Am. J. Respir. Cell Mol. Biol., Vol 11, No. 4, 10 1994, 446-455.
In situ ischemia and hypoxia enhance alveolar macrophage tissue factor expression
CG Compeau, J Ma, KN DeCampos, TK Waddell, GF Brisseau, AS Slutsky and OD Rotstein
Department of Surgery, Toronto General Hospital, Ontario, Canada.
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 (Mphis) during transplantation. An animal model of
lung preservation was developed to examine the hypothesis that ischemia
enhances Mphi 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.
Mphis 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
Mphi procoagulant as tissue factor (TF). Since increased PCA correlated
with decreased airspace pO2 at the end of preservation, the effect of
various O2 concentrations on PCA induction in vivo and in vitro was
examined. Lung inflation during ischemia with decreasing O2 concentrations
confirmed that hypoxia was associated with a rise in Mphi PCA in situ.
However, in vitro exposure of Mphis to hypoxia did not increase Mphi 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 Mphis, thereby confirming
transcriptional TF induction in this group. In addition, enhanced PCA was
observed when Mphis 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 Mphi TF expression. These factors
may contribute to Mphi-mediated ischemic lung injury.
