| Reproductive disorder is one of main reasons for the reduction of domestic animal fertility, while abortion plays a causal role in reproductive disorder. Abortion during earlier pregnancy stage is very common in mammals especially ruminant. Early abortion can cause not only the death of fetus, deduction of milk yield and prolonged calving interval, but also the injury of female animals, such as inducing retention of the afterbirth, endometritis and recurrent miscarriages accompanied by decreased reproductive rate and even female infertility. The occurrence of the above pathological phenomena resulted in hindering animal reproduction and breeding improvement, which made immeasurable financial loss of country and enterprises and provoked great attentions. As we know, endotoxin plays an important role in the occurrence of animal abortion. This stud utilized Lipopolysaccharide (LPS) -induced liver and intestinal injury model, abortion and implantation failure models. The aims are to understand the molecular mechanisms of LPS induced liver and intestine injury as well as abortion, implantation failure. We also explained the anti-abortion effects of traditional Chinese herbal medicine. This study also explained the relationship between LPS and maternal-fetal immunity, and the possible roles of the effective medicine in protecting against early fetal loss.Through studying the LPS-induced mice liver injury model, we found that LPS decreased the expressions of two main tight junction proteins (Occludin and ZO-1), which resulted in increased intestinal permeability. LPS induced reactive oxygen species (ROS) accumulation in the ileum which may be related to the disrupted gut barrier. The serum Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) activities were significantly increased after LPS treatment. These responses were associated with elevated malondialdehyde (MDA) and dramatically reduced superoxide diamutase, catalase, and glutathione peroxidase. Serum nitric oxide (NO) was increased, and the levels of tumor necrosis factor alpha (TNF-α) and keratinocyte chemoattractant (KC) in the liver were elevated. ROS accumulation was also detected in HepG2 cells after LPS treatment. The KC mRNA and inducible NO synthase (iNOS) and nuclear factor kappa B (NF-κB) proteins in the liver were significantly upregulated by LPS challenge. LPS-induced interleukin-8 production in HepG2 cells, which was associated with NF-κB nuclear translocation. The elevated endotoxin levels in serum after LPS challenge was associated with the liver dysfunction and the significantly increased intestinal permeability. The abortion and embryo resorption rates were significantly decreased by pre-fed the concentrated decoction of three Chinese herbal formula (bao tai wu you san, tai shan pan shi san and bai shu san) before LPS treatmetns In LPS-induced abortion mice, the weight of uterus was significantly reduced and the Th1 cytokines (IFN-γ) and the number of CD4+ T cell (but not CD8+ T cell) and macrophage in mice endometrium were dramatically elevated while the amounts of Th2 cytokines (IL-4 and IL-10) was decreased,. LPS caused the imbalance of Th1/Th2 ratio, leading to a Th1 dominant shift in uterus. And the Th1 dominant shift is known to be deleterious to normal pregnancy. The Chinese herbal formula normalized and improved the micro immune environment in mice endometrium.Mice were injected LPS intraperitoneally on Day 3 of gestation to establish the embryo implantation disruption model. LPS challenge significantly increased the serum and uterine NO synthase (NOS) activities and uterine IFN-γlevels, but not IL-10. The above results indicated that LPS also induced embryo implantation failure through altering the immune environment towards Th1 dominant in endometrium during implantation. Oral administration of Baicalin and Quercetin (0.5mg and 1.0 mg) significantly improved the number of implanted embryo and implantation rate compared with LPS treated mice. Baicalin decreased the uterine IFN-γlevel, NOS activities and increased the IL-10 level, resulting in normalized endometrial immune environment. The in vitro study confirms the above in vivo findings. Quercetin downregulated IFN-γmRNA expression and upregulated transforming growth factor-β1 (TGF-β1) mRNA levels compared with those of the LPS treated mice. In conclusion, Baicalin and Quercetin, like the Chinese herbal formula, achieved their anti-abortion and promoting implantation functions by modulating the uterine Th1/Th2 ratio to Th2 dominant which is beneficial to pregnant maintenance and embryo implantation.In conclusion, these studies demonstrate that LPS-induced intestinal barrier dysfunction, which resulting from the down-regulated tight junction proteins, plays an important role in excess LPS absorption into the blood stream; LPS stimulates Kupffer cells and hepatocytes through inducing ROS accumulation and reducing the activities of antioxidant enzymes. NF-κB activation upon LPS challenge might be a causal factor in generating pro-inflammatory cytokines and chemokines which aggravating liver damage; LPS impairs abortion and embryo implantation in mice through increasing the Th1/Th2 ratio; Chinese herbal medicine or certain ingredients in Chinese herbal medicine (Baicalin, Quercetin) demonstrate anti-abortion and beneficial of embryo implantation properties through effectively balancing the immune environment in the uterus and alleviating LPS-induced toxicity.
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