A multidrug cocktail approach attenuates ischemic-type biliary lesions in liver transplantation from non-heart-beating donors

Medical Hypotheses 91 (2016) 47–52

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A multidrug cocktail approach attenuates ischemic-type biliary lesions in liver transplantation from non-heart-beating donors Yilei Deng ⇑, Longshuan Zhao, Xu Lu Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

a r t i c l e

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Article history: Received 11 September 2015 Revised 20 December 2015 Accepted 8 April 2016

a b s t r a c t Ischemic-type biliary lesions (ITBL) are the most troublesome biliary complication after liver transplantation (LT) from non-heart-beating donors (NHBD) and frequently result in death or re-transplantation. In transplantation process, warm ischemia (WI) in the donor, cold ischemia and reperfusion injury in the recipient altogether inducing ischemia–reperfusion injury (IRI) is strongly associated with ITBL. This is a cascading injury process, involving in a complex series of inter-connecting events causing variety of cells activation and damage associated with the massive release of inflammatory cytokines and generation of reactive oxygen species (ROS). These damaged cells such as sinusoidal endothelial cells (SECs), Kupffer cells (KCs), hepatocytes and biliary epithelial cells (BECs), coupled with immunological injury and bile salt toxicity altogether contribute to ITBL in NHBD LT. Developed therapeutic strategies to attenuate IRI are essential to improve outcome after LT. Among them, single pharmaceutical interventions blocking a specific pathway of IRI in rodent models play an absolutely dominant role, and show a beneficial effect in some given controlled experiments. But this will likely prove ineffective in complex clinical setting in which more risk parameters are involved. Therefore, we intend to design a multidrug cocktail approach to block different pathways on more than one stage (WI, cold ischemia and reperfusion) of the process of IRI-induced ITBL simultaneously. This multidrug cocktail will include six drugs containing streptokinase, epoprostenol, thiazolidinediones (TZDs), N-Acetylcysteine (NAC), hemin and tauroursodeoxycholic acid (TUDC). These drugs show protective effects by targeting the different key events of IRI, such as anti-inflammatory, anti-fibrosis, anti-oxidation, anti-apoptosis and reduced bile salt toxicity. Ideally, the compounds, dosage, and method of application of drugs included in cocktail should not be definitive. We can consider removing or adding some drugs to the proposed cocktail based on further research. But given the multitude of different combinations, it is extremely difficult to determent which combination is the optimization design. Nevertheless, regardless of the difficulty, our multidrug cocktail approach designed to block different mechanisms on more than one stage of IRI simultaneously may represent a future preventive and therapeutic avenue for ITBL. Ó 2016 Elsevier Ltd. All rights reserved.

Background Until now, LT remains the only curative treatment for patients with end-stage liver disease. But the number of LT performed is limited by the shortage of donor livers. To expand of the donor pool, livers from non-heart-beating donors (NHBD) are increasingly used [1]. Compared with liver transplants from brain death donors, the use of livers from NHBD is associated with a higher risk for primary non function and ITBL [2]. ITBL, defined as intrahepatic or non-anastomotic, extra-hepatic biliary strictures without hepatic artery thrombosis, are the most troublesome biliary

⇑ Corresponding author. E-mail address: [email protected] (Y. Deng). http://dx.doi.org/10.1016/j.mehy.2016.04.013 0306-9877/Ó 2016 Elsevier Ltd. All rights reserved.

complication and frequently result in death or re-transplantation [3]. For NHBD LT, three main risk factors contributing to ITBL are: WI in the donor, cold ischemia and reperfusion injury in the recipient altogether leading to IRI [3,4]. Ischemia (WI and cold ischemia) interrupts intracellular oxygen and nutrient supple with subsequent depletion of adenosine triphosphate (ATP). ATP depletion and hypothermia disturb cell membrane integrity, which promotes ions (especially Ca2+) and water influx, inducing cellular edema and leakage of contents (especially SECs, KCs and BECs) [5–8]. Once the restoration of blood flow and oxygen supple (reperfusion injury), SECs, KCs, neutrophils and platelets are activated sustained and intensely, initiating the excessive release of cytokines, ROS and pro-coagulants. While these events in turn exacerbate damage to KCs, SECs, BECs and hepatocytes, and then produce more cytokines,

