Journal Of Pediatric Surgery(2).pdf

Journal of Pediatric Surgery (2010) 45, 1791–1796

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Increased susceptibility to liver damage from pneumoperitoneum in a murine model of biliary atresia Pablo Laje a , Fred H. Clark b , Joshua R. Friedman c , Alan W. Flake a,⁎ a

Department of General Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA Department of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, PA, USA c Department of Gastroenterology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA b

Received 22 December 2009; revised 8 February 2010; accepted 25 February 2010

Key words: Biliary atresia; Minimally invasive surgery; Pneumoperitoneum

Abstract Hypothesis: We hypothesized that livers with biliary atresia (BA) are more susceptible to the harmful effects of a high-pressure CO2 pneumoperitoneum (PP) than healthy livers. Methods: A murine model of BA was used in this experiment. Mice were divided into 6 groups: (1) control Balb/c; (2) control Balb/c, CO2-PP; (3) control BA; (4) BA-sham; (5) BA, CO2-PP; and (6) BA, air-PP. Mice from groups 2, 5, and 6 underwent an 8-mm Hg-PP for 60 minutes. Liver samples were collected for histology, colorimetry, and flow cytometry analysis 18 to 24 hours after the procedure. Markers of apoptosis were investigated as indicators of acute cell damage. Results: We observed a statistically significant higher rate of apoptosis in livers with BA exposed to a prolonged CO2-PP or air-PP compared with control groups. There were no significant differences between groups 1 and 2, or between groups 5 and 6. Conclusions: In this animal model, we have shown that livers with BA are more susceptible than healthy livers to injury by a prolonged PP. This injury was caused by both CO2 and air-PP, implying that it is the direct result of pressure. These results may have implications for the success of minimally invasive Kasai procedures. © 2010 Elsevier Inc. All rights reserved.

The most common cause of liver failure requiring liver transplantation in children in developed countries is biliary atresia (BA), an inflammatory disease resulting in destruction and fibrosis of the extrahepatic bile ducts. The prevailing treatment for BA is the Kasai portoenterostomy procedure, which provides palliative bile drainage in approximately 60% of patients. Recently, the Kasai procedure has been

⁎ Corresponding author. Department of Surgery, Abramson Research Center, Philadelphia, PA 19104-4318, USA. Tel.: +1 215 590 3671; fax: +1 215 590 3324. E-mail address: [email protected] (A.W. Flake).

performed using minimally invasive techniques in several centers (minimally invasive surgery or MIS-Kasai) [1-4]. However, initial enthusiasm has been tempered by concern that patients undergoing MIS-Kasai have a higher rate of failure than those undergoing open surgery. At the present time, there is no explanation for this observation, but speculation has focused on technical aspects of the procedure. Nevertheless, there are also possible biologic explanations. One potential explanation for the difference observed between the open and MIS-Kasai could be the liver damage induced by the prolonged, high-pressure CO2 pneumoperitoneum (PP) used during the MIS-Kasai, a procedure that requires several hours to complete.

0022-3468/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2010.02.117

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1792 It has been previously demonstrated that the prolonged PP required for laparoscopy has detrimental effects on the liver as evidenced by a transient increase in the serum ALT/AST levels [5-9]. The mechanism behind this effect is thought to be the transient ischemia produced by the pressurized PP and the subsequent reperfusion injury, with generation of reactive oxygen species that promote inflammation and cell death [10-12]. The ischemia/reperfusion injury is known to affect primarily the periportal areas [13]. In patients with intact liver function, these harmful effects of a PP have minimal clinical significance, and liver function tests typically normalize within 1 week. On the other hand, patients with impaired liver function are at higher risk for more significant liver injury [14-16]. We hypothesized that the prolonged PP associated with the MIS-Kasai could produce a detrimental effect on an already damaged liver, which could contribute to a more rapid progression to liver failure. To test this hypothesis, we used a murine model of rotavirus-induced BA [17-19] to investigate the effects of a prolonged, high-pressure PP on the BA liver.

P. Laje et al. parts per million) under spontaneous ventilation. Mice in groups 3, 5, and 6 were exposed to a continuous, uninterrupted 8 mm Hg CO2 or air-PP for a total of 60 minutes through a percutaneous 16-gauge angiocath placed in the abdominal midline. A 6.0 Prolene (Ethicon, Bridgewater, NJ) purse string suture was placed around the angiocath to avoid gas leakage. The PP pressure and flow (2.5 L/min) were controlled by an electronic insufflator (Endoflator; Karl Storz, Tuttlingen, Germany).

1.4. Liver samples Mice were euthanized 18 to 24 hours after the procedure. For each animal, a portion of the liver was fixed in formalin for histologic analysis, and another portion was cut in smaller pieces, incubated for 20 minutes in 0.05% collagenase IV S (Sigma-Aldrich, St Louis, MO), gently passed through a 1-mL syringe repeatedly, and finally passed through a 70-μm cell strainer, to form a single-cell suspension for flow cytometry and enzymatic analysis.

1.5. Flow cytometry

1. Materials and methods 1.1. Rotavirus The MMU18006 strain of wild-type Rhesus rotavirus, passed 3 times in MA104 cells, was used in all cases, at a titer of 4 × 107 viral particles/mL.

1.2. Mice Balb/c mice were obtained from Charles River Laboratories (Wilmington, MA) and housed in the Laboratory Animal Facility of The Children's Hospital of Philadelphia. Newborn Balb/c mice were inoculated intraperitonealy with 50 μl of wild-type rotavirus at 12 to 24 hours of life, under general anesthesia, by means of a 50-μm needle connected to an electronic microinjector (IM-300 Narishige, Tokyo, Japan). Mice were divided into 6 groups (n = 7 in each group): (1) Balb/c mice, no anesthesia, no PP; (2) Balb/c mice, anesthesia, 8 mm Hg CO2 PP; (3) BA mice, no anesthesia, no PP; (4) Sham-operated BA mice, anesthesia only, no PP; (5) BA mice, anesthesia + 8 mm Hg CO2 PP; and (6) BA mice, anesthesia + 8 mm Hg air-PP. All experimental protocols were reviewed and approved by the Institutional Animal Care and Use Committee at The Children's Hospital of Philadelphia and followed guidelines set forth in the National Institutes of Health's Guide for the Care and Use of Laboratory Animals.

1.3. Surgery On days 16 to 18 of life, mice in groups 3, 4, 5, and 6 underwent general inhalational anesthesia (Isoflurane, 2.5

Cells were counted and stained with annexin V-PE and 7amino-actinomycin D (BD Biosciences, San Jose, CA) according to the manufacturer's instructions and analyzed on a FACSCalibur cytometer (BD Biosciences). