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Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies
Published on: April 11, 2012
ANGIOGENESIS INHIBITOR ENDOSTATIN PROTECTS MICE WITH SEPSIS FROM MULTIPLE ORGAN DYSFUNCTION SYNDROME
1*Translational Medicine Center of Sepsis †Department of Critical Care Medicine, The Third Xiangya Hospital ‡Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.
Abstract:
Endostatin is an endogenous inhibitor of vascular endothelium. It can inhibit endothelial cell migration, proliferation, and vascular angiogenesis and is mainly used for anticancer therapy. We have previously found that endostatin is an important node protein in the pathogenesis of sepsis. However, its impacts on sepsis have not yet been reported. We established a septic mouse model using cecal ligation and puncture (CLP) and gave the mice either endostatin or placebo (saline). The effects of endostatin on serum enzyme, Evans blue leakage, lung wet-to-dry weight ratio, and cytokine (tumor necrosis factor α, interleukin 1β [IL-1β], and IL-6) production were assessed. Survival rates were observed for up to 3 days. In addition, we examined the effects of endostatin on serum vascular endothelial growth factor A (VEGF-A), VEGF-C, and pathological changes and scores of lung tissues as well as the phosphorylation of JNK, p38, and ERKl/2 proteins in lung tissues of mice with sepsis. We found that endostatin can increase the survival of septic mice in a time- and dose-dependent manner probably by reducing multiorgan dysfunctions shown by serum indicators, morphologic changes, Evans blue leakage, wet-to-dry weight ratio, and inflammation of lung tissues. In addition, endostatin could reduce serum tumor necrosis factor α, IL-1β, IL-6, and VEGF-C levels in septic mice as well as inhibit phosphorylation of p38 and ERK1/2 in lung tissues of septic mice. This is the first study demonstrating the protective effect of endostatin on sepsis and its possible underlying mechanisms from the aspects of inhibiting inflammatory responses, blocking VEGF receptor, attenuating VEGF-C expression, and reducing vascular permeability. Overall, the study revealed the potential protect role for endostatin in the treatment of sepsis.
Insights
Endostatin, an angiogenesis inhibitor, shows protective effects in sepsis by improving survival and reducing organ damage. It combats inflammation and vascular leakage, suggesting potential as a sepsis treatment.
Area of Science:
- Biomedical research
- Sepsis pathophysiology
- Endothelial biology
Background:
- Endostatin inhibits angiogenesis and is a key protein in sepsis pathogenesis.
- Previous research indicated endostatin's role in sepsis, but its therapeutic effects were unstudied.
Purpose of the Study:
- To investigate the impact of endostatin on sepsis progression and survival.
- To elucidate the underlying mechanisms of endostatin's protective effects in sepsis.
Main Methods:
- A mouse model of sepsis induced by cecal ligation and puncture (CLP).
- Administration of endostatin or placebo (saline) to septic mice.
- Assessment of survival rates, organ dysfunction markers, inflammatory cytokines, and protein phosphorylation in lung tissue.
Main Results:
- Endostatin significantly increased survival in septic mice in a time- and dose-dependent manner.
- Endostatin reduced organ dysfunction, lung inflammation, and levels of tumor necrosis factor-α, IL-1β, IL-6, and VEGF-C.
- Endostatin inhibited the phosphorylation of p38 and ERK1/2 in lung tissues of septic mice.
Conclusions:
- Endostatin demonstrates a protective role in sepsis, likely by inhibiting inflammatory responses, reducing vascular permeability, and blocking VEGF signaling.
- This study highlights endostatin's potential as a novel therapeutic agent for sepsis treatment.
