Tissue damage causes hyperthermia‐induced loss of intestinal barrier function via an oxidative stress pathway

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This study distinguished between two contrasting mechanisms for loss of the intestinal barrier during hyperthermia: tight junction opening and epithelial damage. The permeabilities of mouse small intestinal segments to fluorescent markers were monitored in vitro in everted gut sacs. Drugs known to open tight junctions (enterotoxin, palmitoyl carnitine, NOC‐12) had no effect at 37°C, though cytocholasin D (20μM) increased permeability. Electron microscopy revealed that cytocholasin D caused gross distortion of the epithelium, unrelated to tight junction opening. In contrast, LDH release (a marker of cytotoxicity) was significantly increased at 41.5°C and light microscopy revealed extensive structural damage to the epithelium. To determine whether oxidant formation could be responsible, protein oxidation was evaluated by carbonyl formation. Hyperthermia caused significant elevations in carbonyls, while co‐treatment of the segments with the antioxidants, N‐acetylcysteine (10 mM) or baicalein (200 μM) reduced carbonyl formation and greatly lowered hyperthermia induced permeability. The data are not consistent with tight junction opening alone being the primary mechanism for loss of barrier function. However, damage to the intestinal epithelial wall and perhaps other elements within the barrier may be responsible, possibly via oxidative stress mechanisms NHLB 53333.