The burden of cannabis use disorder (CUD) in the context of its prevalence and subsequent cardiopulmonary outcomes among cancer patients with severe sepsis is unclear.

To address this knowledge gap, especially due to rising patterns of cannabis use and its emerging pharmacological role in cancer.

By applying relevant International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes to the National Inpatient Sample database between 2016-2020, we identified CUD(+) and CUD(-) arms among adult cancer admissions with severe sepsis. Comparing the two cohorts, we examined baseline demographic characteristics, epidemiological trends, major adverse cardiac and cerebrovascular events, respiratory failure, hospital cost, and length of stay. We used the Pearson χ² d test for categorical variables and the Mann-Whitney U test for continuous, non-normally distributed variables. Multivariable regression analysis was used to control for potential confounders. A P value ≤ 0.05 was considered for statistical significance.

We identified a total of 743520 cancer patients admitted with severe sepsis, of which 4945 had CUD. Demographically, the CUD(+) cohort was more likely to be younger (median age = 58 vs 69, P < 0.001), male (67.9% vs 57.2%, P < 0.001), black (23.7% vs 14.4%, P < 0.001), Medicaid enrollees (35.2% vs 10.7%, P < 0.001), in whom higher rates of substance use and depression were observed. CUD(+) patients also exhibited a higher prevalence of chronic pulmonary disease but lower rates of cardiovascular comorbidities. There was no significant difference in major adverse cardiac and cerebrovascular events between CUD(+) and CUD(-) cohorts on multivariable regression analysis. However, the CUD(+) cohort had lower all-cause mortality (adjusted odds ratio = 0.83, 95% confidence interval: 0.7-0.97, P < 0.001) and respiratory failure (adjusted odds ratio = 0.8, 95% confidence interval: 0.69-0.92, P = 0.002). Both groups had similar median length of stay, though CUD(+) patients were more likely to have higher hospital cost compared to CUD(-) patients (median = 94574 dollars vs 86615 dollars, P < 0.001).

CUD(+) cancer patients with severe sepsis, who tended to be younger, black, males with higher rates of substance use and depression had paradoxically significantly lower odds of all-cause in-hospital mortality and respiratory failure. Future research should aim to better elucidate the underlying mechanisms for these observations.

• Cannabis/marijuana
• Sepsis
• Cardiovascular outcomes
• Major adverse cardiac and cerebrovascular events
• Pulmonological complications
• Cancer

• Cannabinoid receptors
• Ethanol
• Inflammation
• Macrophages

• Animals
• Receptor, Cannabinoid, CB2/metabolism
• Receptor, Cannabinoid, CB2/agonists
• Receptor, Cannabinoid, CB2/genetics
• Receptor, Cannabinoid, CB1/metabolism
• Receptor, Cannabinoid, CB1/genetics
• Humans
• Ethanol/toxicity
• Lung/drug effects
• Lung/metabolism
• Lung/immunology
• Lung/pathology
• Mice, Inbred C57BL
• Pneumonia/chemically induced
• Pneumonia/metabolism
• Male
• Mice
• Cytokines/metabolism
• Macrophages/drug effects
• Macrophages/metabolism
• Macrophages/immunology
• Disease Models, Animal
• Cannabinoid Receptor Agonists/pharmacology
• Binge Drinking/complications
• Binge Drinking/metabolism
• Signal Transduction/drug effects

• P30 ES025128 NIEHS NIH HHS
• U54 MD012392 NIMHD NIH HHS

• analgesics
• cannabinoid receptor
• chronic nociception
• interacting protein
• paw withdrawal threshold

• cannabidiol
• cannabis
• inflammation
• lipopolysaccharide
• macrophages
• tetrahydrocannabinol

• Rats
• Animals
• Dronabinol/pharmacology
• Dronabinol/metabolism
• Endotoxemia/chemically induced
• Endotoxemia/drug therapy
• Endotoxemia/metabolism
• Cyclooxygenase 2/metabolism
• Lipopolysaccharides/pharmacology
• Escherichia coli/metabolism
• Oxidative Stress
• Receptors, Cannabinoid/metabolism
• Endothelium, Vascular/metabolism

