Removal of luminal content protects the small intestine during hemorrhagic shock but is not sufficient to prevent lung injury.

The small intestine plays a key role in the pathogenesis of multiple organ failure following circulatory shock. Current results show that reduced perfusion of the small intestine compromises the mucosal epithelial barrier, and the intestinal contents (including pancreatic digestive enzymes and partially digested food) can enter the intestinal wall and transport through the circulation or mesenteric lymph to other organs such as the lung. The extent to which the luminal contents of the small intestine mediate tissue damage in the intestine and lung is poorly understood in shock. Therefore, rats were assigned to three groups: No-hemorrhagic shock (HS) control and HS with or without a flushed intestine. HS was induced by reducing the mean arterial pressure (30 mmHg; 90 min) followed by return of shed blood and observation (3 h). The small intestine and lung were analyzed for hemorrhage, neutrophil accumulation, and cellular membrane protein degradation. After HS, animals with luminal contents had increased neutrophil accumulation, bleeding, and destruction of E-cadherin in the intestine. Serine protease activity was elevated in mesenteric lymph fluid collected from a separate group of animals subjected to intestinal ischemia/reperfusion. Serine protease activity was elevated in the plasma after HS but was detected in lungs only in animals with nonflushed lumens. Despite removal of the luminal contents, lung injury occurred in both groups as determined by elevated neutrophil accumulation, permeability, and lung protein destruction. In conclusion, luminal contents significantly increase intestinal damage during experimental HS, suggesting transport of luminal contents across the intestinal wall should be minimized

Breakdown of Mucin as Barrier to Digestive Enzymes in the Ischemic Rat Small Intestine

Loss of integrity of the epithelial/mucosal barrier in the small intestine has been associated with different pathologies that originate and/or develop in the gastrointestinal tract. We showed recently that mucin, the main protein in the mucus layer, is disrupted during early periods of intestinal ischemia. This event is accompanied by entry of pancreatic digestive enzymes into the intestinal wall. We hypothesize that the mucin-containing mucus layer is the main barrier preventing digestive enzymes from contacting the epithelium. Mucin breakdown may render the epithelium accessible to pancreatic enzymes, causing its disruption and increased permeability. The objective of this study was to investigate the role of mucin as a protection for epithelial integrity and function. A rat model of 30 min splanchnic arterial occlusion (SAO) was used to study the degradation of two mucin isoforms (mucin 2 and 13) and two epithelial membrane proteins (E-cadherin and toll-like receptor 4, TLR4). In addition, the role of digestive enzymes in mucin breakdown was assessed in this model by luminal inhibition with acarbose, tranexamic acid, or nafamostat mesilate. Furthermore, the protective effect of the mucin layer against trypsin-mediated disruption of the intestinal epithelium was studied in vitro. Rats after SAO showed degradation of mucin 2 and fragmentation of mucin 13, which was not prevented by protease inhibition. Mucin breakdown was accompanied by increased intestinal permeability to FITC-dextran as well as degradation of E-cadherin and TLR4. Addition of mucin to intestinal epithelial cells in vitro protected against trypsin-mediated degradation of E-cadherin and TLR4 and reduced permeability of FITC-dextran across the monolayer. These results indicate that mucin plays an important role in the preservation of the mucosal barrier and that ischemia but not digestive enzymes disturbs mucin integrity, while digestive enzymes actively mediate epithelial cell disruption

Developmental and pathological lymphangiogenesis: from models to human disease.

The lymphatic vascular system, the body's second vascular system present in vertebrates, has emerged in recent years as a crucial player in normal and pathological processes. It participates in the maintenance of normal tissue fluid balance, the immune functions of cellular and antigen trafficking and absorption of fatty acids and lipid-soluble vitamins in the gut. Recent scientific discoveries have highlighted the role of lymphatic system in a number of pathologic conditions, including lymphedema, inflammatory diseases, and tumor metastasis. Development of genetically modified animal models, identification of lymphatic endothelial specific markers and regulators coupled with technological advances such as high-resolution imaging and genome-wide approaches have been instrumental in understanding the major steps controlling growth and remodeling of lymphatic vessels. This review highlights the recent insights and developments in the field of lymphatic vascular biology

