Renin angiotensin II system and lung transplantation: relevance in brain death, IRI and subsequent lung injury

J Fraser; M Nataatmadja; M Passmore; Fraser D Russell; A Corely; G Hart; E Venz; D Chambers; F Kermeen; P Hopkins; B Thomson

doi:10.1016/j.hlc.2010.10.027

Background: Lung transplantation represents the only prospect for improved survival and quality of life for patients with end stage pulmonary disease. The success rate of lung transplantation however is lower than other organ transplants and further study is urgently needed to address this problem. The cumulative insult associated with brain death and ischaemic reperfusion injury are recognised to result in vasoconstriction, tissue remodelling and organ dysfunction. These 2 studies aimed to determine the relevance of ET axis, matrix metalloproteinases and Ang II system in outcome post-lung transplantation. Methods and Materials:Controls: Control broncho alveolar lavage fluid (BAL) and blood (n = 5) was taken from laparoscopic cholecystectomy patients and volunteers respectively. Experimental: BAL; n = 5 was collected during lung transplantation and blood was collected pre and post-cardio pulmonary bypass and 1, 6, 24 and 72 h post-transplant (n = 21). Detection of ET-1, MMP-2, MMP-9, ATR1 and ATR2 expression were assessed using immunohistochemistry, Western blot, zymography and ELISA methods. Results: In comparison to controls, transplant BAL showed increased active MMP-2 and MMP-9, ATR2 and ET-1. Similar distribution of macrophages in control and transplant patients were found, however macrophages expression of ET-1 and MMP-9 were increased from none/mild to moderate/strong (0.2±0.4 vs. 2.6±0.5) and (0±0 vs. 2.4±0.5) respectively. There was a trend for higher plasma concentrations of ET-1 up to 6 h post-transplantation (4.80±1.3 pg/ml; n = 5) compared to pre-transplantation (2.27±0.45 pg/ml; n = 4), and healthy control subjects (1.70±0.31 pg/ml; n = 5), although this did not reach significance (one-way ANOVA). Higher systemic plasma concentrations of AngII and MMP-9 was found at 1 h post-transplantation measured by ELISA methods. MMP2 showed a delayed up-regulation, peaking 6-24 h post-transplantation. The expression of local ATR2 was up-regulated in BAL post-lung transplantation, and this was accompanied by elevated TIMP-1 expression and, to a lesser extent, ET-B, MMP-2 and MMP-9 expression measured by Western blot. Discussion and Conclusion: Increased ET-1, ATR2 and gelatinase activity in BAL indicated early damage to the lung post-BSD. Lung transplant is associated with acute alteration in systemic and local AngII signalling. It is possible that the increase in MMP2, and possibly MMP9, was driven by the elevation in AngII concentration. The increased expression of MMP-2 and MMP-9 in plasma post-transplantation may contribute to increased vascular permeability and activation of resident inflammatory cells in the lung to release of ETB as well as MMP-2 and MMP-9 which is likely to be associated with ischemia reperfusion injury, the progression of lung injury and PGD. The increase of local ATR2expression in BAL samples post-transplantation might suppress IRI following surgery through up regulation of TIMP-1 which likely to result in inhibition of MMP-9 activity. Macrophages activation may contribute to the development of subsequent PGD. ET-1 increase post-transplant suggested the progression of ET-1 dys-regulation post-IRI. Interaction between renin-angiotensin system and endothelin pathways may play an important role in determining tissue injury and repair with up-regulated levels of ATR2 is likely to inhibit ATR1 action resulting in tissue degeneration. These study results may lead to more effective BSD and IRI management and improved outcome post-lung transplant.

Renin angiotensin II system and lung transplantation: relevance in brain death, IRI and subsequent lung injury

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