• Hungarian Scientific Research Fund

IL-10 is a cytokine with pleiotropic functions, particularly known for its suppressive effects on various immune cells. Consequently, it can limit the pathogenesis of inflammatory diseases, such as multiple sclerosis (MS), inflammatory bowel disease, Crohn’s disease, and Epidermolysis bullosa acquisita, among others. Recent evidence however indicates that it plays dual roles in Systemic lupus Erythematosus (SLE) where it may inhibit pro-inflammatory effector functions but seems to be also a main driver of the extrafollicular antibody response, outside of germinal centers (GC). In line, IL-10 promotes direct differentiation of activated B cells into plasma cells rather than stimulating a GC response. IL-10 is produced by B cells, myeloid cells, and certain T cell subsets, including extrafollicular T helper cells, which are phenotypically distinct from follicular helper T cells that are relevant for GC formation. In SLE patients and murine lupus models extrafollicular T helper cells have been reported to support ongoing extrafollicular formation of autoreactive plasma cells, despite the presence of GCs. Here, we discuss the role of IL-10 as driver of B cell responses, its impact on B cell proliferation, class switch, and plasma cells.

• Animals
• B-Lymphocytes
• Germinal Center
• Humans
• Interleukin-10
• Lupus Erythematosus, Systemic
• Mice
• T-Lymphocytes, Helper-Inducer

• Deutsche Forschungsgemeinschaft

The transient receptor potential vanilloid 1 (TRPV1) participates in thermosensation and inflammatory pain, but its immunomodulatory mechanisms remain enigmatic. N-Oleoyl dopamine (OLDA), an endovanilloid and endocannabinoid, is a TRPV1 agonist that is produced in the central nervous system and the peripheral nervous system. We studied the anti-inflammatory effects and TRPV1-dependent mechanisms of OLDA in models of inflammation and sepsis.

Mice were challenged intratracheally or intravenously with LPS, or intratracheally with S. aureus to induce pneumonia and sepsis, and then were treated intravenously with OLDA. Endpoints included plasma cytokines, leukocyte activation marker expression, mouse sepsis scores, lung histopathology, and bacterial counts. The role of TRPV1 in the effects of OLDA was determined using Trpv1^−/− mice, and mice with TRPV1 knockdown pan-neuronally, in peripheral nervous system neurons, or in myeloid cells. Circulating monocytes/macrophages were depleted using clodronate to determine their role in the anti-inflammatory effects of OLDA in endotoxemic mice. Levels of exogenous OLDA, and of endovanilloids and endocannabinoids, at baseline and in endotoxemic mice, were determined by LC–MS/MS.

OLDA administration caused an early anti-inflammatory response in endotoxemic and septic mice with high serum levels of IL-10 and decreased levels of pro-inflammatory cytokines. OLDA also reduced lung injury and improved mouse sepsis scores. Blood and lung bacterial counts were comparable between OLDA- and carrier-treated mice with S. aureus pneumonia. OLDA’s effects were reversed in mice with pan-neuronal TRPV1 knockdown, but not with TRPV1 knockdown in peripheral nervous system neurons or myeloid cells. Depletion of monocytes/macrophages reversed the IL-10 upregulation by OLDA in endotoxemic mice. Brain and blood levels of endovanilloids and endocannabinoids were increased in endotoxemic mice.

OLDA has strong anti-inflammatory actions in mice with endotoxemia or S. aureus pneumonia. Prior studies focused on the role of peripheral nervous system TRPV1 in modulating inflammation and pneumonia. Our results suggest that TRPV1-expressing central nervous system neurons also regulate inflammatory responses to endotoxemia and infection. Our study reveals a neuro-immune reflex that during acute inflammation is engaged proximally by OLDA acting on neuronal TRPV1, and through a multicellular network that requires circulating monocytes/macrophages, leads to the systemic production of IL-10.

The online version contains supplementary material available at 10.1186/s12974-022-02485-z.