Cerebral malaria in children: using the retina to study the brain

Cerebral malaria is a dangerous complication of Plasmodium falciparum infection, which takes a devastating toll on children in sub-Saharan Africa. Although autopsy studies have improved understanding of cerebral malaria pathology in fatal cases, information about in vivo neurovascular pathogenesis is scarce because brain tissue is inaccessible in life. Surrogate markers may provide insight into pathogenesis and thereby facilitate clinical studies with the ultimate aim of improving the treatment and prognosis of cerebral malaria. The retina is an attractive source of potential surrogate markers for paediatric cerebral malaria because, in this condition, the retina seems to sustain microvascular damage similar to that of the brain. In paediatric cerebral malaria a combination of retinal signs correlates, in fatal cases, with the severity of brain pathology, and has diagnostic and prognostic significance. Unlike the brain, the retina is accessible to high-resolution, non-invasive imaging. We aimed to determine the extent to which paediatric malarial retinopathy reflects cerebrovascular damage by reviewing the literature to compare retinal and cerebral manifestations of retinopathy-positive paediatric cerebral malaria. We then compared retina and brain in terms of anatomical and physiological features that could help to account for similarities and differences in vascular pathology. These comparisons address the question of whether it is biologically plausible to draw conclusions about unseen cerebral vascular pathogenesis from the visible retinal vasculature in retinopathy-positive paediatric cerebral malaria. Our work addresses an important cause of death and neurodisability in sub-Saharan Africa. We critically appraise evidence for associations between retina and brain neurovasculature in health and disease, and in the process we develop new hypotheses about why these vascular beds are susceptible to sequestration of parasitized erythrocytes

Leukocyte activation in patients with venous insufficiency

AbstractPurpose: Cell activation may play an important role in the production of venous insufficiency, just as leukocytes participate in the cause of venous ulcer. If activated, monocytes observed on venous endothelium can migrate into the venous wall and produce toxic metabolites and free oxygen radicals that may participate in valve destruction and venous wall weakening. At present, it remains uncertain to what degree leukocytes are actually activated in patients. This study was designed to explore the level of activation and to examine whether patient plasma contains an activator that leads to leukocyte activation of unstimulated naive leukocytes from volunteers without venous insufficiency disease. Methods: Twenty-one patients (4 men, 17 women), who ranged in age from 34 to 69 years (mean age, 53.2 years), with chronic venous disease were compared with 16 healthy control volunteers (4 men, 12 women), who ranged in age from 18 to 65 years (mean age, 48.4 years). All the patients underwent evaluation with Doppler ultrasound scanning and were classified with the CEAP score.1 Nearly all the patients who smoked or were hypertensive were excluded. The blood types (ABO and Rh) of the controls were matched to the study group. Isolates of patient whole blood, plasma, or leukocytes were incubated with isolates of control whole blood, plasma, or leukocytes to separate actual activation from spontaneously observed activation. The granulocyte activation was measured with nitroblue tetrazolium (NBT) reduction and quantitation of granulocyte pseudopod formation. Hydrogen peroxide production in patient plasma was measured with a recently developed electrode method. Results: Leukocytes from healthy blood and patient plasma had significantly higher NBT-positive granulocyte counts than either patient blood, healthy blood, or patient blood incubated in healthy plasma. In a comparison of patient groups across the CEAP classes, the NBT-positive granulocyte counts were significantly greater in classes 4, 5, and 6 than in classes 2 and 3 (P < .001). Pseudopod formation was significantly greater in mixtures of granulocytes in healthy blood and patient plasma than in all other groups. There was no difference in the level of pseudopod formation in control leukocytes incubated with patient plasma in patients across the CEAP spectrum. The patient plasma produced significantly higher hydrogen peroxide values than did the controls. Conclusion: These results suggest that patient plasma may contain an activating factor for granulocytes. The finding that activated neutrophils were fewer in number in patient whole blood than in healthy blood incubated in patient plasma could suggest that activated neutrophils in patients with chronic venous insufficiency might be trapped in the peripheral circulation. It is unknown what factors in the plasma might induce activation of naive neutrophils, but such activators could possibly be important in the pathogenesis of primary venous dysfunction and the development of chronic venous insufficiency. (J Vasc Surg 1999;30:148-56.