Resolvin Conjugates in Tissue Regeneration 1 Promote Alveolar Fluid Clearance by Activating Alveolar Epithelial Sodium Channels and Na, K-ATPase in Lipopolysaccharide-Induced Acute Lung Injury

Abstract

Acute respiratory distress syndrome (ARDS), a common and fatal clinical condition, is characterized by the destruction of epithelium and augmented permeability of the alveolar-capillary barrier. Resolvin conjugates in tissue regeneration (RCTR1) is an endogenous lipid mediator derived from DHA, exerting pro-resolution effects in the process of inflammation. In our research, we evaluated the role of RCTR1 in alveolar fluid clearance (AFC) in Lipopolysaccharide-induced ARDS/ALI rat model. Rats were injected with RCTR1 (5 μg/kg) via caudal veins 8h after LPS (14 mg/kg) treatment, then AFC was estimated after 1h of ventilation. Primary type II alveolar epithelial cells (AEC II) were incubated with LPS (1 ug/ml) with or without RCTR1 (10 nM) for 8 h. Our results showed that RCTR1 significantly enhanced the survival rate, promoted the AFC, and alleviated LPS-induced ARDS/ALI in vivo. Furthermore, RCTR1 remarkably elevated the protein expression of sodium channels and Na, K-ATPase, and the activity of Na, K-ATPase in vivo and in vitro. Additionally, RCTR1 also decreased Nedd4-2 level via up-regulating P-Akt expression. Besides, inhibitors of ALX, cAMP, and PI3K (BOC-2, KH-7, and LY294002) notably inhibited the effects of RCTR1 on AFC. In summary, RCTR1 enhances the protein levels of sodium channels and Na, K-ATPase, and the Na, K-ATPase activity to improve AFC in ALI through ALX/cAMP/PI3K/Nedd4-2 pathway, suggesting that RCTR1 may become a therapeutic drug for ARDS/ALI.

Hypoxia Aggravates Inhibition of Alveolar Epithelial Na-Transport by Lipopolysaccharide-Stimulation of Alveolar Macrophages

“…It appears that in severe lung injury other mediators such as NO, proteases, and oxidants involved in different signaling pathways may also participate along with alveolar epithelial cell injury [ 7 ]. Recent reports showing the resolution of lung edema and injury in-vivo and in-vitro through ALX/cAMP/PI3K/Nedd4-2 and WNK4/SPAK axis [ 47 , 48 ] support this argument. For example, Resolvin conjugates in tissue regeneration 1 (RCTR1), a series of docosahexaenoic acid–derived lipid mediators which can be released from macrophages when externally applied to LPS induced lung injury model upregulates ENaC abundance and improves alveolar fluid clearance [ 47 ].…”

“…Recent reports showing the resolution of lung edema and injury in-vivo and in-vitro through ALX/cAMP/PI3K/Nedd4-2 and WNK4/SPAK axis [ 47 , 48 ] support this argument. For example, Resolvin conjugates in tissue regeneration 1 (RCTR1), a series of docosahexaenoic acid–derived lipid mediators which can be released from macrophages when externally applied to LPS induced lung injury model upregulates ENaC abundance and improves alveolar fluid clearance [ 47 ]. Mesenchymal stem cells secrete a wide range of cytokines, growth factors, and microRNAs [ 49 ] attenuating edematous lung injury via enhancing γ-ENaC expression, through activating PI3K/AKT signaling [ 36 ].…”

Stereochemistry and functions of the new cysteinyl‐resolvin, 4S,5R‐RCTR1, in efferocytosis and erythrophagocytosis of human senescent erythrocytes

“…Recently, for example, Ma et al demonstrated that PCTR1 inhibits macrophage pyroptosis, attenuates lung damage, and improves mouse survival in LPS‐induced sepsis 50 . In addition, RCTR1 accelerates the rate of alveolar fluid clearance and promotes the resolution of inflammation in acute lung injury 51 . Thus, it is likely that the 4S,5R‐RCTR1 will also demonstrate potent protective actions across diverse disease models.…”

“…50 In addition, RCTR1 accelerates the rate of alveolar fluid clearance and promotes the resolution of inflammation in acute lung injury. 51 Thus, it is likely that the 4S,5R-RCTR1 will also demonstrate potent protective actions across diverse disease models. SPMs are biosynthesized from omega-3 essential PUFAs, primarily docosahexaenoic acid (DHA) and EPA, in the presence of active enzymes including lipoxygenases, hydrolases, and GSTs that produce and act on specific epoxide-containing intermediates.…”

Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS)

“…Moreover, the important role of the macrophage-derived specialized pro-resolving mediators (SPMs) in promoting AFC during ARDS has been gradually recognized [ 284 ]. For example, the resolvin conjugates in tissue regeneration 1 [ 285 ] as well as the maresin conjugates in tissue regeneration 1 [ 204 ] belong to SPMs, which have been recently implicated to upregulate ENaC and Na,K-ATPase by activating the cAMP/PI3K/AKT signaling pathways, and results in alleviating pulmonary edema in preclinical ARDS models. However, there is a lack of significant clinical studies of either administered exogenously or induction of endogenous SPMs in ARDS patients.…”