Protective effects of avasopasem manganese (GC4419) against sepsis-induced acute lung injury: A comprehensive experimental study.

Abstract

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, characterised by excessive oxidative stress and cytokine release. This study evaluated the protective effects of avasopasem manganese (AVA), a superoxide dismutase mimetic, on sepsis-induced lung injury in a murine model.

Methods: Sepsis was induced in mice via cecal ligation and puncture (CLP). The study included five groups (n = 8/group): Sham (control), CLP (Sepsis) and CLP + AVA at doses of 2.5, 5 or 10 mg/kg. Serum and lung tissue samples were analysed for pro-inflammatory cytokines (tumour necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6), oxidative stress markers (malondialdehyde, MDA) and antioxidant enzyme activity (superoxide dismutase, SOD; glutathione, GSH; catalase, CAT). Quantitative real-time PCR (qRT-PCR) assessed cytokine mRNA expression, while histopathological examination evaluated lung tissue damage.

Results: Serum and lung tissue levels of TNF-α, IL-1β, IL-6 and MDA were lowest in the healthy control group and highest in the sepsis group (p < .001). A significant dose-dependent decrease in cytokine levels was observed with increasing doses of AVA. Regarding antioxidants, SOD, GSH and CAT enzyme activities were highest in the control group and lowest in the sepsis group (p < .05). A significant increase in antioxidant enzyme activity was observed with increasing doses of AVA. In molecular analyses, the expression levels of TNF-α, IL-1β and IL-6 were highest in the sepsis group, while relative messenger RNA (mRNA) expression results changed inversely with the drug dosage. Histopathological analyses revealed inflammation, edema and hyaline membrane formation in the sepsis group, whereas increasing doses of the drug showed improvement in lung tissue.

Conclusions: AVA demonstrated a significant protective effect against sepsis-induced lung injury through its antioxidant and anti-inflammatory properties. The most effective dose was determined to be 10 mg/kg. These findings suggest the potential use of AVA as an adjunctive agent in sepsis treatment.