The endothelin axis and gelatinase activity in alveolar macrophages after brain-stem death injury: A pilot study

Background: Endothelin-1 (ET-1) is a potent vasoconstricting mitogen that has been implicated in the development of primary graft dysfunction. Increased activity of matrix metalloproteinases (MMPs), specifically MMP-2 and -9, has been associated with tissue damage in acute lung injury and after lung transplantation. Using a validated model of brain-stem death (BSD), we aimed to determine whether alveolar macrophage up-regulation in the pulmonary system is an early feature of BSD injury and if expression levels of ET-1, endothelin A receptors (ETAR) and endothelin B receptors (ETBR), as well as MMP-2 and -9, are increased in comparison to sham controls. Methods: Six control and 8 experimental Wistar-Kyoto rats had a balloon catheter inserted into their subdural space. In the experimental group the balloon was inflated for 4 hours. Lung specimens were immunohistochemically labeled with CD68, ET-1, ETAR , ETBR, MMP-2 and MMP-9, and 10 fields per slide were assessed. Results: The ratio of alveolar macrophages to polymorphonuclear neutrophils was significantly greater in the BSD group than in controls (9 +/- 4.1 vs 3 +/- 0.5, P = 0.004) and adventitial macrophages increased in BSD lung parenchyma (p < 0.0001). ET-1, ETAR and ETBR levels were elevated in the experimental group (27.6 +/- 5.7 vs 7 +/- 2.3, 36.1 +/- 4.6 vs 17.7 +/- 2.6 and 60 +/- 7.1 vs 19.8 +/- 3.7, p < 0.0001 inclusive). BSD expression of MMP-2 and MMP-9 was double that of controls (14.9 +/- 3.4 vs 30.7 +/- 3.4 and 14.2 +/- 2.2 vs 37 +/- 3.6, respectively, p < 0.0001 inclusive). Conclusions: Alveolar macrophages are rapidly recruited after BSD and may affect peri-operative lung function via increased expression of ET-1, ETAR, ETBR, MMP-2 and MMP-9. J Heart Lung Transplant 2007;26: 1040-7. Copyright (c) 2007 by the International Society for Heart and Lung Transplantation.