Journal
ONCOTARGET
Volume 6, Issue 34, Pages 35478-35495Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6071
Keywords
sepsis; EGFR; tumor necrosis factor-alpha; cardiac failure; Pathology Section
Categories
Funding
- National Natural Science Foundation of China [81301664, 81173168]
- Natural Science Foundation of Guangdong Province [S2013010014312]
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To study the effect of EGFR activation on the generation of TNF-alpha and the occurrence of cardiac dysfuncetion during sepsis, PD168393 and erlotinib (both are EGFR inhibitors) were applied to decreased the production of TNF-alpha and phosphrylation of ERK1/2 and p38 induced by LPS in cardiomyocytes. These results were further proved by specifically knocked down the expression of EGFR in vitro. Both TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor, and TGF-alpha neutralizing antibody could inhibit the activation of EGFR and the generation of TNF-alpha mRNA after LPS treatment. The increase of TGF-alpha in response to LPS could also be suppressed by TAPI-1. On the other hand, exogenous TGF-alpha increased the expression of TNF-alpha mRNA and partially reversed the inhibitory effect of TAPI-1 on expression of TNF-alpha mRNA in response to LPS indicating that the transactivation of EGFR by LPS in cardiomyocytes needs the help of TACE and TGF-alpha. In endotoxemic mice, inhibition the activation of EGFR not only decreased TNF-alpha production in the myocardium but also improved left ventricular pump function and ameliorated cardiac dysfunction and ultimately improved survival rate. All these results provided a new insight of how EGFR regulation the production of TNF-alpha in cardiomyocytes and a potential new target for the treatment of cardiac dysfunction in sepsis.
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