Cipepofol attenuates endothelial barrier dysfunction in acute lung injury through DUSP1-dependent suppression of MAPK signaling.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Cipepofol attenuates endothelial barrier dysfunction in acute lung injury through DUSP1-dependent suppression of MAPK signaling.
Συγγραφείς: Zhou S; Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China., He X; Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China., Ni X; Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China., Wang A; Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: wangaz@sjtu.edu.cn., Xu X; Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: 2015xuxiaotao@sjtu.edu.cn.
Πηγή: Biochemical pharmacology [Biochem Pharmacol] 2026 Aug; Vol. 250 (Pt 1), pp. 117995. Date of Electronic Publication: 2026 Apr 19.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE
Imprint Name(s): Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
Ιατρικοί όροι (MeSH): Acute Lung Injury*/metabolism , Acute Lung Injury*/drug therapy , Acute Lung Injury*/pathology , MAP Kinase Signaling System*/drug effects , MAP Kinase Signaling System*/physiology , Dual Specificity Phosphatase 1*/metabolism , Dual Specificity Phosphatase 1*/genetics, Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Sepsis/drug therapy ; Sepsis/metabolism ; Receptors, GABA-A/metabolism ; Capillary Permeability/drug effects ; Animals ; Humans ; Male ; Mice ; Mice, Inbred C57BL
Περίληψη: Vascular endothelial cell dysfunction leads to the breakdown of endothelial barrier integrity, which contributes to sepsis-induced acute lung injury (ALI). The study investigates the role of Cipepofol in regulating endothelial permeability and inflammation during sepsis using a cecal ligation and puncture (CLP) mouse model and human umbilical vein endothelial cells (HUVECs). Our findings demonstrate that Cipepofol treatment inhibits cytoskeletal stress fiber formation and upregulates junction proteins VE-cadherin, thereby preserving endothelial barrier function. These effects were mediated through the γ-aminobutyric acid type A (GABAA) receptor α1 subunit (GABAA receptor α1). Cipepofol improved sepsis outcomes, including decreased lung injury, leukocyte infiltration, and vascular permeability. Mechanistically, cipepofol-dependent GABAA receptor α1 modulated the expression of dual-specificity phosphatase 1 (DUSP1) in lung tissue and endothelial cells of septic mice. DUSP1 knockdown exacerbated p38 and extracellular signal-regulated kinase (ERK)-MAPK signaling and mitochondrial dysfunction, and abolished the protective effects of Cipepofol against lipopolysaccharide (LPS)-induced mitochondrial oxidative stress. Conversely, genetic or pharmacological inhibition of GABAA receptor α1 reversed Cipepofol-mediated suppression of p38/ERK-MAPK signaling and reactive oxygen species (ROS) accumulation, confirming DUSP1 as a key downstream mediator. Together, our study unveils that Cipepofol preserves endothelial integrity by depending on GABAA receptor α1 to modulate DUSP1 expression, thereby suppressing p38/ERK-MAPK signaling and mitochondrial dysfunction. These findings highlight a potential therapeutic strategy for sepsis-induced ALI.
(Copyright © 2026 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Σχόλια: Erratum in: Biochem Pharmacol. 2026 Jun 11;251(Pt 2):118134. doi: 10.1016/j.bcp.2026.118134.. (PMID: 42275890)
Erratum in: Biochem Pharmacol. 2026 Jun 15;251(Pt 2):118146. doi: 10.1016/j.bcp.2026.118146.. (PMID: 42296764)
Contributed Indexing: Keywords: Acute lung injury; Cipepofol; DUSP1; GABA(A) receptor α1
Substance Nomenclature: EC 3.1.3.48 (Dual Specificity Phosphatase 1)
EC 3.1.3.48 (Dusp1 protein, mouse)
EC 3.1.3.48 (DUSP1 protein, human)
0 (Receptors, GABA-A)
Entry Date(s): Date Created: 20260421 Date Completed: 20260611 Latest Revision: 20260615
Update Code: 20260616
DOI: 10.1016/j.bcp.2026.117995
PMID: 42013957
Βάση Δεδομένων: MEDLINE