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 suggested that ischemic lung preservation has a stimulatory effect on donor alveolar macrophages (M phi s) during transplantation. An animal model of lung preservation was developed to examine the hypothesis that ischemia enhances M phi procoagulant activity (PCA) as a potential mechanism contributing to lung reperfusion injury. Histologic examination of ischemic lungs reperfused ex vivo revealed evidence of alveolar fibrin 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 human plasma characterized this M phi procoagulant as tissue factor (TF). Since increased PCA correlated with decreased airspace pO(2) at the end of preservation, the effect of various O-2 concentrations on PCA induction in vivo and in vitro was examined. Lung inflation during ischemia with decreasing O-2 concentrations confirmed that hypoxia was associated 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 hypoxia alone was not responsible for induction of this procoagulant effect. Northern blot analysis demonstrated an increase in TF mRNA levels from in situ but not in vitro M phi s, thereby confirming transcriptional TF induction in this group. In addition, enhanced PCA was observed when M phi s were suspended in the bronchoalveolar lavage supernatant from the ischemic lungs stored at 21 degrees C. This suggests that in situ lung ischemia and hypoxia may produce soluble factors that either directly or indirectly stimulate M phi TF expression. These factors may contribute to M phi-mediated ischemic lung injury.