期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 177, 期 22, 页码 5078-5095出版社
WILEY
DOI: 10.1111/bph.15226
关键词
acute respiratory distress syndrome (ARDS); microbiome; staphylococcal enterotoxin-B (SEB); Delta(9)-tetrahydrocannabinol (THC)
资金
- Ministry of Higher Education and Scientific Research (MOHESR), Iraq
- NIH [P01AT003961, P20GM103641, R01AI123947, R01AI129788, R01AT006888, R01ES030144]
Background and Purpose: Staphylococcal enterotoxin-B (SEB) is one of the most potent bacterial superantigens that exerts profound toxic effects by inducing a cytokine storm. Inhaled SEB can cause acute respiratory distress syndrome (ARDS), which is often fatal and with no effective treatments. Experimental Approach: Efficacy of Delta(9)-tetrahydrocannabinol (THC) was tested in a mouse model of SEB-mediated ARDS, in which lung inflammation, alterations in gut/lung microbiota and production of short-chain fatty acids (SCFAs) was measured. Gene dysregulation of lung epithelial cells was studied by transcriptome arrays. Faecal microbiota transplantation (FMT) was performed to confirm the role of microbiota in suppressing ARDS. Key Results: While SEB triggered ARDS and 100% mortality in mice, THC protected the mice from fatality. Pyrosequencing analysis revealed that THC caused significant and similar alterations in microbiota in the lungs and gut of mice exposed to SEB. THC significantly increased the abundance of beneficial bacterial species,Ruminococcus gnavus, but decreased pathogenic microbiota, Akkermansia muciniphila.FMT confirmed that THC-mediated reversal of microbial dysbiosis played crucial role in attenuation of SEB-mediated ARDS. THC treatment caused an increase in SCFA, of which propionic acid was found to inhibit the inflammatory response. Transcriptome array showed that THC up-regulated several genes like lysozyme1 and lysozyme2, beta-defensin-2, claudin, zonula-1, occludin-1, Mucin2 and Muc5b while down-regulating beta-defensin-1. Conclusion and Implications: The study demonstrates for the first time that THC attenuates SEB-mediated ARDS and toxicity by altering the microbiota in the lungs and the gut as well as promoting antimicrobial and anti-inflammatory pathways.
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