Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease. COPD is impacted by cigarette smoking with no therapeutic options. We utilized a high copy cDNA library genetic selection approach in the amoeba Dictyostelium discoideum to identify genetic protectors from cigarette smoke (CS). Adenine nucleotide translocase (Salvioli et al.), a mitochondrial ADP/ATP transporter, was protective against CS in Dictyostelium and human bronchial epithelial cells. ANT2 gene expression is reduced in lung tissue from COPD patients and in a mouse smoking model. ANT1 and ANT2 overexpression resulted in enhanced oxidative respiration and ATP flux. In addition to ANT's presence in the mitochondria, ANT resides at the plasma membrane in airway epithelial cells and regulates airway homeostasis. ANT2 overexpression stimulates airway surface hydration by ATP and maintains ciliary beating after CS exposure, which are key functions of the airway. Our study highlights the potential of ANT upregulation and/or agonists in protecting from dysfunctional mitochondrial metabolism, airway hydration, and ciliary motility in COPD.

Juveniles of many species engage in rough-and-tumble play behaviors, and these social encounters are important for the expression of typical social behaviors. Play is a highly motivated and rewarding behavior, which suggests that the mesocorticolimbic dopamine system is likely important for reinforcing the behavior. Indeed, systemic dopamine receptor antagonists decrease the expression of play behaviors, but the specific dopaminergic networks important for play are not known. In this study, we examined immediate-early gene expression in specific dopaminergic cell groups after juvenile male and female rats played or did not play. Subjects were housed with a same-sex sibling, and spontaneous play behavior (or lack thereof) was observed for 1 hr. Brains were harvested and immunohistochemistry was used to localize Fos and tyrosine hydroxylase. Cells expressing both proteins were counted in midbrain and forebrain dopaminergic cell groups. Females that played had more double-labeled cells in the ventral tegmental area (VTA) than females that did not play, but there was no effect of play on double-labeled cell counts in any brain region in males. Furthermore, many measures of play in females were positively correlated with the number of double-labeled cells in the VTA, including play duration and pin duration. Our results suggest that play in females likely induces dopamine release from mesocorticolimbic neurons to reinforce play behaviors. Our results also highlight a sex difference in the neural networks mediating play, thus emphasizing the importance of studying the neurobiology of play in both males and females.

Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar tissue (in emphysema) and airway remodeling (leading to chronic bronchitis) which cause difficulties in breathing. It is a growing public health concern with few therapeutic options that can reverse disease progression or mortality. This is in part because current treatments mainly focus on ameliorating symptoms induced by inflammatory pathways as opposed to curing disease. Hence, emerging research focused on upstream pathways are likely to be beneficial in the development of efficient therapeutics to address the root causes of disease. Some of these pathways include mitochondrial function, cytoskeletal structure and maintenance, and airway hydration, which are all affected by toxins that contribute to COPD. Because of the complexity of COPD and unknown targets for disease onset, simpler model organisms have proven to be useful tools in identifying disease-relevant pathways and targets. This review summarizes COPD pathology, current treatments, and therapeutic discovery research, with a focus on the aforementioned pathways that can advance the therapeutic landscape of COPD.

The authors have declared no conflicts of interest exist. AbstractAirway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease (COPD). COPD is the 4 th leading cause of death in the US and is impacted by cigarette smoking with no therapeutic options. We utilized a genetic selection approach in the amoeba Dictyostelium discoideum as a comparative discovery tool in lung biology to identify genetic protectors from cigarette smoke (CS). Adenine nucleotide translocase (ANT), a mitochondrial ADP/ATP transporter, was protective against CS in Dictyostelium and human bronchial epithelial cells. ANT2 gene expression is reduced in lung tissue from COPD patients and in a mouse smoking model. ANT1and ANT2 overexpression resulted in enhanced oxidative respiration and ATP flux. In addition to ANT's presence in the mitochondria, ANT1 and ANT2 reside at the plasma membrane in airway epithelial cells and this localization plays a role in how ANTs regulate airway homeostasis. ANT2 overexpression stimulates airway surface liquid hydration by ATP and maintains ciliary beating after CS exposure, which are key functions of the airway. Our study highlights the potential of ANT modulation in protecting from dysfunctional mitochondrial metabolism, airway hydration, and ciliary motility in COPD.