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The role of endocannabinoids (eCB) and cognate receptors in the regulation of inflammation is clinically relevant; however, the role of cannabinoid receptors (CBRs) specifically in pulmonary inflammation and associated lung pathobiology remains elusive. For this study, we investigated the effects of binge cannabinoid exposure on pathogen-induced pulmonary inflammation. We also describe a binge ethanol + cannabinoid adolescent mouse model of pathogen-induced pulmonary inflammation by <jats:italic>Klebsiella pneumoniae<\/jats:italic> (<jats:italic>K. pneumoniae<\/jats:italic>) infection. We show that adolescent cannabinoid exposure primes the lung to a more severe inflammation in adulthood, and this response is mitigated by cannabinoid antagonists. We also show that ethanol and cannabinoid pre-exposure followed by microbial challenge yielded CBR-dependent pulmonary immune activation via danger-associated molecular pattern (DAMP) release. This research may shed light on CB signaling as it relates to DAMPs and can provide a framework to develop potential novel therapeutics in polysubstance use disorders.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1539813","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T04:10:48Z","timestamp":1751861448000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Cannabinoids and alcohol co-exposure modulate pathogen-induced pulmonary immune 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