ArticleBMC pulmonary medicine2021
SPAK-p38 MAPK signal pathway modulates claudin-18 and barrier function of alveolar epithelium after hyperoxic exposure.
Article in BMC pulmonary medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 19 citations in OpenAlex.
- Neonatal hyperoxia promotes macrophage senescence and lung injury via a p38MAPK-dependent secretome.American journal of respiratory cell and molecular biology · 2026Article
- Advances in research on hyperoxia-induced acute lung injury: from pathogenesis to therapy.Frontiers in cell and developmental biology · 2026Review
- Targeting Claudin18.2 for cancer theranostics: From molecular imaging to precision therapy.iScience · 2025Review
- Pancreatic Cancer: Pathogenesis and Clinical Studies.MedComm · 2025Review
- Oxidative stress-induced NCC activation in the development of nocturnal polyuria in mice: Therapeutic potential of a sustained hydrogen-releasing silicon-based agent.Biochemistry and biophysics reports · 2025Article
- Targeting solid tumor antigens with chimeric receptors: cancer biology meets synthetic immunology.Trends in cancer · 2024Review
- Zolbetuximab for Claudin18.2-positive gastric or gastroesophageal junction cancer.Therapeutic advances in medical oncology · 2024Review
- Dark horse target Claudin18.2 opens new battlefield for pancreatic cancer.Frontiers in oncology · 2024Review
- Post-translational modifications and bronchopulmonary dysplasia.Frontiers in pediatrics · 2024Review
- Expression patterns of claudins in cancer.Heliyon · 2023Review
- Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications.Frontiers in oncology · 2023Review
- Tight Junctions, the Epithelial Barrier, and Toll-like Receptor-4 During Lung Injury.Inflammation · 2022Review
- Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy.Biomarker research · 2022Review
- Role of SPAK-NKCC1 signaling cascade in the choroid plexus blood-CSF barrier damage after stroke.Journal of neuroinflammation · 2022Article
- Knockdown of long non-coding RNA CDKN2B-AS1 suppresses the progression of breast cancer by miR-122-5p/STK39 axis.Bioengineered · 2021Article
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Authors and funding
6 authors at 2 institutions in 1 country.
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Abstract
backgroundHyperoxia downregulates the tight junction (TJ) proteins of the alveolar epithelium and leads to barrier dysfunction. Previous study has showed that STE20/SPS1-related proline/alanine-rich kinase (SPAK) interferes with the intestinal barrier function in mice. The aim of the present study is to explore the association between SPAK and barrier function in the alveolar epithelium after hyperoxic exposure.
methodsHyperoxic acute lung injury (HALI) was induced by exposing mice to > 99% oxygen for 64 h. The mice were randomly allotted into four groups comprising two control groups and two hyperoxic groups with and without SPAK knockout. Mouse alveolar MLE-12 cells were cultured in control and hyperoxic conditions with or without SPAK knockdown. Transepithelial electric resistance and transwell monolayer permeability were measured for each group. In-cell western assay was used to screen the possible mechanism of p-SPAK being induced by hyperoxia.
resultsCompared with the control group, SPAK knockout mice had a lower protein level in the bronchoalveolar lavage fluid in HALI, which was correlated with a lower extent of TJ disruption according to transmission electron microscopy. Hyperoxia down-regulated claudin-18 in the alveolar epithelium, which was alleviated in SPAK knockout mice. In MLE-12 cells, hyperoxia up-regulated phosphorylated-SPAK by reactive oxygen species (ROS), which was inhibited by indomethacin. Compared with the control group, SPAK knockdown MLE-12 cells had higher transepithelial electrical resistance and lower transwell monolayer permeability after hyperoxic exposure. The expression of claudin-18 was suppressed by hyperoxia, and down-regulation of SPAK restored the expression of claudin-18. The process of SPAK suppressing the expression of claudin-18 and impairing the barrier function was mediated by p38 mitogen-activated protein kinase (MAPK).
conclusionsHyperoxia up-regulates the SPAK-p38 MAPK signal pathway by ROS, which disrupts the TJ of the alveolar epithelium by suppressing the expression of claudin-18. The down-regulation of SPAK attenuates this process and protects the alveolar epithelium against the barrier dysfunction induced by hyperoxia.
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