Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis

Abstract

Administration of lipopolysaccharide (LPS) to experimental animals leads to diminished mesenteric perfusion, increased ileal mucosal [H+] , and increased gut epithelial permeability to hydrophilic solutes. We sought to determine whether these phenomena are causally related. Experiments were performed in anesthetized pigs. Permeability was assessed by measuring the plasma-to-lumen clearance of fluorescein isothiocyanate dextran (4,000 Da; FD-4) by a segment of ileum perfused with Ringer lactate solution. Mucosal perfusion (Qmuc) and [H4+] were estimated using laser-Doppler flowmetry and tonometry, respectively. In an initial series of experiments, we showed that mucosal permeability was linearly correlated with mucosal [H+] in animals subjected to graded degrees of mechanically induced mesenteric ischemia (n = 14, R2 = 0.58, P < 0.002) or injected with graded doses of LPS (n = 11, R2 = 0.93, P < 0.0001). In a second series of experiments, we induced mucosal acidosis in normal pigs by mechanical ventilation with either a hypoxic (n = 7) or a hypercapnic (n = 5) gas mixture. In both groups, ileal mucosal permeability to FD-4 increased significantly (P < 0.05), although transmesenteric release of lactate increased significantly only in the hypoxic group. Qmuc was unchanged in both groups. These data suggest that mucosal acidosis, even in the absence of tissue ischemia or hypoxia, increases intestinal permeability to a macromolecular hydrophilic solute. Tissue acidosis may be an important factor contributing to LPS-induced gut mucosal hyperpermeability.

Isoflurane-induced acidosis depresses basal and PGE2-stimulated duodenal bicarbonate secretion in mice

“…These results suggest that active transcellular bicarbonate transport is much greater than the paracellular transport of this ion and that an increase in the paracellular transport has little impact on total alkalinization. Finally, tissue acidosis has been shown to increase (23), whereas elevation of the serosal bicarbonate concentration decreases, paracellular permeability (19,20), possibly suggesting that the Na 2 CO 3 infusion would decrease rather than increase the paracellular permeability to bicarbonate.…”

Physiologically relevant increase in temperature causes an increase in intestinal epithelial tight junction permeability

“…The disruption of intestinal TJ barrier results in a "leaky" TJ barrier, allowing paracellular permeation of toxic luminal substances (2). It is well established that various types of stresses including hemorrhagic shock (2,14,15), endotoxemia (62,66), psychogenic stress (54,67,68), exertional stress (3,6), and heat stroke (20,26,30,69) cause an increase in intestinal permeability to luminal endotoxins and lead to bacterial translocation (2,3,6,14,15,20,26,30,69). The gut-derived endotoxins and pathogenic bacteria have been proposed to be an important causative factor of morbidity and death during clinically relevant stresses such as heat stroke (22,23), sepsis (72), burn injury (27,71), ischemia-reperfusion injury (24), and in the critically ill (52).…”

Resveratrol Prevented Lipopolysaccharide-Induced Endothelial Dysfunction in Rat Thoracic Aorta Through Increased eNOS Expression

“…During sepsis, a significant decrease in endothelium-dependent relaxation has been demonstrated in blood vessels from endotoxemic animals (12,13), which is characterized by impaired production of NO by eNOS (14)(15)(16). Furthermore, it has been reported that sepsis leads to decreased eNOS phosphorylation in rabbit mesenteric arteries (17).…”