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Updated: Jul 11, 2026
Study of Experimental Organ Donation Models for Lung Transplantation
Published on: March 15, 2024
The endothelin axis and gelatinase activity in alveolar macrophages after brain-stem death injury: a pilot study
Allison J Sutherland1, Robert S Ware, Clay Winterford
1Discipline of Medicine, Prince Charles Hospital, Chermside, Queensland, Australia. a.sutherland@uq.edu.au
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.
Insights
Brain-stem death (BSD) rapidly increases alveolar macrophages and expression of endothelin-1 (ET-1), its receptors (ET(A)R, ET(B)R), and matrix metalloproteinases (MMP-2, MMP-9), potentially impacting lung function.
Area of Science:
- Physiology
- Immunology
- Transplantation Science
Background:
- Endothelin-1 (ET-1) is a vasoconstrictor linked to primary graft dysfunction.
- Matrix metalloproteinases (MMPs), specifically MMP-2 and -9, are associated with lung tissue damage.
- Brain-stem death (BSD) models are used to study early injury mechanisms.
Purpose of the Study:
- To investigate early alveolar macrophage changes in BSD.
- To quantify expression levels of ET-1, ET(A)R, ET(B)R, MMP-2, and MMP-9 in BSD.
- To compare these markers against sham controls in a rat model.
Main Methods:
- Wistar-Kyoto rats underwent either BSD induction or sham procedure.
- Balloon catheter insertion and inflation used to induce BSD.
- Immunohistochemistry assessed CD68, ET-1, ET(A)R, ET(B)R, MMP-2, and MMP-9 expression in lung tissue.
Main Results:
- BSD significantly increased the alveolar macrophage to neutrophil ratio.
- Expression of ET-1, ET(A)R, and ET(B)R was significantly elevated in BSD lungs.
- MMP-2 and MMP-9 levels were doubled in BSD lungs compared to controls.
Conclusions:
- Alveolar macrophages are rapidly recruited following BSD.
- Increased ET-1, ET(A)R, ET(B)R, MMP-2, and MMP-9 expression occurs early after BSD.
- These molecular changes may influence peri-operative lung function.
