Platelet-activating factor mediates intercellular adhesion molecule-1-dependent radical production in the nonhypoxic...

It has been reported that reperfusion is the most important factor in ischemia-reperfusion (I/R) injury. However, causes of I/R injury in the lung are controversial, because oxygen is always supplied if ventilation continues. Therefore, we hypothesized that nonhypoxic ischemia without reperfusion is sufficient for lung injury. To test our hypothesis, we measured both hydrogen peroxide (H2O2) production in the pulmonary circulation, by digital imaging fluorescent dichlorofluorescein, and microvascular permeability (MVP), by the Evans blue extravasation technique in the nonhypoxic ischemia rat lung. We made a nonhypoxic ischemia rat lung by clamping the left pulmonary artery. Both H2O2 production and MVP increased in the nonhypoxic ischemia rat lung. We also determined the effect of oxygen removal by clamping the bronchus in advance of pulmonary artery occlusion, intercellular adhesion molecule-1 (ICAM-1) neutralization with monoclonal antibody 1A29, and platelet-activating factor (PAF) receptor antagonist CV6209 on H2O2 production and MVP. These treatments inhibited both H2O2 production and MVP increase. At high-power viewing of the fluorescent dichlorofluorescein image, H2O2 was detected in the leukocytes within pulmonary capillaries. These data indicate that the nonhypoxic ischemia without reperfusion alone causes radical production and increases MVP. Furthermore, PAF and ICAM-1 contribute to these reactions.