Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis.
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.
Salzman
A L
AL
Department of Surgery, Massachusetts General Hospital, Boston 02114.
Wang
H
H
Wollert
P S
PS
Vandermeer
T J
TJ
Compton
C C
CC
Denenberg
A G
AG
Fink
M P
MP
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001158:Arteries; D003911:Dextrans; D004731:Endotoxins / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D005740:Gases / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D006859:Hydrogen / Q000097:blood; D007082:Ileum / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008297:Male; D009994:Osmolar Concentration; D010100:Oxygen / Q000097:blood; D010539:Permeability / Q000187:drug effects; D013152:Splanchnic Circulation; D013552:Swine; D014680:Veins
D003911:Dextrans; D004731:Endotoxins; D005740:Gases; D007773:Lactates; C015219:fluorescein isothiocyanate dextran; D019344:Lactic Acid; D006859:Hydrogen; D016650:Fluorescein-5-isothiocyanate; D010100:Oxygen