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To date, it is unclear which mechanisms are involved in the development of brain-related problems in COPD. In this study, a cigarette smoke and lipopolysaccharide (LPS) exposure murine model was used to induce COPD-like features and assess the impact on brain and behavior. Mice were daily exposed to cigarette smoke for 72 days, except for days 42, 52, and 62, on which mice were intratracheally exposed to the bacterial trigger LPS. Emphysema and pulmonary inflammation as well as behavior and brain pathology were assessed. Cigarette smoke-exposed mice showed increased alveolar enlargement and numbers of macrophages and neutrophils in bronchoalveolar lavage. Cigarette smoke exposure resulted in lower body weight, which was accompanied by lower serum leptin levels, more time spent in the inner zone of the open field, and decreased claudin-5 and occludin protein expression levels in brain microvessels. Combined cigarette smoke and LPS exposure resulted in increased locomotion and elevated microglial activation in the hippocampus of the brain. These novel findings show that systemic inflammation observed after combined cigarette smoke and LPS exposure in this COPD model is associated with increased exploratory behavior. Findings suggest that neuroinflammation is present in the brain area involved in cognitive functioning and that blood-brain barrier integrity is compromised. These findings can contribute to our knowledge about possible processes involved in brain-related comorbidities in COPD, which is valuable for optimizing and developing therapy strategies.<\/jats:p>","DOI":"10.1152\/ajplung.00485.2021","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T08:02:06Z","timestamp":1655193726000},"page":"L251-L265","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Increased exploration and hyperlocomotion in a cigarette smoke and LPS-induced murine model of COPD: linking pulmonary and systemic inflammation with the brain"],"prefix":"10.1152","volume":"323","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1816-2705","authenticated-orcid":false,"given":"Charlotte E.","family":"Pelgrim","sequence":"first","affiliation":[{"name":"Division of Pharmacology, Utrecht Institute for Pharmaceutical         Sciences, Faculty of Science, Utrecht University, 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