Sex differences in aggressive intensities and brain steroids during status resolution in a sex changing fish, Lythrypnus dalli.

For vertebrates living in social hierarchies, the neuroendocrine system regulates temporal aspects of aggressive interactions during status establishment. In teleost fishes, the sex steroids 17ß-estradiol (E2) and 11-ketotestosterone (KT), and the glucocorticoid, cortisol (CORT) are associated with aggression in distinct phases of their life history. Bluebanded gobies, Lythrypnus dalli, exhibit bidirectional sexual plasticity by responding to changes in their social structure by escalating aggression associated with neural changes that precede gonadal reorganization to the opposite sex. Here, we used a novel experimental design to investigate systemic (waterborne) and neural steroids associated with the earliest behavioral changes associated with feminization and masculinization during protandrous and protogynous sex change respectively. In stable social groups of wild-caught L. dalli comprising of one male and two females, we disrupted hierarchy by adding or removing a male, providing a social context for intrasexual aggression. Within only 30 min, males exhibited high rates of physical aggression inside the nest to maintain their territory, while females exhibited high rates of chases outside the nest to reestablish social status. During this period of instability, while waterborne steroids were not affected, brain E2 was higher in all fish and CORT was lower in male brains. Brain KT was higher in males who emerged as dominant compared to dominant females. Overall, a combination of differences in brain E2, CORT, and KT were important in the regulation of hierarchy re-establishment and maintenance. Rapid responses during conspecific aggressive encounters are likely mediated by neural steroid synthesis that precede changes in systemic steroids.

Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is recognized as a disease of accelerated lung aging. Over the past two decades, mounting evidence suggests an accumulation of senescent cells within the lungs of patients with COPD that contributes to dysregulated tissue repair and the secretion of multiple inflammatory proteins, termed the senescence-associated secretory phenotype (SASP). Cellular senescence in COPD is linked to telomere dysfunction, DNA damage, and oxidative stress. This review gives an overview of the mechanistic contributions and pathologic consequences of cellular senescence in COPD and discusses potential therapeutic approaches targeting senescence-associated signaling in COPD.

Airway Resistance Caused by Sphingomyelin Synthase 2 Insufficiency in Response to Cigarette Smoke.

Sphingomyelin synthase is responsible for the production of sphingomyelin (SGM), the second most abundant phospholipid in mammalian plasma, from ceramide, a major sphingolipid. Knowledge of the effects of cigarette smoke on SGM production is limited. In the present study, we examined the effect of chronic cigarette smoke on sphingomyelin synthase (SGMS) activity and evaluated how the deficiency of Sgms2, one of the two isoforms of mammalian SGMS, impacts pulmonary function. Sgms2-knockout and wild-type control mice were exposed to cigarette smoke for 6 months, and pulmonary function testing was performed. SGMS2-dependent signaling was investigated in these mice and in human monocyte-derived macrophages of nonsmokers and human bronchial epithelial (HBE) cells isolated from healthy nonsmokers and subjects with chronic obstructive pulmonary disease (COPD). Chronic cigarette smoke reduces SGMS activity and Sgms2 gene expression in mouse lungs. Sgms2-deficient mice exhibited enhanced airway and tissue resistance after chronic cigarette smoke exposure, but had similar degrees of emphysema, compared with smoke-exposed wild-type mice. Sgms2-/- mice had greater AKT phosphorylation, peribronchial collagen deposition, and protease activity in their lungs after smoke inhalation. Similarly, we identified reduced SGMS2 expression and enhanced phosphorylation of AKT and protease production in HBE cells isolated from subjects with COPD. Selective inhibition of AKT activity or overexpression of SGMS2 reduced the production of several matrix metalloproteinases in HBE cells and monocyte-derived macrophages. Our study demonstrates that smoke-regulated Sgms2 gene expression influences key COPD features in mice, including airway resistance, AKT signaling, and protease production.

Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease.

S100 calcium-binding protein A9 (S100A9) is elevated in plasma and bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared with in young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9-/- mice or mice administered paquinimod were exposed to chronic cigarette smoke. S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and forced expiratory volume in 0.05 s/forced vital capacity, compared with age-matched wild-type or vehicle-administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK and c-RAF phosphorylation, matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) release into the airways. Paquinimod administered to nonsmoked, aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor LY3214996 or the c-RAF inhibitor GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing Toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), or extracellular matrix metalloproteinase inducer (EMMPRIN) prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke-induced and age-related COPD.