The Mechanism Study Of Barrier Injury And Intervene On Intestinal Mucosa During Rats Exposed To High Altitude

BACKGROUNDThe plateau characterizes with hypoxia, cold, high wind, high evaporation, high radiation, climate variability, etc. When people enter this area, The high altitude of plateau induce lower air pressure, less oxygen content, air drying, which caused the body lower blood oxygen and decreasing oxygen partial pressure, it make the body difficult for O2 to diffuse into the vascular system , resulting in such physiological responses: Respiratory rate increased, more air inhaled into the lung; Heart rate and cardiac output increased to enhance blood flow in the body and lung; the body produce red blood cells and hemoglobin gradually to improve the ability of blood oxygen transport; in fact, even adjusting for the above, people who ascend to high altitude recently hardly has normal physiological performance at all. Lead to a cascade of biosynthetic and physiological events involve in respiratory, nervous, digestive and other multi-system. High altitude sickness is focus on respiratory, circulating and nervous dysfunction in the domestic and aboard high altitude medical field currently. But the digestive system, especially in gut barrier injury has little research. With in-depth study on complex physiological functions of intestinal, people Noted that gut not only the vital organ which play the role of digestion and absorption of nutrients, But also has immune, endocrine and mucosal barrier functions. gut barrier function(GBF) has become a hot research on present. gut mucosal injury cause gut barrier dysfunction to deteriorate the primary disease. Even lead to multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS). Become a vicious cycle, threatening life. So the research on pathogenesis and approaches to induce high altitude hypoxia mode in natural environment are urgently in need. It is the foundation for Follow-up clinical trials.AIMSThrough establishment of animal model of HA of rats in different altitude and time-point induced by high altitude hypoxia, Observe pathological changes in the intestinal mucosa dynamically. Detect expression of hypoxia-related factors by immunohistochemical methods, identified whether mucosal protective agent Gln have a preventive and therapeutic effect on oxygen-induced damage of intestinal mucosa.METHODSThis study is to establish different time-point and altitudes high altitude hypoxic animal model, observe morphological changes of intestinal mucosa under optical microscopy and electron microscopy, and then make quantitative evaluation. Examine hypoxia inducible factor-1α(HIF-1α) and inducible nitric oxide synthase (iNOS) expression in intestinal by use of immunohistochemistry. We investigate whether the plateau effect gut barrier injury and specific mechanism of the two factors. We use mucosal protective agent glutamine (Gln) to intervene the experiment group, saline as control. We survey Parameters alteration in microstructure and hypoxia-related factors. Further evaluation of glutamine can decrease intestinal mucosal injury exposed to high altitude. the effect of down-regulation of iNOS gene expression may be one of the protective mechanism in mucosa.RESULT(1)The animal model of rats with mucosa injury induced by HA has been successfully established. HE shows: Light microscope features: in the High altitude groups, intestinal villi appeared as swelling, shortening, thickening, lodging, integration or even exfoliation, lamina propria exposed and inflammatory granulocyte was present. SEM features: The most obvious changes in altitude group were architectural disorganization and shortening of villi, Many epithelia showed inflammatory exudation, necrotic changes or dissolved of the epithelia, where honeycomb-like structure could be found. Pore sizes, diameters of 10 to 20. These date show that HAH induce intestinal injury characterize with altitude– dependent and time-dependent.(2) our data also clear demonstrate expression of iNOS and HIF-1αexpression in intestinal tissue of HA model. The presence of both factors in High altitude 3848m group (3848m of altitude, ma xian mountain yuzhong, china)and high altitude 4767m group (Qinghai High Altitude Medical Research center, kekexili, 4767m of altitude) had significantly higher than plain control group. Also in 24h, 48h,72h which compare with plain group. suggesting Hypoxia triggers various tissues injury and increasing of transcription factors of iNOS and HIF-1αas the mucosal morphological alteration. statistical results showed that HIF-1αand iNOS protein expression have positive correlation, which indicates that HIF-1αmay play an important role in the expression of iNOS and intestinal mucosal injury.(3) Intestinal mucosa protective agent glutamine can decrease intestinal mucosal injury exposed to high altitude. Histological morphology in Plateau drug intervention group 24h, 48h, 72h are better than control group at the same time-point. The expression of injury factor iNOS in the mucosa lower than the control group, the effect of down-regulation of iNOS gene expression may be one of the protective mechanisms in mucosa.CONCLUSIONSWe have been successfully established the animal model of rats with mucosa injury induced by HA in natural environment, confirmed the effect of high-altitude hypoxia on intestinal mucosa injury. Indicating that HIF-1αand iNOS play an important role of the pathogenesis on hypoxic injury. Intestinal mucosal protective agents Gln could effectively inhibit the hypoxic injury, and relate to reduced iNOS gene expression. This research provided some experimental data and theoretical foundation for deeply investigate mechanisms and new therapeutic ways of HA gastroenterological mucosal injury.