Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia (IH) and is associated with a host of health complications. Although the lung is the first organ to sense changes in oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor- (HIF)-responsive pathways. We hypothesized that exposure to IH would lead to cell-specific up and downregulation of diverse expression pathways. We identified changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells showed the most prominent transcriptional changes. Upregulated genes in myofibroblast cells were enriched for genes associated with pulmonary hypertension and included targets of several drugs currently used to treat chronic pulmonary diseases. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.

Obstructive sleep apnea (OSA) results from intermittent episodes of airway collapse and hypoxia and is associated with a host of health complications including dementia, diabetes, heart failure, and stroke. Cellular mechanisms causing disease progression across multiple systems in OSA are unknown. Although it is known that pulmonary diseases share general mechanisms, such as systemic inflammation and oxidative stress, there is an incomplete understanding of the early-stage changes to the lung from OSA. Using intermittent hypoxia (IH) as a mouse model of OSA, we showed profound cell-type specific changes in genome-wide expression in the lung. With single-cell RNA analysis, we identified substantial similarities between lungs of mice exposed to IH and human lung tissue from patients with pulmonary disease--most notably pulmonary hypertension, COPD, and asthma. Many IH-responsive genes encode targets of drugs currently available to treat pulmonary disease. Present data provide insights into the initiation of specific cellular responses which drive disease progression in a model of OSA. This information can help direct therapies to the most relevant cells and molecular pathways.

No abstract

Stress during adolescence clearly impacts brain development and function. Sex differences in adolescent stress-induced or exacerbated emotional and metabolic vulnerabilities could be due to sex-distinct gene expression in hypothalamic, limbic and prefrontal brain regions. However, adolescent stress-induced gene expression changes in these key brain regions were unclear. RNA extraction from whole brain regions, instead of discrete nuclei, dilutes gene expression results. In this study, female and male adolescent Sprague Dawley rats received one-hour restraint stress every day from postnatal day (PD) 32 to PD44, their plasma corticosterone levels were measured, and their body weights, food intake and body composition were monitored. On PD44, their brains and blood samples were collected. Circulating levels of adioposity hormones (leptin and insulin) and sex hormones (estradiol and testosterone) were measured. Gene expression in nine subregions was measured using RNA sequencing (RNA-Seq). Differentially expressed (DE) genes were analyzed using bootstrapped receiver operating characteristic (bROC) approach. The results indicated that sex differences in stress-induced DE genes were widespread, being identified in the hypothalamus, limbic system, and prefrontal cortex of adolescent brains. Additionally, this study revealed canonical pathways enriched in stress compared to nonstress rats, which were predictive of well-known sex-distinct maladies in the literature, providing examples of the DE genes likely involved in producing sex-distinct and stress-induced diseases. In summary, findings from this study suggest sex biases in stress-induced transcriptional changes during adolescence, indicating a molecular basis for sex differences witnessed in stress-induced or exacerbated emotional and metabolic disorders throughout life. Future studies are warranted to test the implications of the DE genes identified in this study in sex-distinct stress-induced susceptibilities.