D-carvone attenuates LPS-induced acute lung injury via TLR4/NF-κB and Nrf2/HO-1 signaling pathways in rats

Naunyn Schmiedebergs Arch Pharmacol. 2025 Sep;398(9):12215-12225. doi: 10.1007/s00210-025-04024-y. Epub 2025 Mar 21.

Abstract

Acute lung injury (ALI) is a severe respiratory disorder associated with high morbidity and mortality. Lipopolysaccharide (LPS) is widely used to induce ALI in animal models. D-carvone, a natural monoterpene, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effects of D-carvone on LPS-induced ALI in rats. Thirty-six male rats were randomly divided into six groups (n = 6): control, D-carvone (10 mg/kg and 20 mg/kg p.o.), LPS (10 mg/kg E. coli lipopolysaccharide i.p.), and LPS + D-carvone (LPS with either 10 or 20 mg/kg D-carvone). D-carvone was administered orally once daily for 10 days. On day 10, sepsis was induced with LPS administration, and samples were collected after 6 h under deep anesthesia. LPS administration caused significant lung injury, as evidenced by increased histopathological scores, upregulation of pro-inflammatory markers (TLR4, IL-1β, TNF-α), and oxidative stress (increased MDA, decreased GSH and SOD). Treatment with D-carvone at both doses significantly attenuated these changes. D-carvone downregulated pro-inflammatory markers, upregulated anti-inflammatory (NRF2) and anti-apoptotic (Bcl-2) proteins, and reduced the levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8) in lung tissues. In conclusion, D-carvone protects against LPS-induced ALI in rats, possibly through its anti-inflammatory and antioxidant properties. These findings suggest that D-carvone could be a potential therapeutic candidate for preventing and treating ALI.

Keywords: Apoptosis; Cytokines; D-carvone; Inflammation; Lung injury; Oxidative stress; Sepsis.

MeSH terms

  • Acute Lung Injury* / chemically induced
  • Acute Lung Injury* / drug therapy
  • Acute Lung Injury* / metabolism
  • Acute Lung Injury* / pathology
  • Acute Lung Injury* / prevention & control
  • Animals
  • Anti-Inflammatory Agents* / pharmacology
  • Anti-Inflammatory Agents* / therapeutic use
  • Antioxidants / pharmacology
  • Cyclohexane Monoterpenes* / pharmacology
  • Cytokines / metabolism
  • Heme Oxygenase (Decyclizing) / metabolism
  • Lipopolysaccharides
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / metabolism

Substances

  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • Toll-Like Receptor 4
  • Nfe2l2 protein, rat
  • Cyclohexane Monoterpenes
  • NF-kappa B
  • carvone
  • Tlr4 protein, rat
  • Anti-Inflammatory Agents
  • Hmox1 protein, rat
  • Antioxidants
  • Heme Oxygenase (Decyclizing)
  • Cytokines