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  • Title: The endothelin axis and gelatinase activity in alveolar macrophages after brain-stem death injury: a pilot study.
    Author: Sutherland AJ, Ware RS, Winterford C, Fraser JF.
    Journal: J Heart Lung Transplant; 2007 Oct; 26(10):1040-7. PubMed ID: 17919625.
    Abstract:
    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 (ET(A)R) and endothelin B receptors (ET(B)R), 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, ET(A)R, ET(B)R, 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, ET(A)R and ET(B)R 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, ET(A)R, ET(B)R, MMP-2 and MMP-9.
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