ABSTRACT
PURPOSE: The Salton Sea, California's largest lake, is designated as an agricultural drainage reservoir. In recent years, the lake has experienced shrinkage due to reduced water sources, increasing levels of aerosolized dusts in surrounding regions. Communities surrounding the Salton Sea have increased asthma prevalence versus the rest of California; however, a connection between dust inhalation and lung health impacts has not been defined. METHODS: We used an established intranasal dust exposure murine model to study the lung inflammatory response following single or repetitive (7-day) exposure to extracts of dusts collected in regions surrounding the Salton Sea (SSDE), complemented with in vitro investigations assessing SSDE impacts on the airway epithelium. RESULTS: In these investigations, single or repetitive SSDE exposure induced significant lung inflammatory cytokine release concomitant with neutrophil influx. Repetitive SSDE exposure led to significant lung eosinophil recruitment and altered expression of genes associated with allergen-mediated immune response, including Clec4e. SSDE treatment of human bronchial epithelial cells (BEAS-2B) induced inflammatory cytokine production at 5- and 24-hours post-treatment. When BEAS-2B were exposed to protease activity-depleted SSDE (PDSSDE) or treated with SSDE in the context of protease-activated receptor-1 and -2 antagonism, inflammatory cytokine release was decreased. Furthermore, repetitive exposure to PDSSDE led to decreased neutrophil and eosinophilic influx and IL-6 release in mice compared to SSDE-challenged mice. CONCLUSION: These investigations demonstrate potent lung inflammatory responses and tissue remodeling in response to SSDE, in part due to environmental proteases found within the dusts. These studies provide the first evidence supporting a link between environmental dust exposure, protease-mediated immune activation, and respiratory disease in the Salton Sea region.
ABSTRACT
Endogenous hydrogen sulfide (H2 S), synthesized by cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE), is a potent vasodilator that can be stimulated by estradiol-17ß (E 2 ß) in uterine artery (UA) smooth muscle (UASMC) in vivo; however, the underlying mechanisms are unknown. This study tested a hypothesis that E 2 ß stimulates H 2 S biosynthesis by upregulating CBS expression via specific estrogen receptor (ER). Treatment with E 2 ß stimulated time- and concentration- dependent CBS and CSE messenger RNA (mRNA) and protein expressions, and H 2 S production in cultured primary UASMC isolated from late pregnant ewes, which were blocked by ICI 182,780. Treatment with specific ERα or ERß agonist mimicked these E 2 ß-stimulated responses, which were blocked by specific ERα or ERß antagonist. Moreover, E 2 ß activated both CBS and CSE promoters and ICI 182,780 blocked the E 2 ß-stimulated responses. Thus, E 2 ß stimulates H 2 S production by upregulating CBS and CSE expression via specific ER-dependent transcription in UASMC in vitro.
