Abstract
BackgroundAcute lung injury (ALI) is characterized by alveolar damage, increased levels of pro-inflammatory cytokines and impaired alveolar fluid clearance. Recently, we showed that the deletion of Apoptosis signal-regulating kinase 1 (ASK1) protects against hyperoxia-induced acute lung injury (HALI) by suppressing IL-1β and TNF-α. Previously, our data revealed that the suppressor of cytokine signaling-1 (SOCS-1) overexpression restores alveolar fluid clearance in HALI by inhibiting ASK-1 and suppressing IL-1β levels. Furthermore, IL-1β is known to inhibit the expression of epithelial sodium channel α-subunit (ENaC) via a p38 MAPK signaling pathway.ObjectiveTo determine whether SOCS-1 overexpression in MLE-12 cells would protect against IL-1β-mediated depletion of αENaC by suppressing ASK-1 expression.MethodsWe co-transfected MLE-12 cells with SOCS-1 overexpressing plasmid with or without IL-1β in the presence or absence of sodium channel inhibitor, amiloride. We measured potential difference, transepithelial current, resistance, and sodium uptake levels across MLE-12 cells. We studied the effect of ASK-1 depletion, as well as ASK-1 and SOCS-1 overexpression on αENaC expression.ResultsSOCS-1 overexpression sufficiently restored transepithelial current and resistance in MLE-12 cells treated with either IL-1β or amiloride. The αENaC mRNA levels and sodium transport were increased in SOCS-1 overexpressing MLE-12 cells exposed to IL-1β. Depletion of ASK-1 in MLE-12 cells increased αENaC mRNA levels. Interestingly, SOCS-1 overexpression restored αENaC expression in MLE-12 cells in the presence of ASK-1 overexpression.ConclusionCollectively, these findings suggest that SOCS-1 may exert its protective effect by rescuing αENaC expression via suppression of ASK-1.
Highlights
Acute lung injury (ALI) is a debilitating syndrome characterized by alveolar barrier damage in alveolar capillary endothelial cells and type I pneumocytes, resulting in a large uptake of fluid and macromolecules [1]
suppressor of cytokine signaling-1 (SOCS-1) overexpression restored αENaC expression in MLE-12 cells in the presence of Apoptosis signal–regulating kinase-1 (ASK-1) overexpression. Collectively, these findings suggest that SOCS-1 may exert its protective effect by rescuing αENaC expression via suppression of ASK-1
SOCS-1 suppresses the effect of IL-1β on potential difference (PD) and transepithelial current (TEC) across MLE-12 cells
Summary
Acute lung injury (ALI) is a debilitating syndrome characterized by alveolar barrier damage in alveolar capillary endothelial cells and type I pneumocytes, resulting in a large uptake of fluid and macromolecules [1]. The most common cause of ALI in patients is sepsis, pneumonia, or surgical procedures that involve transfusions and gastric aspirations Patients subjected to such conditions exhibit activation of inflammatory mediators, cytokines (e.g., IL-1β, IL-8, and TNFα), and lipid mediators (e.g. LT B4) in lung tissue [2]. Hyperoxia-induced oxidative stress is a critical model that is indicative of the toxic effects produced by acute lung injury, such as impairing the viability of epithelial and endothelial barriers, inhibiting oxidative phosphorylation, and inducing the release of toxic aldehydes (e.g. 4-HNE, MDA) and pro-inflammatory cytokines [10, 11]. Acute lung injury (ALI) is characterized by alveolar damage, increased levels of pro-inflammatory cytokines and impaired alveolar fluid clearance. IL-1β is known to inhibit the expression of epithelial sodium channel α-subunit (ENaC) via a p38 MAPK signaling pathway
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