Abstract
Pulmonary edema following reperfusion is a major clinical problem. Changes in endothelial cell shape induced by oxidant injury may account for immediate capillary leakage associated with reperfusion injury. In these experiments we examined the role of tumor necrosis factor-α (TNF-α) in acute endothelial cell injury following ischemia–reperfusion. Sprague–Dawley rats were treated with a neutralizing antisera directed against TNF-α prior to production of distal ischemia. These rats demonstrated a significant reduction (P< 0.05) in acute lung edema in response to 4 hr of ischemia and 30 min of reperfusion when compared to rats undergoing the same procedure without antisera treatment. Anin vitromodel was developed to determine if TNF-α had a direct effect on endothelial cell response to ischemia–reperfusion. The effects of TNF-α and oxidant stress on the integrity of cultured endothelial cell monolayers was measured. Rat pulmonary artery endothelial cell monolayers reactedin vitroto oxidant stress by an increase in permeability. The cells changed shape and an increase in diffusion of125I-albumin across cell monolayers resulted when these cells were exposed to 50 μMhydrogen peroxide (H2O2) or plasma from the ischemic hind limb of a Sprague–Dawley rat (50 μl/ml). Pretreatment of cultured cells with low levels of recombinant mouse TNF-α significantly affected both the cell shape change and the increase in permeability (P< 0.05). Increased permeability of cell monolayersin vitrowas not due to cell lysis as determined by media lactate dehydrogenase levels. The effect appeared to be due to cellular rounding and contraction seen using video time lapse microscopy. These data suggest a direct effect of TNF-α on endothelial cells, whereby the cells are rendered more susceptible to oxidant injury accompanying reperfusion.
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