Abstract
Sepsis is a complex, multifactorial, rapidly progressive disease characterized by an overwhelming activation of the immune system and the countervailing antiinflammatory response. In the current study in murine peritoneal macrophages, chlorogenic acid suppressed endotoxin-induced high mobility group box 1 (HMGB1) release in a concentration-dependent manner. Administration of chlorogenic acid also attenuated systemic HMGB1 accumulation in vivo and prevented mortality induced by endotoxemia and polymicrobial sepsis. The mechanisms of action of chlorogenic acid included attenuation of the increase in toll-like receptor (TLR)-4 expression and suppression of sepsis-induced signaling pathways, such as c-Jun NH₂-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB, which are critical for cytokine release. The protection conferred by chlorogenic acid was achieved through modulation of cytokine and chemokine release, suppression of immune cell apoptosis and augmentation of bacterial elimination. Chlorogenic acid warrants further evaluation as a potential therapeutic agent for the treatment of sepsis and other potentially fatal systemic inflammatory disorders.
Highlights
The dramatic rise in the incidence of sepsis, a systemic inflammatory response secondary to infection that leads to multiorgan failure and death, has been fuelled by an increase in the number of invasive surgical techniques performed during the past several decades
Chlorogenic acid suppressed the release of macrophage inflammatory protein (MIP)-2, tumor necrosis factor (TNF)-α and IL-1β in LPS-stimulated macrophages (Figures 1B, D, E), but it did not affect the release of IL-6
Our results showed that chlorogenic acid significantly inhibited nuclear factor (NF)-κB, Jun NH2-terminal kinase (JNK) and p38 mitogenactivated protein kinase (MAPK) activation, but no extracellular signal–regulated kinase (ERK) inhibitory effects were observed
Summary
The dramatic rise in the incidence of sepsis, a systemic inflammatory response secondary to infection that leads to multiorgan failure and death, has been fuelled by an increase in the number of invasive surgical techniques performed during the past several decades. The importance of high mobility group box 1 (HMGB1) in sepsis was suggested by the observation that increased serum concentrations of HMGB1 were associated with decreased survival in septic patients [2]. With Xigris® (activated protein C) having shown limited survival benefit in a restricted population [3], there is a substantial need for an effective therapy that will decrease morbidity and mortality associated with sepsis. Chlorogenic acid is a phenolic compound found in many plants, and its antioxidant activity is more accessible than many other flavonoids [4]. Recent studies have reported that chlorogenic acid is protective against acute lung injury induced by lipopolysaccharide (LPS) [7], and chlorogenic acid was shown to protect animals challenged by intraperitoneal injection of LPS via the suppression of hepatic toll-like receptor (TLR)-4 mRNA expression [8]. In addition to its antioxidant effects, chlorogenic acid suppresses cellular apoptosis and blocks the activation of nuclear factor (NF)-κB, activator protein (AP)-1 and mitogenactivated protein kinase (MAPK) in vitro [9,10]
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