Luteolin Enhances Transepithelial Sodium Transport in the Lung Alveolar Model: Integrating Network Pharmacology and Mechanism Study

Abstract

Luteolin (Lut), a natural flavonoid compound existing in Perilla frutescens (L.) Britton, has been proven to play a protective role in the following biological aspects: inflammatory, viral, oxidant, and tumor-related. Lut can alleviate acute lung injury (ALI), manifested mainly by preventing the accumulation of inflammation-rich edematous fluid, while the protective actions of Lut on transepithelial ion transport in ALI were seldom researched. We found that Lut could improve the lung appearance/pathological structure in lipopolysaccharide (LPS)-induced mouse ALI models and reduce the wet/dry weight ratio, bronchoalveolar protein, and inflammatory cytokines. Meanwhile, Lut upregulated the expression level of the epithelial sodium channel (ENaC) in both the primary alveolar epithelial type 2 (AT2) cells and three-dimensional (3D) alveolar epithelial organoid model that recapitulated essential structural and functional aspects of the lung. Finally, by analyzing the 84 interaction genes between Lut and ALI/acute respiratory distress syndrome using GO and KEGG enrichment of network pharmacology, we found that the JAK/STAT signaling pathway might be involved in the network. Experimental data by knocking down STAT3 proved that Lut could reduce the phosphorylation of JAK/STAT and enhance the level of SOCS3, which abrogated the inhibition of ENaC expression induced by LPS accordingly. The evidence supported that Lut could attenuate inflammation-related ALI by enhancing transepithelial sodium transport, at least partially, via the JAK/STAT pathway, which may offer a promising therapeutic strategy for edematous lung diseases.

Anthrahydroquinone‑2,6‑disulfonate attenuates PQ‑induced acute lung injury through decreasing pulmonary microvascular permeability via inhibition of the PI3K/AKT/eNOS pathway

“…For instance, Okabe et al ( 54 ) found that orthotopic fetal lung tissue direct injection into the lungs of mice showed a preventive effect against PQ-induced ALI. Meanwhile, Chen et al ( 55 ) discovered that luteolin enhances trans-epithelial sodium transport in 3D alveolar epithelial organoid, effectively reducing respiratory symptoms. These studies have fully proven that organoid technology has broad application prospects in the field of personalized medicine.…”

Lonicera japonica Thunb extract ameliorates lipopolysaccharide-induced acute lung injury associated with luteolin-mediated suppression of NF-κB signaling pathway

“…For example, Lut reduced the LPS-induced fatal toxicity and expression of pro-inflammatory factors in mice [ 28 ]. In addition, Lut blocked prostate cancer cell growth and promoted their apoptosis [ 17 ]. Studies have displayed the regulatory effects of Lut on neutrophils [ 29 – 31 ].…”

“…Human alveolar epithelial cells (BEAS-2B) were provided by procell (Wuhan, China) and cultivated in DMEM (Solarbio, Beijing, China) that contained 1% antibiotics and 10% fetal bovine serum (FBS) (Solarbio) under 37 °C with 5% CO 2 . To construct ALI cell model, BEAS-2B cells (1.0 × 10 4 /well) were inoculated in the 96-well plates, followed by 12 h treatment with 10 µg/mL LPS or PBS (Solarbio) [ 17 ]. For drug treatment group, cells were treated with LTE at 10 ug/mL (Xian Musen Bioengineering, Xian, China) or Lut (Solarbio) at 10 µM for 24 h and then stimulated with LPS(10 µg/mL, 12 h) [ 17 , 18 ].…”

“…To construct ALI cell model, BEAS-2B cells (1.0 × 10 4 /well) were inoculated in the 96-well plates, followed by 12 h treatment with 10 µg/mL LPS or PBS (Solarbio) [ 17 ]. For drug treatment group, cells were treated with LTE at 10 ug/mL (Xian Musen Bioengineering, Xian, China) or Lut (Solarbio) at 10 µM for 24 h and then stimulated with LPS(10 µg/mL, 12 h) [ 17 , 18 ].…”

Phytochemicals and Vitamin D for a Healthy Life and Prevention of Diseases

“…Sustainable Development Goals (SDGs) [8]. Acute lung injury (ALI) such as COVID-19 induces extensive lung inflammation and finally causes fatal respiratory failure [9]. In addition, chronic-inflammation-induced lung disorders such as interstitial pneumonia gradually damage lung alveoli, and COPD sometimes manifests as a sequela of COVID-19; both of these disorders are becoming major problems [10,11].…”