrahydrocannabinol (THC) at 19.5%, cannabidiol at around 20%, and tetrahydrocannabinolic acid (THCA) at around 24%.

The report authors describe the case of a woman in her 80s, diagnosed with non-small cell lung cancer. She also had mild chronic obstructive pulmonary disease (COPD), osteoarthritis, and high blood pressure, for which she was taking various drugs.

Cannabis has a long ‘medicinal’ history in modern medicine, having been first introduced in 1842 for its analgesic, sedative, anti-inflammatory, antispasmodic and anticonvulsant effects. And it is widely believed that cannabinoids can help people with chronic pain, anxiety and sleep disorders; cannabinoids are also used in palliative care, the authors add.

Cbd and lung disease

GOIs down-regulated by cannabis oil extract at the 1:400 and 1:800 test dilutions (dose response experiment). HSAEpC were exposed to each of three dilutions of cannabis oil extract in ethanol for 24 h. Each fold change result is based on four cannabis oil extract treatment replicates and six control replicates. There were no down-regulated genes at the 1:1600 dilution. Legend: Black, 1:400 dilution; Grey, 1:800 dilution

NONE (all in vitro experiments).

Chronic obstructive pulmonary disease (COPD) is a respiratory ailment characterized by airway inflammation and irreversible obstruction, resulting in breathing difficulty, mucus production and coughing/wheezing, among other symptoms. As with other diseases of aging, COPD has been increasing in the global population; by 2012, COPD had become the fourth leading cause of death worldwide and is projected to become the 3rd leading cause of death in 2020 (Ferkol and Schraufnagel 2014; Gold Reports 2018). COPD and asthma, a recurring but reversible respiratory disease, share a number of common airway obstruction and inflammation symptoms. In fact, there are two competing hypotheses (termed the British hypothesis and the Dutch hypothesis) relating to the pathophysiology of these diseases (Ghebre et al. 2015). These differences in scientific consensus are addressed in part through an overlapping condition called asthma-COPD overlap syndrome, or ACOS (Gold Reports 2018; Allinson and Wedzicha 2017; Hines and Peebles 2017). ACOS provides a rationale for subsets of COPD patients with asthma-like features and vice versa (Christenson et al. 2015). That said, as distinct diseases, COPD and asthma appear to be fundamentally different from an immunological standpoint: In asthma, allergens trigger an antibody-mediated immune response via the actions of T helper 2 (Th2) cytokines such as interleukins IL-5, IL-13, IL-25 and IL-33, as well as certain Th2-related chemotactic factors. Whereas, in COPD the cumulative effects of cigarette smoke and other chemical irritants result in a pro-inflammatory cell-mediated immune response facilitated by cytokines such as IL-1 beta, IL-6, tumor necrosis factor (TNF) alpha and a variety of T helper 1 (Th1) related chemotactic factors (Barnes 2016, 2009; Schuijs et al. 2013; Barnes 2017). While there is, to date, no cure for COPD, there are various standard treatment drugs available, notably, bronchodilators and corticosteroids (Gold Reports 2018; Allinson and Wedzicha 2017; Hines and Peebles 2017; Rosenberg and Kalhan 2017). However, such treatments have variable effectiveness and often have potentially serious side effects. There have been both anecdotal reports (e.g., on the internet) and scientific studies of the use of orally-administered cannabis oil extract or other cannabinoids derived from the leaves of the marijuana plant, Cannabis sativa, to alleviate symptoms of COPD (Pickering et al. 2011). Cannabis oil extract is a complex mixture of substances with potential pharmacological properties (Elsohly and Slade 2005; Amin and Ali 2019). However, certain components of cannabis oil extract, such as cannabidiol, are known to have anti-inflammatory properties (Cabral et al. 2015; Klein 2005). Cannabidiol and other phytocannabinoids, such as 9-tetrahydrocannabinol, were shown to inhibit pro-inflammatory and Th1 cytokines in vitro and in in vivo models of lipopolysaccharide (LPS) induced lung injury, elicit an anti-inflammatory and Th2 immune response and potentially restore a Th1/Th2 balance in vitro, and shift the immune response profile from Th1 to Th2 in a murine model of diabetes (Petrosino et al. 2018; Ribeiro et al. 2012, 2015; Yuan et al. 2002; Weiss et al. 2006). As COPD represents a respiratory disease with a pro-inflammatory and Th1 immune response profile, the purpose of the present exploratory study was to determine if cannabis oil extract could up-regulate the in vitro expression of Th2, anti-inflammatory and related immune response genes in human small airways epithelial cells (HSAEpC). HSAEpC cells were selected as the model in vitro cell culture system for these studies in part because of the role of airway epithelial cells in respiratory system immune responses (Gras et al. 2013; Hallstrand et al. 2014; Hirota and Knight 2012; Lloyd and Saglani 2015). COPD can adversely affect immune response, host defense, cell and tissue repair and lung function in airway epithelial cells (De Rose et al. 2018). Accordingly, cannabis oil extract was tested for its effects on the expression of 84 respiratory immune response-related genes in HSAEpC using pathway-focused polymerase chain reaction (PCR) array technology. This pathway-focused array was composed of genes encoding Th2 cytokines and chemokines, cytokine and chemokine receptors, transcription factors, immune cell molecules and related proteins. Bioinformatics software was used to analyze the gene expression profiling data generated from these experiments.

