Abstract
During lipopolysaccharide (LPS)-induced sepsis, the liver plays central roles in toxins phagocytosis and clearance to protect the whole body. The liver cells were constantly irritated by LPS which leads to liver injury. While most anti-LPS agents showed little clinical activity against LPS-induced liver injury. Here, the protective effects of the synthetic peptide AWRK6 against LPS-induced liver injury have been investigated in vivo and in vitro. In mice liver homogenate, LPS administration elevated ALT (alanine aminotransferase), iNOS (inducible nitric oxide synthase) and repressed SOD (superoxide dismutase) activities and these changes were remarkably reversed by AWRK6. Histologically, AWRK6 effectively alleviated the histological changes and repressed LPS-induced neutrophils infiltration. By TUNEL assay on liver sections, AWRK6 was proven to inhibit apoptosis induced by LPS in mice livers, which was also verified by the protein levels of cleaved-caspase 9, Bax and Bcl-2. In addition, by in vitro study using HepG2 cells, AWRK6 was found to recover the LPS-reduced cell viability and reduce LPS-induced apoptosis. For mechanisms, AWRK6 was demonstrated to alleviate the LPS-induced phosphorylation of ERK, JNK and p38 MAPK, indicating the involvement of MAPKs in the protection of AWRK6 against liver injury. In summary, we have found the synthetic peptide AWRK6 as a promising novel agent for LPS-induced liver injury, by inhibiting cell apoptosis through MAPK signaling pathways, which might bring new strategies for the treatment of acute and chronic liver injuries.
Highlights
Lipopolysaccharides (LPS), a major component of gram-negative bacteria outer membrane, can induce sepsis and the mortality exceeds 20% [1]
The liver cells were constantly irritated by LPS, leading to liver injury [3,4]
Most anti-LPS agents, such as antibiotics and antibodies, showed little clinical activity against liver injury, such as the polymyxin antibiotics colistin and polymyxin B (PMB), which became clinically available for LPS neutralization in the 1950s before being shortly restricted due to its toxicity [5,6]
Summary
Lipopolysaccharides (LPS), a major component of gram-negative bacteria outer membrane, can induce sepsis and the mortality exceeds 20% [1]. The liver cells were constantly irritated by LPS, leading to liver injury [3,4]. It is urgent to develop novel agents and strategies against LPS, especially for liver injury. Recent studies revealed that antimicrobial peptides LL-37 and β-defensin could protect septic mice from death by neutralizing LPS [9,10]. LIinng of liver imnjiucreywinithhiLstPoSp-iantdhuocleodgiecnaldaontoaxleymsiisa,[1A3W], wRKh6ileptrheveednetetdailLePdSf-uinndcuticoendslaetnhdalmityecbhyanbliosmcksinogf LAPWS RK6 againsbtinLdPinSg-intodLuBcPedanlidvearttiennjuuartyinwg ethree sretillelausenkofnIoLw-1nβ., IL-6 and TNF-α. ALnivisemr sc.elAl WapRoKpt6oswisasanfoduMndAPasKapnaothvwelaaygseancttifvoartiLoPnSw-inerdeuced liver ienxjaumriiense,dthtoouagchceisnshtihbeitfiunngdlaivmeernctaelllmapecohpatnoissmis.s. AWRK6 was found as a novel agent for LPS-. Induced liver injuries, though inhibiting liver cell apoptosis
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