Abstract
Tussilagone, extracted from Tussilago farfara is an oriental medicine used for asthma and bronchitis. We investigated its mechanism of action, its inhibitory effects on lipopolysaccharide-induced inflammation in macrophages, and its impact on viability in a cecal ligation and puncture (CLP)-induced mouse model of sepsis. Tussilagone suppressed the expression of the inflammatory mediators, nitric oxide and prostaglandin E2, and the inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 (HMGB1), in lipopolysaccharide-stimulated RAW 264.7 cells and peritoneal macrophages. Tussilagone also reduced the activation of the mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) involved in the activation of various inflammatory mediators in activated macrophages. Moreover, tussilagone administration (1 mg/kg and 10 mg/kg) produced decreased mortality and lung injury in CLP-activated septic mice. Augmented expression of cyclooxygenase (COX)-2 and TNF-α in pulmonary alveolar macrophages of septic mice were attenuated by tussilagone administration. Tussilagone also suppressed the induction of nitric oxide, prostaglandin E2, TNF-α and HMGB1 in the serum of the septic mice. Overall, tussilagone exhibited protective effects against inflammation and polymicrobial sepsis by suppressing inflammatory mediators possibly via the inhibition of NF-κB activation and the MAP kinase pathway. These results suggest the possible use of tussilagone for developing novel therapeutic modalities for sepsis and other inflammatory diseases.
Highlights
Sepsis is a major life-threatening issue caused by a dysregulated immune response to aggressive infection
TS inhibits the LPS-induced production of the inflammatory mediators nitric oxide (NO) and prostaglandin E2 (PGE2) [11,21.12.]T
RHeofewreevnecre,sthe oral administration of TS suppressed the activation of these factors in the septic animals (Figure 8A–D). These results suggest that TS can protect against the damaging systemic inflammation 1t.hat Koicmcu, rYs.Kd.u; Yrienog, Mse.pGs.;isO. h, B.K.; Kim, H.Y.; Yang, H.J.; Cho, S.S.; Gil, M.; Lee, K.J
Summary
Sepsis is a major life-threatening issue caused by a dysregulated immune response to aggressive infection. Sepsis remains a leading cause of death worldwide [1,2]. Excessive inflammation is associated with the initial stages of sepsis. Strong activation of the innate immune system is mediated by pathogens. The excessive activation of macrophages can lead to systematic inflammation and organ damage [3]. The activation of nuclear factor κB (NF-κB) promotes the expression of pro-inflammatory cytokines and inflammatory mediators including tumor necrosis factor alpha (TNF-α), nitric oxide (NO) and prostaglandin E2 (PGE2) [4]. High-mobility group box (HMIGnt.BJ.1M)ol.iSsci.a201c7y, 1t8o, 2k74in e identified as a late mediator of sepsis [5] and that p2loaf y14s a critical role in endotEhxecleisaslivceeilnlflbamarmriaetirondiissrausspoctiiaotnedbwyithretahreriannitigailnstgagtehseofascetpinsis.cySttroonskgealcetitvoantioinnotof thaecontractile phenotypienn[a6te].immHuMneGsyBs1temcoins tmreibduiatteeds btyoptahtheoghenigs.hMlaectrhopahliatgyesoefxesrtepposwiservfuilarelgautlea-taorcytirnoglesdinownstream effectors [t7h,e8]in. The effects of TS in animal models of inflammation remain to be elucidated
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