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 (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.
Sutherland
Allison J
AJ
Discipline of Medicine, Prince Charles Hospital, Chermside, Queensland, Australia. a.sutherland@uq.edu.au
Ware
Robert S
RS
Winterford
Clay
C
Fraser
John F
JF
D000818:Animals; D001926:Brain Death / Q000378:metabolism* / Q000473:pathology; D001933:Brain Stem / Q000293:injuries*; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism*; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology; D010865:Pilot Projects; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism
D019332:Endothelin-1; D016232:Endothelins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9