Elsevier

Transplant Immunology

Volume 28, Issue 4, June 2013, Pages 193-197
Transplant Immunology

Balance of pro- and anti-inflammatory cytokines in cirrhotic patients undergoing liver transplantation

https://doi.org/10.1016/j.trim.2013.04.001Get rights and content

Highlights

  • OLT in cirrhotic patients is characterized by a transient cytokine elevation.

  • IL-6, IL-8, IL-10 but not IL-1 and TNF-α are increased.

  • The dynamic pro- vs. anti-inflammatory cytokine relationship is preserved.

  • Pro-inflammatory cytokine levels and MELD score are correlated.

  • Cytokine balance rather than absolute plasma concentrations should be considered.

Abstract

This study was prospectively aimed at having better information about the natural history of serum cytokines in cirrhotic patients undergoing liver transplant surgery and at assessing their ability to set up an appropriate dynamic relationship between pro-inflammation and anti-inflammation. The levels of six cytokines (TNF-α, IL-1, IL-2, IL-6, IL-8, IL-10) were measured in blood samples collected at different time points before, during and after (48 h) the transplant procedure from the radial artery of 62 consecutive cirrhotic patients who underwent orthotopic liver transplantation.

IL-1 always stayed within the normal range; IL-2 showed elevated baseline levels but decreased up to half at the end of the study (p < 0.0001). IL-6 peaked at the end of surgery and returned to baseline 48 h afterwards. The same happened to IL-8 concentrations. IL-10 levels shown above the normal threshold at baseline, peaked at the end of surgery (p < 0.0001) and were halved at the end of the study (p < 0.0001). TNF-α peaked at the end of surgery without, however, being different from baseline levels (p = 0.6). The physiologic pattern of cytokine release and their dynamic relationship was found to be preserved with a quick return to a balance between pro-inflammation and anti-inflammation as shown by the IL-6/IL-10 and TNF-α/IL10 ratios (used to assess the inflammatory balance). A correlation was found between perioperative pro-inflammatory cytokine levels and the severity of the liver disease necessitating OLT. In summary, cirrhotic patients can achieve a balanced inflammatory response to surgery which is considered a primary requirement for uneventful grafts and patients' postoperative recovery.

Introduction

Cytokines are a group of endogenous proteins which play a pivotal role in regulating the inflammatory response to surgery through a predictable set of adaptive events. This process, which is designed to maximize the organism's healing potential, is initiated locally, at the site of surgical trauma, by macrophages and monocytes that release pro-inflammatory cytokines. In particular, tumour necrosis factor alpha (TNF-a) and interleukin-1 (IL-1) initiate a cascade of mediators which are directly responsible for the various events associated with inflammation [1], [2], [3], [4], [5], [6]. The increase in the circulating blood of pro-inflammatory cytokines triggers immune cells to release anti-inflammatory cytokines (e.g., IL-10) with the aim of downregulating, through complex feedback mechanisms, the pro-inflammatory process so to maintain homeostasis [1], [2], [3], [4], [5], [6]. From the clinical point of view, the role of circulating inflammatory cytokines is not much clear yet. They might serve as biomarkers for certain clinical events, such as infections (i.e., IL6 in sepsis) or inflammation [7]. In addition, they might serve as marker for metabolic changes or stress [3], [4], [5]. It has been also reported that pre-existing chronic diseases can interact with the patients' capability to set up a balanced inflammatory response to surgery which, therefore, may result in being exaggerated (leading to hyper-inflammation) or inadequate (leading to immunosuppression) possibly causing compromised outcomes and organ dysfunction [2], [3], [7], [8]. In particular, it has been shown that liver cirrhosis leads to an over-expression of various pro- and anti-inflammatory cytokines resulting in a significant derangement of the whole inflammatory response [9], [10], [11], [12]. Therefore, we designed a study to obtain better information about the natural history of serum cytokines in cirrhotic patients undergoing liver transplantation with the aim of assessing if they are still capable to set up an appropriate physiologic relationship between pro-inflammation and anti-inflammation leading to a balanced response to surgery trauma.

Section snippets

Materials and methods

This study involved all of the patients who underwent orthotopic liver transplantation (OLT) at our Centre during 9 consecutive months who gave their informed consent. Anaesthetic and intraoperative management were the same in all cases as previously described [13]. According to the standard protocol at our Centre, a centrifugal pump-driven veno-venous extracorporeal by-pass with heparinised tubing was placed to drain the infra-diaphragmatic venous circulation into the superior vena cava to

Results

Data from 62 of the 67 enrolled patients were analysed (47 males, 15 females). Five patients were excluded because they were transplanted for liver cancer without cirrhosis. Our patients' age was 51.7 ± 8.6 years (range 26–64) and BMI was 24.7 ± 2.2 kg m2. The underlying diseases necessitating liver transplantation were 59 cases of liver cirrhosis (45 viral, 10 alcoholic and 4 cryptogenic) and three of primary biliary cirrhosis. The MELD score of the study population was 19 ± 6.

The studied cytokines

Discussion

Our data show that cirrhotic patients undergoing OLT can have a preserved capability to release cytokines according to a physiological pattern that enables them to restore a balanced relationship between pro-inflammation and anti-inflammation after extensive surgery. This finding is of interest because, as shown by a bulk of research and clinical work, a balanced inflammatory response to surgery almost always results in uneventful recovery whereas a dysregulation of this response predisposes

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    No grants and other financial support were used to perform this research.

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