Dexamethasone Attenuates LPS-induced Acute Lung Injury through Inhibition of NF-κB, COX-2, and Pro-inflammatory Mediators

Abstract

Dexamethasone (DEX) is a synthetic glucocorticoid with potent anti-inflammatory effects that is widely used to treat inflammatory diseases. The aim of the present study was to investigate the possible protective effect of DEX on the lipopolysaccharides (LPS)-induced acute lung injury (ALI) in a mouse model. Animals were pretreated with DEX (5 and 10 mg/kg, i.p.) for seven days and acute lung injury was induced by intranasal (i.n.) administration of LPS on day 7. In the present study, administration of LPS resulted in significant increase in neutrophils and lymphocytes count whereas a substantial reduction in T cell subsets (CD3(+) and CD4(+)) and pro-inflammatory (IL-6 and TNF-α) cytokines occurred, which were reversed by DEX treatment. RT-PCR analysis revealed an increased mRNA expression of IL-6, TNF-α, COX-2, iNOS, and NF-κB p65 and decreased IL-10 in the LPS group, which were reversed by treatment with DEX in lung tissues. Western blot analysis revealed an increased expression of COX-2, iNOS and NF-κB p65 in the LPS-group, which was reduced by treatment with DEX. Compared with the LPS group, the DEX treatment also demonstrated a considerable increase in the protein expression level of IL-10 cytokine. Administration of LPS resulted in marked increase in malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity whereas noticeable decrease in glutathione (GSH) content. These changes were significantly reversed by treatment with DEX. The histological examinations revealed protective effect of DEX while LPS group aggravated lung injury. The present findings demonstrate the potent anti-inflammatory action of the DEX against acute lung injury induced by LPS.

Lipopolysaccharide (LPS) enhances prostate cancer metastasis potentially through NF‐κB activation and recurrent dexamethasone administration fails to suppress it in vivo

“…Animal model studies have demonstrated that DEX administration decreased lung tumor incidence in tobacco smoke‐exposed mice, and potentiates the effect of chemotherapeutic drugs . As an anti‐inflammatory drug, DEX is known to control the endotoxin‐induced lung inflammation and inflammatory cytokines . Clinical trial studies have shown the beneficial role of DEX in septic shock or systemic inflammatory condition .…”

IL‐1α inhibits proliferation and adipogenic differentiation of human adipose‐derived mesenchymal stem cells through NF‐κB‐ and ERK1/2‐mediated proinflammatory cytokines

“…During the early stage (0–3 days) of adipogenic differentiation, the expression of multiple proinflammatory cytokines (e.g., IL‐1β, IL‐6, IL‐8, and CCL2) dramatically decreases, which might contribute to suppression of NF‐κB and ERK1/2 pathways, as both can positively regulate proinflammatory cytokines (Al‐Harbi et al, ; Chen et al, ). Dexamethasone in adipogenic medium is a strong inhibitor of NF‐κB (Laberge et al, ; Al‐Harbi et al, ). In the present study, inhibition of the ERK1/2 pathway was detected by a Western blot, although the source of this inhibition was not clear.…”

Glucocorticoid resistance as a major drive in sepsis pathology

“…In one study, dexamethasone completely prevented TNF-induced SIRS, but was no longer protective when given 6h-8h after TNF challenge, suggesting the establishment of a quick GC resistance after TNF [119]. Also in numerous other models of acute, lethal inflammation, GCs protect when given in a close time frame compared to the challenge [170][171][172]. The protective power of GCs in pre-clinical sepsis models is less spectacular, but still significant.…”