title: The endothelin axis and gelatinase activity in alveolar macrophages after brain-stem death injury: a pilot study.
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.
authors.affiliation: Discipline of Medicine, Prince Charles Hospital, Chermside, Queensland, Australia. a.sutherland@uq.edu.au
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Sutherland
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ware
authors.forename: Clay
authors.initials: C
authors.lastname: Winterford
authors.forename: John F
authors.initials: JF
authors.lastname: Fraser
mesh_terms: 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
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9