Gastrointestinal Mucosal Barrier Injury Induced By High Altitude Hypoxia And Its Relation With Multiple Organ Dysfunction Syndrome

Objective and backgroundThe area that locates 3000m above the sea level is called Plateau in the sense of medicine. Quick enter into the plateau hypoxia environment of 3000m above the sea level can damage the function of organs seriously, or even cause acute severe mountain sickness (ASMS) that threatens the life and health of people enormously. High altitude pulmonary edema(HAPE) and high altitude cerebral edema(HACE) are the highest of disease incidence and the most difficult to cure of tow high altitude acute critical diseases that may cause various complicating diseases if not cured in time, among which multiple organ dysfunction syndrome (MODS) is the most complicated,difficult to cure and death rate. The nosogenesis of ASMS complicating with MODS is not clear up to now. Previous research elucidated that the stress factors like trauma, burn, serious infection and hemorrhagic shock etc,may cause gastrointestinal mucosa injury, which leads to the translocation of intestinal toxin and bacteria, eliciting systematic inflammation reaction syndrome (SIRS), then inducing MODS. It had been discovered in the plateau clinical practices that ASMS patients were often associated with serious gastrointestinal dysfunction (GD). However, it hasn't been reported whether the GD is resulted from gastrointestinal mucosal barrier injury caused by plateau hypoxia and is the basic reason of ASMS complicating with MODS. Through retrospective analysis of the cases, the clinical observation of ASMS patients and the animal study, the relations between gastrointestinal mucosal barrier injury caused by acute plateau hypoxia and MODS were discussed, and preliminary study on protection of Glutamine of high altitude gastrointestinal dysfunction(GD) was carried out.Object and method1. In the retrospective study, the clinical data of 3,184 inpatients of General Hospital of Tibetan Military Command suffering from acute severe mountain sicknes(sASMS)in the past 50 years (from June, 1958 to June, 2007) were collected. Statistical analysis was performed to study the relation of GD and MODS in these patients. For the prospective study, 10 admitted patients of ASMS and ten healthy volunteers into Tibet in a week were included and allocated to observation group and control group. Glutamine (Gln) capsule in 30g/d was orally ingested by both groups for 3 days after the first day of admission. Gastroscopic examination was performed on the ASMS patients and the healthy volunteers, whose gastric and duodenal mucosa was scrutinized in the next morning in hospital. The levels of serum diamine oxidase (DAO), malondialdehyde (MDA), endotoxin and lactulose/ mannitol (L/ M) ratio were detected respectively before and after treatment to evaluate the relationship between SIRS and gastrointestinal mucosus membrane permeability.2. In the animal study, 40 adult male SD rats were randomly divided into control group(C), high altitude hypoxia group (H), high altitude hypoxia and hunger group (HH) and Gln protection group (HG). After lived in the low-pressure chamber with a simulated altitude of 7000m for 3 days(72 hours), the test groups were determined by their diet, variation in physique, tissue, ultrastructure and observations on lanthanum nitrate trace, apoptosis of epithelial cells, bowel bacteria immigration, serum DAO activity, MDA, nitrogen monoxidum(NO), endotoxin level, concentration of Gln and small intestine DAO activity were carried out separately.Result1. 49.8% of the patients with ASMS were complicated with GD, among whom 1.5% were with dark stool and 1.0% with occult blood in stool. 21.7% (18 /83) of ASMS who appeared GD were complicated with MODS, It indicated that GD plays a major role in the pathogenesis of MODS in ASMS patients.2. Endoscopic examination showed extensive edema and localized hemorrhage in gastrointestinal mucous membrane with dotted and patched erosion in gastric antrum and fundus. The pre-treatment DAO, MDA, and endotoxin were higher in the observation group than those in the control group (all P<0.01). After 3 days of Gln capsule treatment, DAO, MDA and endotoxin were significantly decreased in the observation group (P<0.05 or P<0.01). The pre-treatment L/M ratio in observation group was significantly higher than that in healthy control group (150.69+/-19.91 vs.117.91+/-17.78, P<0.01). The L/M ratio was significantly decreased to 129.37+/-19.75 (P<0.05) after the treatment. However, no significant change in the healthy control group was observed. 3. The test rats has significant pathological injury in their intestinal mucous membrane, and the result of the light microscopy were as follows: intestinal mucous membrane atrophy, fewer and disordered chorionic villi, obvious edema of lamina propia of mastoid chorionic villi and infiltration of inflammatory corpuscle, lodging and slough of most chorionic corpuscle, beaker cell loss, red blood cells'oozing around blood capillary. The result of the scanning electron microscope was as follows: epithelial cells atrophy, slough of microvilli. The result of the transmission electron microscope was as follows: the broadening of the tight junction gap, chondriosome swelling, Golgi complex dilatation, irregular nuclei, and margined chromation. Lanthanum nitrate tracing indicated that lanthanide entered into epithelial cells'tight junction gap and part of external basement membrane tissue spaces or cells. TUNEL detected that the number of apoptotic cells of intestinal epithelial cells increased. The injury intestinal mucous membrane of hypoxia rats became serious when they were hungry, while relieved after giving Gln. There were no obvious changes in control group.4. Bacterial culture was negative in all organs of rats in control group. Bacteria translocation of lymphonodi mesenterici and spleen appeared in high altitude hypoxia group. In high altitude hypoxia and hunger group, bacteria translocation has arisen in most of the organs except peripheral blood, in which mesenteric lymph node has the most cell translocation, with spleen in the next place. Bacteria translocation had decreased obviously in Gln protection group, which had significant differences(P<0.05) compared with high altitude hypoxia group. The serum endotoxin, DAO, MDA increased apparently, and serum SOD, Gln and small intestine DAO, Gln decreased remarkably in high altitude hypoxia group and in high altitude hypoxia and hunger group, which had significant differences(P<0.05 or P <0.01) compared with control group. Compared with Gln protection group and high altitude hypoxia group, the former serum endotoxin, DAO, MDA decreased apparently, while serum SOD, Gln and small intestine DAO, Gln increased remarkably(P <0.01).Conclusion1. Acute severe mountain sickness (ASMS) patients are often complicated with gastrointestinal dysfunction (GD). High altitude GD may plays a major role in the pathogenesis of MODS in ASMS patients.2. Intestinal mucosal barrier serious injury, increased intestinal mucous membrane permeability, bacteria translocation in mesenteric lymph node and spleen in SD rats appears when exposed to the acute high altitude hypoxia. Hungry will increase the degree of injury of intestinal mucous membrane in SD rats, which will stimulate translocation of bacteria and endotoxin.3. Pre-disposal treatment of giving Gln plays a protecting role in gastrointestinal mucosal injury in high altitude. It will significantly reduce intestinal mucous membrane permeability, decrease translocation of bacteria in mesenteric lymph node and spleen and relieve systemic inflammatorome reaction.4. The occurrence of intestinal mucous membrane injury when exposed to the acute high altitude hypoxia is concerned with the increase of oxygen free radicals such as DAO, MDA, the release of the proinflammatory cytokines and the decrease of antioxidant compounds such as SOD, NO etc.