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ROS and adhesion molecules [5–8]. This cascading injury process forms a vicious cycle, and ultimately leads to direct and secondary bile duct injury. In addition, immunologically mediated injury and the hydrophobic bile salt toxicity to hepatocytes and BECs also contribute to ITBL [3,4]. Interventions destined to modulate the key point in this cascading injury are considered beneficial for the outcome after LT. At present, intervention strategies to ameliorate IRI have nearly focused on single pharmacological studies. In some animal models and few clinical trials, these single pharmacological interventions have shown protective effects by targeting some particular mechanism such as anti-inflammatory, anti-fibrosis, anti-oxidation, anti-apoptosis and reduced bile salt toxicity [9–11]. But virtually none are currently applied in the complex clinical setting [12]. No single intervention can completely eliminate IRI in view of the complexity and diversity of interrelated factors. It seems more logical and realistic to block different pathways on more than one stage of IRI-induced ITBL simultaneously.

transforming growth factor-b (TGF-b) signaling pathway, and then alleviating the process of liver and biliary fibrosis after the inflammatory injury [18]. TGF-b is one of most important fibrosispromoting cytokine. Activation of TGF-b not only promotes the proliferation and activation of hepatic stellate cell (HSC) but also induce epithelial to mesenchymal transition (EMT) in hepatocytes and bile duct epithelium [18]. Both of pathological mechanisms contribute to the excessive production and deposition of extracellular matrix (ECM) in injured liver and bile duct. NAC The overexpression of ROS is one of the earliest and most important pathological events in hepatic IRI after LT. Glutathione can react with ROS, constituting an important component of the endogenous antioxidant system. NAC, a precursor of glutathione, can enter cells more easily to replenish the depleted hepatic glutathione storage in IRI because of a smaller molecular weight [19,20].

Hypothesis Whatever the complexity of the pathophysiological mechanism of ITBL, there exist some inherent characteristics: excessive release of inflammatory mediators, increased generation of ROS, bile salt toxicity, massive apoptosis in hepatocytes and BECs. Therefore, we intend to design a multidrug cocktail approach to prevent ITBL in NHBD LT, including streptokinase, epoprostenol, TZDs, NAC, hemin and TUDC. At different stages (WI, cold ischemia and reperfusion), this multidrug cocktail approach is able to simultaneously and effectively target different pathways of IRI, as follows: improvement of microcirculation (streptokinase, epoprostenol and hemin), inhibition of inflammation and post-inflammatory fibrosis (TZDs), anti-oxidation (NAC and hemin), anti-apoptosis (hemin and TUDC), and reduced bile salt toxicity (TUDC). All of these drugs have been proven beneficial for outcome of liver transplantation. And each of them is widely used in clinical practice and proved nontoxic or mild side effects, which also impels us to make this hypothesis. Based on this hypothesis, such a multidrug cocktail approach is expected to reduce ITBL in NHBD LT by inhibition of IRI and bile salt toxicity, resulting in a lower degree of bile duct injury and better liver function, and increased graft and recipient survival. Below we briefly discuss the protective effects of the main component in this multidrug cocktail approach, and emphasis on inhibition of IRI. Epoprostenol Epoprostenol, a naturally occurring prostaglandin, is well known to decrease the systemic and pulmonary arterial pressures and inhibit platelet aggregation, improving the microcirculatory perfusion [13]. TZDs TZDs are the well known synthetic agonists of peroxisome proliferator-activated receptor c (PPARc). Activation of PPARc by TZDs not only inhibits the inflammatory cascade in IRI, but also attenuates the organ fibrosis following the inflammatory damage [14,15]. To date, the potential protective mechanism of TZDs against hepatic IRI can be summarized as follows, (1): inhibition of the expression of multiple inflammatory mediators, chemokines and adhesion molecules, especially inhibition of nuclear factor-jB (NF-jB) activities in KCs and hepatocytes. (2): prevention the excessive hepatocyte apoptosis by suppressing the production of inducible nitric oxide synthase (iNOS) [14–17]. (3): blocking

