Search

To better understand the mechanisms of ischemia-reperfusion (I/R) injury, we tested the hypothesis that protein synthesis is involved in the production of tumor necrosis factor (TNF) and in the microvascular transport changes in I/R. To evaluate the hypothesis, we inhibited protein synthesis with topically applied actinomycin D (AMD), measured I/R-induced changes in microvascular transport, and bioassayed the venous plasma levels of TNF. The rat cremaster muscle I/R model consisted of 4 h of ischemia followed by 2 h of reperfusion. Changes in transport were determined by integrated optical intensity (IOI) using FITC-Dextran 150 as tracer. Animals were separated into four groups: 1) control (C), 2) control treated with AMD (C + AMD), 3) I/R, and 4) I/R treated with AMD (I/R + AMD). The mean (+/-SE) maximal IOI in C and C + AMD were 3.0 +/- 1.0 and 3. 7 +/- 0.7 units, respectively. I/R elevated mean maximal IOI to 21.8 +/- 1.9 units (P < 0.05 vs. C, C + AMD, I/R + AMD). Treatment with AMD reduced the I/R-induced mean maximal IOI to 9.7 +/- 2.0 units (P < 0.05 vs. I/R). In I/R group, plasma TNF levels increased (relative to preischemia baseline) immediately after the release of the vascular occlusion to 250 pg/ml and reached a peak value of 342 pg/ml at 60 min of reperfusion. In the I/R + AMD group, AMD reduced TNF increase to 44 pg/ml. The C and C + AMD groups showed no differences in TNF values during the 6 h of observation. We conclude that protein synthesis and TNF generation are at least partially involved in I/R-induced changes in microvascular transport.

Ischemia-reperfusion injury remains a difficult problem facing vascular surgeons because of its associated high morbidity and mortality. The basis for tissue injury during ischemia depends on depletion of tissue oxygen and energy substrates. Cell injury, as documented cellular edema and lysosomal degranulation, begins after only 30 min of ischemia. Irreversible cellular changes occur after 4-6 h of skeletal muscle ischemia. Following acute arterial occlusion, the restoration of blood flow heralds the onset of biochemical events, forming the basis of what is known as the reperfusion syndrome. This tissue injury is maximal in areas with the greatest blood flow during reperfusion. Endothelium-leukocyte interactions play an important role in ischemia-reperfusion injury. Both endothelial and white blood cells have the biochemical machinery and capacity to generate molecular signals, to express adhesion proteins, and to produce toxic metabolic by-products. Since the microcirculatory changes in ischemia-reperfusion injury parallel those seen in inflammation, the leukocyte-endothelial interaction can explain many of the reactions associated with the early phases of ischemia-reperfusion injury.