Pathway-focused quantitative polymerase chain reaction (qPCR) assays

CCL22, CCL24 and CCL26 were three chemokine genes up-regulated by cannabis oil extract. They encode chemokine (C-C motif) ligands 22, 24 and 26, respectively. While within the limits of the qPCR detection threshold, their basal expressions in PBS and ethanol controls were low, especially for CCL24, which led to a high fold change. CCL22 was the only chemokine gene of the three that was up-regulated at both the 1:400 and 1:800 dilutions. Chemokine (C-C motif) ligand 22 has been described as both a Th2-attracting and homeostatic chemokine (Ying et al. 2008; Zlotnik and Yoshie 2012). Macrophage CCL22 gene expression in COPD has been the subject of several studies. CCL22 up-regulation has been found in sputum macrophages from COPD patients (Frankenberger et al. 2011). Eapen et al. observed a reduction in M2 (Th2) macrophages and an increase in M1 (Th1, pro-inflammatory) macrophages in the small airway walls of smokers and COPD patients (Eapen et al. 2017). However, they also reported that CCL22, along with Th2-related genes IL4, IL10 and IL13 were up-regulated in bronchiolar lavage fluid from COPD patients. In the same study, mRNA levels of CCL22 was increased in the lungs of mice chronically exposed to cigarette smoke relative to normal controls. The authors noted that these chemokines and cytokines were characteristic of a Th2 (or for macrophages, M2) immune response.

One prominent up-regulated GOI is IL4, which encodes interleukin IL-4, a known Th2 cytokine (Barczyk et al. 2006; Borish and Steinke 2003; May and Fung 2015; Röcken et al. 1996). There is already a body of research showing that increased IL-4 production can exacerbate eosinophilia and allergen-induced asthma, at least in those instances where the disease is Th2-driven. Conversely, IL-4 could modulate COPD pathophysiology in cases where COPD can be identified as a Th1-mediated inflammatory disease (Barnes 2016; Cornwell et al. 2010; Cosio et al. 2009). In one patient study, COPD severity was correlated with lower levels of IL-4, while higher IL-4 levels contributed to wound repair in the lung epithelium (Perotin et al. 2014). IL-4 also is a signaling molecule in the JAK-STAT signaling pathway (David et al. 2001). By binding to its cell surface receptor, a cytokine such as IL-4 causes receptor dimerization, mediating a signaling process involving Janus kinase phosphorylation and the subsequent phosphorylation and dimerization of STAT proteins. The activated STAT proteins in turn induce the transcription and expression of a variety of genes involved with promoting or maintaining immune responses (Yew-Booth et al. 2015). IL13RA2, which encodes IL-13 receptor alpha 2, also was up-regulated. This receptor has more complicated regulatory activities that can involve IL-4, IL-13 and their related receptors (Andrews et al. 2013, 2009; Chomarat and Banchereau 1998). In fact, while IL4 and IL13RA2 were up-regulated, IL4R (encoding IL-4 receptor) and IL13RA1 (encoding IL-13 receptor alpha 1) were downregulated at the 1:400 sample dilution. These results suggest that, despite cannabis oil extract containing a mixture of cannabinoid compounds, it was selectively regulating Th2 cytokine and cytokine receptor gene expression. The activation of the JAK-STAT signaling pathway via IL-4 or other upregulated GOIs may also promote lung epithelial cell migration and repair (Bansal et al. 2012; Crosby and Waters 2010; Kida et al. 2008). Additionally, IL-13 receptor alpha 2 has been found to inhibit the detrimental tissue remodeling induced by IL-13 in murine models of both lung inflammation and eosinophilic esophagitis, a chronic inflammation of the esophagus (Zheng et al. 2008; Zuo et al. 2010).


Two other GOIs down-regulated by cannabis oil extract that may have relevance to COPD were LTB4R (alternatively, BLT1 or LTB4R1), which encodes leukotriene B4 receptor, and EPX, which encodes eosinophil peroxidase. Leukotriene B4 is an arachidonic acid-derived, neutrophil recruiting, pro-inflammatory lipid molecule, and both this leukotriene and its receptor have a role in the pathophysiology of COPD (Dong et al. 2016; Marian et al. 2006; Pace et al. 2013). The targeting of the B4 receptor has been considered as a viable approach to the treatment of COPD (Grönke et al. 2008; Hicks et al. 2010). Accordingly, the down-regulation of LTB4R by cannabis oil extract appears to be yet another indication of its anti-inflammatory potential. Interestingly, PPAR-gamma, which was up-regulated by cannabis oil extract, can also counteract inflammation mediated by leukotriene B4 in COPD (Yin et al. 2014). While eosinophil peroxidase does not appear to have been investigated as target for the treatment of COPD, it has been identified as a biomarker of the disease (Nair et al. 2013; Yang et al. 2017).

The gene with the highest fold changes at all three sample dilutions was IL1RL1, which encodes IL-1 receptor-like 1 (also known as ST2). This protein is present in lung mucosa, including airway epithelial cells, and has a critical role in the Th2-mediated immune response (Coyle et al. 1999; Traister et al. 2015; Zhao and Zhao 2015). The observed levels of IL1RL1 up-regulation by all three cannabis oil extract dilutions may make this gene a suitable biomarker for further in vitro and in vivo studies.