HO-1 activation and hemin The concomitant occurrence of high levels of hemolysis seems inevitable during hepatic IRI, which leads to the excessive release of free heme. As a hydrophobic molecule, the free heme can intercalate in graft endothelial cells (ECs) membranes where it catalyzes ROS formation by the Fenton reaction, exerting the cytotoxic effect. Rapid heme degradation should be desirable for prevention of hepatic IRI [21]. Heme oxygenase (HO) can convert heme into carbon monoxide (CO), free iron (Fe2+) and biliverdin, greatly reducing the cytotoxicity [22]. In addition, the end-products of heme catabolism also show benefits in many aspects of IRI, especially CO. Analogous to NO, endogenous production of CO can inhibit platelet aggregation and stimulate vasodilatation, and then improves hepatic microcirculation [23]. And CO could protect SECs from apoptosis by activation of the p38 mitogen-activated protein kinase (MAPK) [24]. Therefore, drug-induced up-regulation of HO may be a reasonable therapeutic strategy for hepatic IRI. Hemin is a FDA-approved drug available in porphyria and can significantly induce HO-1 expression [25]. TUDC Apart from IRI, bile salt toxicity also contributes to ITBL. A high bile salt/phospholipid ratio in bile produced early after LT prevents the formation of mixed micelles of bile salts and phospholipids. Subsequently, nonmicellar bile salts trigger severe hepatocytes and BECs injury because of their detergent properties to cellular membrane [26,27]. Ursodeoxycholic acid (UDCA) as a non-toxic, hydrophilic bile salt, can replace the hydrophobic bile salts in the bile pool to reduce bile salt toxicity [28]. TUDC is the most hydrophilic conjugate of UDCA. UDCA may be the first FDA-approved anti-apoptotic drug. In vitro, UDCA shows anti-apoptotic effects at low micromolar concentrations, which can be achieved easily in the human body to protect hepatocytes and cholangiocytes against apoptosis [29]. In primary biliary cirrhosis (PBC) and PSC patients, UDCA significantly reverses aberrant HLA class I molecules expression on hepatocytes [30], which may also play a role in prevention of ITBL because of a higher incidence of ITBL in post-transplant PSC patients. Evaluation of the hypothesis There are several steps to take to test our hypotheses.

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Table 1 Compounds, dosage, method and time of application, experimental or clinical evidence relevant for the selection of drugs included in multidrug cocktail approach. Compound

Dosage

Method and time of application

Experimental or clinical evidence

Epoprostenol

500 lg, donor 250 lg, preflush

Improving microcirculatory perfusion and preservation, increasing graft resistance to IRI [31,34–37]

NAC

150 mg/kg, donor 150 mg/kg and 10 mg/kg, recipient

Hemin

50 mg/kg, donor 50 mg/kg, recipient

Streptokinase

500,000 U, preflush

Pioglitazone

20 mg/kg, recipient

TUDC

10 mg/kg, donor 10 mg/kg, recipient

Donor preconditioning: IV, within the 30 min before cardiac arrest Donor liver pre-flush: Pre-flush, with 1 L of warm Ringers solution through the portal vein and through the hepatic artery Donor preconditioning: IV, within the 2 h before cardiac arrest Recipient: IV, infused over the 15 min before reperfusion (a loading dose of 150 mg/kg) and maintained at 10 mg/ kg/h for 7 h Donor preconditioning: IV, within the 24 h before cardiac arrest Recipient: IV, within the 24 h before reperfusion Donor liver pre-flush: Pre-flush, with 1 L of warm Ringers solution through the portal vein and through the hepatic artery Recipient: IG, within 2 h before reperfusion and maintained at 20 mg/kg/d for postoperative 7 d Donor preconditioning: IG, within 1 h before cardiac arrest Recipient: IG, within 1 h before reperfusion and maintained at 10 mg/kg/d for postoperative 7 d

Improving intracellular tissue oxygenation and liver function, preventing liver IRI [38–42]

Reducting oxidative stress and inflammatory mediators, improving liver function and graft survival, attenuating liver IRI [43–47]

Improving microcirculatory perfusion and preservation, improving postpreservation viability and energetic recovery [31,48,49] Reducing inflammation mediators, attenuating IRI and fibrotic involution in several organs, improving liver histology and fibrosis [14,15,17,18,50–53] Reducing bile salt toxicity, reducing BECs and endothelial damage, improving liver function, attenuating liver IRI [36,54–59]

IV, intravenously; IRI, ischemia–reperfusion injury; min, minute; h, hour; d, day; TUDC, tauroursodeoxycholic acid; IG, intragastrically; BECs, biliary epithelial cells.

