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

ABSTRACT: Cannabis smoking is the dominant route of delivery, with the airway epithelium functioning as the site of first contact. The endocannabinoid system is responsible for mediating the physiological effects of inhaled phytocannabinoids. The expression of the endocannabinoid system in the airway epithelium and contribution to normal physiological responses remains to be defined. To begin to address this knowledge gap, a curated dataset of 1090 unique human bronchial brushing gene expression profiles was created. The dataset included 616 healthy subjects, 136 subjects with asthma, and 338 subjects with COPD. A 32-gene endocannabinoid signature was analysed across all samples with sex and disease-specific analyses performed. Immunohistochemistry and immunoblots were performed to probe in situ and in vitro protein expression. CB₁, CB₂, and TRPV1 protein signal is detectable in human airway epithelial cells in situ and in vitro, justifying examining the downstream endocannabinoid pathway. Sex status was associated with differential expression of 7 of 32 genes. In contrast, disease status was associated with differential expression of 21 of 32 genes in people with asthma and 26 of 32 genes in people with COPD. We confirm at the protein level that TRPV1, the most differentially expressed candidate in our analyses, was upregulated in airway epithelial cells from people with asthma relative to healthy subjects. Our data demonstrate that the endocannabinoid system is expressed in human airway epithelial cells with expression impacted by disease status and minimally by sex. The data suggest that cannabis consumers may have differential physiological responses in the respiratory mucosa.

SUBMITTER: Fantauzzi MF

PROVIDER: S-EPMC7737429 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The high heterogeneity of psychiatric disorders leads to a lack of diagnostic precision. Therefore, the search of biomarkers is a fundamental aspect in psychiatry to reach a more personalized medicine. The endocannabinoid system (ECS) has gained increasing interest due to its involvement in many different functional processes in the brain, including the regulation of emotions, motivation, and cognition. This article reviews the role of the main components of the ECS as biomarkers in certain psychiatric disorders. Studies carried out in rodents evaluating the effects of pharmacological and genetic manipulation of cannabinoid receptors or endocannabinoids (eCBs) degrading enzymes were included. Likewise, the ECS-related alterations occurring at the molecular level in animal models reproducing some behavioral and/or neuropathological aspects of psychiatric disorders were reviewed. Furthermore, clinical studies evaluating gene or protein alterations in post-mortem brain tissue or in vivo blood, plasma, and cerebrospinal fluid (CSF) samples were analyzed. Also, the results from neuroimaging studies using positron emission tomography (PET) or functional magnetic resonance (fMRI) were included. This review shows the close involvement of cannabinoid receptor 1 (CB1r) in stress regulation and the development of mood disorders [anxiety, depression, bipolar disorder (BD)], in post-traumatic stress disorder (PTSD), as well as in the etiopathogenesis of schizophrenia, attention deficit hyperactivity disorder (ADHD), or eating disorders (i.e. anorexia and bulimia nervosa). On the other hand, recent results reveal the potential therapeutic action of the endocannabinoid tone manipulation by inhibition of eCBs degrading enzymes, as well as by the modulation of cannabinoid receptor 2 (CB2r) activity on anxiolytic, antidepressive, or antipsychotic associated effects. Further clinical research studies are needed; however, current evidence suggests that the components of the ECS may become promising biomarkers in psychiatry to improve, at least in part, the diagnosis and pharmacological treatment of psychiatric disorders.

Project description:BackgroundAirway remodeling might explain lung function decline among asthmatic children. Extracellular matrix (ECM) deposition by human lung fibroblasts (HLFs) is implicated in airway remodeling. Airway epithelial cell (AEC) signaling might regulate HLF ECM expression.ObjectivesWe sought to determine whether AECs from asthmatic children differentially regulate HLF expression of ECM constituents.MethodsPrimary AECs were obtained from well-characterized atopic asthmatic (n = 10) and healthy (n = 10) children intubated during anesthesia for an elective surgical procedure. AECs were differentiated at an air-liquid interface for 3 weeks and then cocultured with HLFs from a healthy child for 96 hours. Collagen I (COL1A1), collagen III (COL3A1), hyaluronan synthase (HAS) 2, and fibronectin expression by HLFs and prostaglandin E2 synthase (PGE2S) expression by AECs were assessed by using RT-PCR. TGF-β1 and TGF-β2 concentrations in media were measured by using ELISA.ResultsCOL1A1 and COL3A1 expression by HLFs cocultured with AECs from asthmatic patients was greater than that by HLFs cocultured with AECs from healthy subjects (2.2-fold, P < .02; 10.8-fold, P < .02). HAS2 expression by HLFs cocultured with AECs from asthmatic patients was 2.5-fold higher than that by HLFs cocultured with AECs from healthy subjects (P < .002). Fibronectin expression by HLFs cocultured with AECs from asthmatic patients was significantly greater than that by HLFs alone. TGF-β2 activity was increased in cocultures of HLFs with AECs from asthmatic patients (P < .05), whereas PGES2 was downregulated in AEC-HLF cocultures (2.2-fold, P < .006).ConclusionsHLFs cocultured with AECs from asthmatic patients showed differential expression of the ECM constituents COL1A1 and COL3A1 and HAS2 compared with HLFs cocultured with AECs from healthy subjects. These findings support a role for altered ECM production in asthmatic airway remodeling, possibly regulated by unbalanced AEC signaling.

Project description:BackgroundCannabis consumption by pregnant women continues to increase worldwide, raising concerns about adverse effects on fetal growth and deleterious impacts on the newborn, in connection with evidence of placental transfer of cannabis compound. Cannabis action is mediated by the endocannabinoid system (ECS), which expression is well established in the brain but unknown in the developing testis. The fetal testis, whose endocrine function orchestrates the masculinization of many distant organs, is particularly sensitive to disruption by xenobiotics. In this context, we aimed to determine whether cannabis exposure has the potential to directly impact the human fetal testis.MethodsWe determined the expression of components of the ECS in the human fetal testis from 6 to 17 developmental weeks and assessed the direct effects of phytocannabinoids Δ9-trans-tetrahydrocannabinol (THC) and cannabidiol (CBD) on the testis morphology and cell functions ex vivo.ResultsWe demonstrate the presence in the human fetal testis of two key endocannabinoids, 2-arachidonylglycerol (2-AG) and to a lower level anandamide (AEA), as well as a range of enzymes and receptors for the ECS. Ex vivo exposure of first trimester testes to CBD, THC, or CBD/THC [ratio 1:1] at 10-7 to 10-5 M altered testosterone secretion by Leydig cells, AMH secretion by Sertoli cells, and impacted testicular cell proliferation and viability as early as 72 h post-exposure. Transcriptomic analysis on 72 h-exposed fetal testis explants revealed 187 differentially expressed genes (DEGs), including genes involved in steroid synthesis and toxic substance response. Depending on the molecules and testis age, highly deleterious effects of phytocannabinoid exposure were observed on testis tissue after 14 days, including Sertoli and germ cell death.ConclusionsOur study is the first to evidence the presence of the ECS in the human fetal testis and to highlight the potential adverse effect of cannabis consumption by pregnant women onto the development of the male gonad.

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

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