IN-SITU ISCHEMIA AND HYPOXIA ENHANCE ALVEOLAR MACROPHAGE TISSUE FACTOR EXPRESSION

Alveolar and interstitial fibrin deposition is a prominent pathologic feature in many acute lung injury syndromes. Previous studies have sug gested that ischemic lung preservation has a stimulatory effect on don or alveolar macrophages (M phi s) during transplantation. An animal mo del of lung preservation was developed to examine the hypothesis that ischemia enhances M phi procoagulant activity (PCA) as a potential mec hanism contributing to lung reperfusion injury. Histologic examination of ischemic lungs reperfused ex vivo revealed evidence of alveolar fi brin deposition. M phi s lavaged from lungs stored for at least 8 h at 21 degrees C exhibited increased PCA. The use of factor-deficient hum an plasma characterized this M phi procoagulant as tissue factor (TF). Since increased PCA correlated with decreased airspace pO(2) at the e nd of preservation, the effect of various O-2 concentrations on PCA in duction in vivo and in vitro was examined. Lung inflation during ische mia with decreasing O-2 concentrations confirmed that hypoxia was asso ciated with a rise in M phi PCA in situ. However, in vitro exposure of M phi s to hypoxia did not increase M phi PCA, suggesting that hypoxi a alone was not responsible for induction of this procoagulant effect. Northern blot analysis demonstrated an increase in TF mRNA levels fro m in situ but not in vitro M phi s, thereby confirming transcriptional TF induction in this group. In addition, enhanced PCA was observed wh en M phi s were suspended in the bronchoalveolar lavage supernatant fr om the ischemic lungs stored at 21 degrees C. This suggests that in si tu lung ischemia and hypoxia may produce soluble factors that either d irectly or indirectly stimulate M phi TF expression. These factors may contribute to M phi-mediated ischemic lung injury.