Animals and NHBD liver transplant model The porcine model of NHBD LT is set up as described previously in the literature [31,32]. Briefly, inbred female Neijiang pigs (30–35 kg) will be used as donors and recipients. In donors, livers will be exposed to 45 min WI. To mimic NHBD, WI is defined as the period from the initiation of cardiac arrest until the start of cold perfusion, and cardiac arrest will be induced by ventricular fibrillation. Subsequently, livers will be stored at 4 °C for 4 h until transplantation. According to the technique of LT in pigs described by Oike et al. [33], donor livers will be transplanted in recipients without using venovenous bypass. However, biliary reconstruction will not be performed. Bile is drained externally with a catheter inserting in the common bile duct. To prevent interruption of the enterohepatic biliary circulation, bile will be readministered through a jejunostomy catheter. During surgery, arterial blood pressure and central venous pressure will be monitored. Infusion of intravenous fluids is individually guided by clinical signs of hypovolemia, hemodynamic parameters, and laboratory blood analysis. When severe hypotension (mean arterial pressure <40 mmHg) up to a period of 30 min during the anhepatic phase, 500 mL of oxyplatin will be administered intravenously. Postoperatively, animals received tacrolimus (0.05 mg/kg bid). The postoperative observation period is limited to 7 days. Animals surviving less than 7 days were autopsied to identify the cause of death. Experiments will be approved by the local animal care committee. Experimental groups Control group After exposure to 45 min in situ WI, donor livers are flushed with 10L of 4 °C histidine-tryptophan-ketoglutarate (HTK) preservation solution via the portal vein and the hepatic artery by gravity. Immediately, livers are harvested, weighed, cold stored (4 h) and transplanted.

Multidrug cocktail approach group Compounds, dosage, method and time of application, experimental or clinical evidence relevant for the selection of drugs included in multidrug cocktail approach are summarized in Table 1. Donor preconditioning. Prior to cardiac arrest, epoprostenol (500 lg), NAC (150 mg/kg) and hemin (50 mg/kg) are given by intravenous, and TUDC is given by gavage. Donor liver pre-flush. After exposure to 45 min in situ WI, donor livers are first pre-flushed with 1L of warm Ringers solution (37 °C) containing streptokinase (500,000 U) and epoprostenol (250 lg) via the portal vein and the hepatic artery by gravity. And then, donor livers are flushed-out with 5 L of 4 °C HTK solution. Other basic operation is the same as control group. Recipient. Recipients will receive the following drugs. Prior to reperfusion, pioglitazone (TZDs, 20 mg/kg) and TUDC (10 mg/kg) are administered by gavage, and hemin (50 mg/kg) is given by intravenous. A loading dose of 150 mg/kg NAC is infused intravenously over the 15 min before reperfusion and maintained at 10 mg/kg/h for 7 h. After transplantation, pioglitazone (20 mg/kg/ d) and TUDC (10 mg/kg/d) are maintained continuously until postoperative day 7. Other basic operation is the same as control group. Detection indicators and statistical analysis Detection indicators and methods do not differ between control group and multidrug cocktail approach group. Detection indicators, methods and significance in two groups are summarized in Table 2. Continuous data are presented as means ± standard deviations. Differences within one group are analyzed using the Anova-test. Differences between control group and multidrug cocktail approach group are compared using the t test. A p value < 0.05 is considered significant.

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Table 2 Detection indicators, methods and significance in experiment. Indicator

Sample

Method

Significance

AST,TBIL, TGF-b1,MDA

Serum: Collected before laparotomy and at 15 min, 1 h, 3 h, 12 h, 24 h, 48 h, 3 d and 7 d after reperfusion

AST, TBIL: Routine chemical methods TGF-b1: Using a porcine-specific ELISA assay kit MDA: Using the Spectrophotometer

TNF-a, IL-6

Serum: Collected before laparotomy and at 15 min, 1 h, 3 h, 12 h, 24 h, 48 h after reperfusion Bile: Collected before cardiac arrest and 3 h after reperfusion and daily thereafter

Using a porcine-specific ELISA assay kit

AST, TBIL: Assessment of liver function TGF-b1: The proinflammatory and pro-fibrotic cytokine MDA: Oxidative stress Pro-inflammatory cytokines

Bile salt/phospholipid ratio

BDISS, IRI score

Large wedge liver biopsies: Taken before cardiac arrest and 1 h after reperfusion

TGF-b1, a-SMA, Collagen 1 mRNA and protein Survival

Normal CBD and CBD obtained 3d and 7d after surgery The number of survivors at 7d after transplantation