• ALI
• Cytokines
• Endovanilloid
• IL-10
• Inflammation
• N-Oleoyl dopamine
• Neuro-immune
• TRPV1

Given the abundancy of angiotensin converting enzyme 2 (ACE‐2) receptors density, beyond the lung, the intestine is considered as an alternative site of infection and replication for severe acute respiratory syndrome by coronavirus type 2 (SARS‐CoV‐2). Cannabidiol (CBD) has recently been proposed in the management of coronavirus disease 2019 (COVID‐19) respiratory symptoms because of its anti‐inflammatory and immunomodulatory activity exerted in the lung. In this study, we demonstrated the in vitro PPAR‐γ‐dependent efficacy of CBD (10⁻⁹‐10⁻⁷ M) in preventing epithelial damage and hyperinflammatory response triggered by SARS‐CoV‐2 spike protein (SP) in a Caco‐2 cells. Immunoblot analysis revealed that CBD was able to reduce all the analyzed proinflammatory markers triggered by SP incubation, such as tool‐like receptor 4 (TLR‐4), ACE‐2, family members of Ras homologues A‐GTPase (RhoA‐GTPase), inflammasome complex (NLRP3), and Caspase‐1. CBD caused a parallel inhibition of interleukin 1 beta (IL‐1β), IL‐6, tumor necrosis factor alpha (TNF‐α), and IL‐18 by enzyme‐linked immunosorbent assay (ELISA) assay. By immunofluorescence analysis, we observed increased expression of tight‐junction proteins and restoration of transepithelial electrical resistance (TEER) following CBD treatment, as well as the rescue of fluorescein isothiocyanate (FITC)–dextran permeability induced by SP. Our data indicate, in conclusion, that CBD is a powerful inhibitor of SP protein enterotoxicity in vitro.

• Caco-2
• Cannabidiol
• NLRP3
• SARS-CoV-2 spike (S) protein

• canine inflammatory response
• cannabidiol
• ex vivo
• whole dog blood

• 2-Acyl glycerol
• Anandamide
• Cannabinoid
• Endocannabinoid
• Phytocannabinoid

• ACEA
• cannabinoid CB1 receptors
• inflammation
• interleukin 6
• skeletal muscle

• Primary Sjogren’s syndrome
• cytokines
• the interstitial lung disease

Canine atopic dermatitis (AD) is a multifactorial allergic disease associated with immune and abnormal skin barrier dysfunction and it is one of the primary causes of pruritus. Using a novel in vitro model of AD, here we tried to revert the alteration of transcriptional regulation of AD canine key genes testing a nutraceutical mixture containing flavonoids, stilbene, and cannabinoids, which are already well-known for their applications within dermatology diseases. The nutraceutical mixture induced in inflamed cells a significant downregulation (p < 0.05) of the gene expression of ccl2, ccl17, and tslp in keratinocytes and of ccl2, ccl17, and il31ra in monocytes. Consistent with the observed alterations of tslp, ccl2, ccl17, and il31ra messenger RNA (mRNA) levels, a significant increase (p < 0.05) of DNA methylation at specific CpG sites on the gene regulatory regions was found. These results lay the foundation for the use of these natural bioactives in veterinary medicine and provide a model for deeper understanding of their mechanisms of action, with potential translation to human research.

• epigenetic
• phytocannabinoids
• polyphenols
• skin inflammation
• veterinary research

• Fc gamma receptors
• Nrf2
• TSPO
• biomarkers
• cannabinoids
• sex differences

• COVID-19
• Coronavirus
• Immunology
• Mortality rate
• Vitamin D

• Betacoronavirus/physiology
• COVID-19
• Cholecalciferol/administration & dosage
• Cholecalciferol/blood
• Coronavirus Infections/drug therapy
• Coronavirus Infections/epidemiology
• Coronavirus Infections/mortality
• Coronavirus Infections/prevention & control
• Dietary Supplements/analysis
• Humans
• Immunologic Factors
• Metabolic Networks and Pathways
• Pandemics/prevention & control
• Pneumonia, Viral/drug therapy
• Pneumonia, Viral/epidemiology
• Pneumonia, Viral/mortality
• Pneumonia, Viral/prevention & control
• SARS-CoV-2
• Vitamin D Deficiency/drug therapy
• Vitamin K 2/administration & dosage
• Vitamin K 2/blood