Nebulized platelet-derived extracellular vesicles attenuate chronic cigarette smoke-induced murine emphysema.

Chronic obstructive pulmonary disease (COPD) is a prevalent lung disease usually resulting from cigarette smoking (CS). Cigarette smoking induces oxidative stress, which causes inflammation and alveolar epithelial cell apoptosis and represents a compelling therapeutic target for COPD. Purified human platelet-derived exosome product (PEP) is endowed with antioxidant enzymes and immunomodulatory molecules that mediate tissue repair. In this study, a murine model of CS-induced emphysema was used to determine whether nebulized PEP can influence the development of CS-induced emphysema through the mitigation of oxidative stress and inflammation in the lung. Nebulization of PEP effectively delivered the PEP vesicles into the alveolar region, with evidence of their uptake by type I and type II alveolar epithelial cells and macrophages. Lung function testing and morphometric assessment showed a significant attenuation of CS-induced emphysema in mice treated with nebulized PEP thrice weekly for 4 weeks. Whole lung immuno-oncology RNA sequencing analysis revealed that PEP suppressed several CS-induced cell injuries and inflammatory pathways. Validation of inflammatory cytokines and apoptotic protein expression on the lung tissue revealed that mice treated with PEP had significantly lower levels of S100A8/A9 expressing macrophages, higher levels of CD4+/FOXP3+ Treg cells, and reduced NF-κB activation, inflammatory cytokine production, and apoptotic proteins expression. Further validation using in vitro cell culture showed that pretreatment of alveolar epithelial cells with PEP significantly attenuated CS extract-induced apoptotic cell death. These data show that nebulization of exosomes like PEP can effectively deliver exosome cargo into the lung, mitigate CS-induced emphysema in mice, and suppress oxidative lung injury, inflammation, and apoptotic alveolar epithelial cell death.

The acute toxic and neurotoxic effects of 3,4-methylenedioxymethamphetamine are more pronounced in adolescent than adult mice.

3,4-methylenedioxymethamphetamine (MDMA) recently achieved breakthrough status from the Food and Drug Administration (FDA) for post-traumatic stress disorder (PTSD). However, evidence indicates that exposure to toxic doses of MDMA can lead to long-lasting dysregulation of brain monoaminergic neurotransmitters, primarily from studies conducted in young adult rodents. To date, there is a paucity of data on whether toxic doses of MDMA can differentially affect neurotransmitter systems in adolescents and mature adults, which is an important question as adolescents and adults may be differentially vulnerable to MDMA abuse. In the current study, adolescent (6-7 weeks of age) and mature adult (16-18 weeks of age) male, Swiss-Webster mice were exposed to MDMA (20 mg/kg) using a binge-like dosing regimen (4 administrations spaced every 2 h). Acute lethality, acute hyperthermia, and acute decreases in body weight following MDMA administration were more pronounced in adolescent than adult mice. Likewise, acute loss of striatal dopamine neurochemistry was also exacerbated in adolescents, as determined by high-pressure liquid chromatography coupled to electrochemical detection. Exposure to MDMA induced greater turnover of dopamine into its major metabolite dihydroxyphenylacetic acid (DOPAC) in adolescents, but not in adults, suggesting a novel mechanism through which adolescents may show increased vulnerability to the acute toxic and neurotoxic effects of MDMA, or conversely that mature adults show greater protection. These data caution that MDMA exposure in adolescence may be particularly dangerous and that the therapeutic window for MDMA may differ between adolescents and mature adults.