Total biliary bile salt: Using the Spectrophotometer Biliary phospholipid: Using the commercially available enzymatic method Biopsies: HE staining BDISS: Based on the extent of bile duct epithelial damage and ductular reaction [60,61] IRI score: Based on the extent of hepatocyte loss, sinusoidal congestion and dilatation [31,62]ALL assessments were performed blindly by a single pathologist Real-time PCR and Western-blot Performed blindly by a single pathologist

Bile salt toxicity

BDISS: Severity of bile duct injury IRI score: Severity of IRI

Severity of biliary fibrosis

AST, aspartate aminotransferase; TBIL, total bilirubin; TGF-b1, transforming growth factor b1; MDA, malondialdehyde; min, minute; h, hour; d, day; TNF-a, tumor necrosis factor a; IL-6, Interleukin-6; BDISS, bile duct injury severity score; IRI, ischemia–reperfusion injury; a-SMA, Smooth muscle actin a; CBD, Common bile duct.

Consequences of the hypothesis and discussion Whatever the complexity of the pathological process of IRIinduced ITBL, we should not suspect that many key mechanisms have been unmasked in the past few decades. Developed therapeutic strategies to prevent IRI are essential to improve outcome after LT and this is more important for NHBD LT, mainly including development of newer preservation solutions [63], pharmacological treatments of donors or recipients [34–59], ischemic preconditioning [64] and machine perfusion preservation [65]. However, among them, single intervention studies in rodent models especially pharmacological interventions play an absolutely dominant role, and few strategies have been tested in large animal models and clinical trials. So far, virtually no treatment strategies are currently used in clinical practice. In some given controlled experiments, single pharmacological intervention blocking a specific pathway show a beneficial effect, but likely will prove ineffective in complex clinical setting in which more risk parameters are involved. Therefore, we intend to design a multidrug cocktail approach to block different pathways on more than one stage (WI, cold ischemia and reperfusion) of the process of IRI-induced ITBL simultaneously. Among them are improvement of microcirculation (streptokinase, epoprostenol and hemin), inhibition of inflammation and postinflammatory fibrosis (TZDs), anti-oxidation (NAC and hemin), anti-apoptosis (hemin and TUDC), and reduced bile salt toxicity (TUDC). And in this hypothesis, we mainly focus on (1) optimizing donor liver quality by multidrug donor preconditioning and donor liver pre-flush and (2) attenuate IRI and bile salt toxicity in recipients by administrating multiple drugs. Considering clinical application, selected drugs in our cocktail approach are widely used in clinical practice and proved nontoxic or mild side effects. With regard to the biliary fibrosis in ITBL, currently no drug is shown effective on completely reverse fibrotic involution in liver cirrhosis nor in primary biliary disorders. But increasing experiments have confirmed that TZDs can attenuate the fibrotic involution in several organs mainly via blockade of TGF-b signaling

pathway, such as liver, kidney, lung, heart and even bile duct [18,53,66–68]. Of course, in our hypothesis, recipients follow up period is limited to 7 days, which may be short and not observe the occurrence of biliary strictures. The better approach is to substantially extend the follow-up period and include more animals, but this seems to be difficult in a large animal model for financial and realistic factors. Alternatively, we try to determine bile salt toxicity and some key fibrosis factors (TGF-b1, a-SMA and collagen 1) to optimize our hypothesis, which may have more practical significance. To our knowledge, there are very few studies to explore the effect of multidrug regulation strategy. One critical reason is that it is difficult to identify which components of cocktail afford the effect observed. This will also be a problem encountered in our hypothesis but has little impact on research, because we focus on the combined effect in this cocktail rather than any single drug alone. Here, we are just trying to put forward a cocktail approach and to document that blockage of different key events at different stages (donor, preservation and recipient) simultaneously should be a more valuable option to prevent ITBL after NHBD LT. Ideally, the compounds, dosage, and method of application of drugs included in cocktail should not be definitive. Based on further research, we can consider removing or adding some drugs to the proposed cocktail. However, given the multitude of different combinations, it is extremely difficult to determent which combination is the optimization design. Nevertheless, regardless of the difficulty, our multidrug cocktail approach designed to block different mechanisms on more than one stage of IRI simultaneously may represent a future preventive and therapeutic avenue for ITBL.

Conflict of interest statement All authors declare that they do not have any financial and personal relationships with other people or organizations that would bias their work.

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