Rhamnetin, a Natural Flavonoid, Ameliorates Organ Damage in a Mouse Model of Carbapenem-Resistant Acinetobacter baumannii-Induced Sepsis.

Abstract

In sepsis, the persistence of uncontrolled inflammatory response of infected host cells eventually leads to severe lung and organ failure and, ultimately, death. Carbapenem-resistant Acinetobacter baumannii (CRAB), causative bacteria of sepsis and lung failure in acute cases, belongs to a group of critical pathogens that cannot be eradicated using the currently available antibiotics. This underlines the necessity of developing new modes of therapeutics that can control sepsis at the initial stages. In this study, we investigated the anti-inflammatory activities in vitro and in vivo and the antiseptic effects of rhamnetin, a naturally occurring flavonoid. We found that among its isoforms, the potency of rhamnetin was less explored but rhamnetin possessed superior anti-inflammatory activity with least cytotoxicity. Rhamnetin showed significant anti-inflammatory effects in lipopolysaccharide-, CRAB-, and Escherichia coli (E. coli)-stimulated mouse macrophages by inhibiting the release of interleukin-6 and nitric oxide. In a mouse model of sepsis infected with clinically isolated CRAB or E. coli, rhamnetin significantly reduced the bacterial burden in the organs. In addition, normalized pro-inflammatory cytokine levels in lung lysates and histological analysis of lung tissue indicated alleviation of lung damage. This study implies that a potent natural product such as rhamnetin could be a future therapeutic for treating carbapenem-resistant gram-negative sepsis.