Luteolin attenuates lipopolysaccharide-induced acute lung injury/acute respiratory distress syndrome by activating alveolar epithelial sodium channels via cGMP/PI3K pathway

Hou, Yapeng; Li, Jun; Ding, Yan; Cui, Yong; Nie, Hongguang

doi:10.1016/j.jep.2021.114654

Cited by 23 publications

(12 citation statements)

References 41 publications

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“…Mice with ENaC-α KO were proved to exhibit severe ARDS at birth and even to die within 40 h after birth due to the inability to remove fluid from the lungs [ 31 ]. Up-regulation of ENaC expression was demonstrated to promote AFC and to alleviate lung edema in animal models of ALI [ 32 , 33 ]. It is worth noting that there is a closely relationship between serum PEBP4 levels and sodium ion concentration [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway

Shi,

Huang,

et al. 2024

Cell. Mol. Life Sci.

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Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase β1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.

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Section: Discussionmentioning

confidence: 99%

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway

Shi,

Huang,

et al. 2024

Cell. Mol. Life Sci.

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“…The reason may be explained by the phenomenon that the activation of NF-κB pathway related to proinflammatory stimuli might downregulate serine-threonine kinase SGK1 expression, a stimulator of ENaC, and lead to decreased α-ENaC mRNA level consequently [ 13 , 17 , 60 , 61 ]. Unfortunately, given that A549 cells could not be a perfect model to establish alveolar epithelial barrier due to the disability to form tight junction, we chose permeabilized H441 cell monolayer as an alternative model in studying the function of epithelial sodium transport [ 23 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…H441 cell (ATCC, Manassas, USA) monolayers were cultured on 24-well Transwell inserts (3413, Corning-Costar, Lowell, USA) as described previously [ 23 ]. Cells were seeded at a density about 5 × 10 6 cells/cm 2 , then cultured in a humidified atmosphere of 5% CO 2 at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Submersion and hypoxia inhibit alveolar epithelial Na+ transport through ERK/NF-κB signaling pathway

Zhou

Hou

et al. 2023

Respir Res

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Background Hypoxia is associated with many respiratory diseases, partly due to the accumulation of edema fluid and mucus on the surface of alveolar epithelial cell (AEC), which forms oxygen delivery barriers and is responsible for the disruption of ion transport. Epithelial sodium channel (ENaC) on the apical side of AEC plays a crucial role to maintain the electrochemical gradient of Na+ and water reabsorption, thus becomes the key point for edema fluid removal under hypoxia. Here we sought to explore the effects of hypoxia on ENaC expression and the further mechanism related, which may provide a possible treatment strategy in edema related pulmonary diseases. Methods Excess volume of culture medium was added on the surface of AEC to simulate the hypoxic environment of alveoli in the state of pulmonary edema, supported by the evidence of increased hypoxia-inducible factor-1 expression. The protein/mRNA expressions of ENaC were detected, and extracellular signal-regulated kinase (ERK)/nuclear factor κB (NF-κB) inhibitor was applied to explore the detailed mechanism about the effects of hypoxia on epithelial ion transport in AEC. Meanwhile, mice were placed in chambers with normoxic or hypoxic (8%) condition for 24 h, respectively. The effects of hypoxia and NF-κB were assessed through alveolar fluid clearance and ENaC function by Ussing chamber assay. Results Hypoxia (submersion culture mode) induced the reduction of protein/mRNA expression of ENaC, whereas increased the activation of ERK/NF-κB signaling pathway in parallel experiments using human A549 and mouse alveolar type 2 cells, respectively. Moreover, the inhibition of ERK (PD98059, 10 µM) alleviated the phosphorylation of IκB and p65, implying NF-κB as a downstream pathway involved with ERK regulation. Intriguingly, the expression of α-ENaC could be reversed by either ERK or NF-κB inhibitor (QNZ, 100 nM) under hypoxia. The alleviation of pulmonary edema was evidenced by the administration of NF-κB inhibitor, and enhancement of ENaC function was supported by recording amiloride-sensitive short-circuit currents. Conclusions The expression of ENaC was downregulated under hypoxia induced by submersion culture, which may be mediated by ERK/NF-κB signaling pathway.

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“…RAW264.7 cells were plated in 96-well plates at a density of 2000 cells per well. The cells were treated with different concentrations of luteolin (5,10,20,40,60, 80, 100, 120, and 140 μM). After 24 h, 10 μL of cell counting kit 8 reagent was added to each well, and the cells were incubated at 37°C for 2 h. When the medium's color turned orange, the culture was terminated, and a microplate reader was used to measure the absorbance at 490 nm.…”

Section: Cell Viabilitymentioning

confidence: 99%

A Network Pharmacology-Based Treatment Analysis of Luteolin for Regulating Pyroptosis in Acute Lung Injury

Zhang

Jiang

et al. 2023

Shock

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Background: Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome, are complicated pulmonary inflammatory conditions for which standard therapeutics are still not well established. Although increasing research has indicated the anti-inflammatory, anticancer, and antioxidant effects of luteolin, especially in lung diseases, the molecular mechanisms underlying luteolin treatment remain largely unclear. Methods: The potential targets of luteolin in ALI were explored using a network pharmacology-based strategy and further validated in a clinical database. The relevant targets of luteolin and ALI were first obtained, and the key target genes were analyzed using a protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The targets of luteolin and ALI were then combined to ascertain the relevant pyroptosis targets, followed by Gene Ontology analysis of core genes and molecular docking of key active compounds to the antipyroptosis targets of luteolin in resolving ALI. The expression of the obtained genes was verified using the Gene Expression Omnibus database. In vivo and in vitro experiments were performed to explore the potential therapeutic effects and mechanisms of action of luteolin against ALI. Results: Fifty key genes and 109 luteolin pathways for ALI treatment were identified through network pharmacology. Key target genes of luteolin for treating ALI via pyroptosis were identified. The most significant target genes of luteolin in ALI resolution included AKT1, NOS2, and CTSG. Compared with controls, patients with ALI had lower AKT1 expression and higher CTSG expression. Luteolin simply reduced systemic inflammation and lung tissue damage in septic mice. Furthermore, we blocked AKT1 expression and found luteolin reduced the degree of lung injury and affected NOS2 levels. Conclusions: As demonstrated by a network pharmacology approach, luteolin may exert an antipyroptosis effect on ALI via AKT1, NOS2, and CTSG.

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Luteolin attenuates lipopolysaccharide-induced acute lung injury/acute respiratory distress syndrome by activating alveolar epithelial sodium channels via cGMP/PI3K pathway

Cited by 23 publications

References 41 publications

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway

Submersion and hypoxia inhibit alveolar epithelial Na+ transport through ERK/NF-κB signaling pathway

A Network Pharmacology-Based Treatment Analysis of Luteolin for Regulating Pyroptosis in Acute Lung Injury

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