title: In situ ischemia and hypoxia enhance alveolar macrophage tissue factor expression.
abstract: 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.
authors.affiliation: Department of Surgery, Toronto General Hospital, Ontario, Canada.
authors.forename: C G
authors.initials: CG
authors.lastname: Compeau
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.forename: K N
authors.initials: KN
authors.lastname: DeCampos
authors.forename: T K
authors.initials: TK
authors.lastname: Waddell
authors.forename: G F
authors.initials: GF
authors.lastname: Brisseau
authors.forename: A S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: O D
authors.initials: OD
authors.lastname: Rotstein
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008855:Microscopy, Electron, Scanning; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D014404:Tubulin / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014404:Tubulin; D005337:Fibrin; D013925:Thromboplastin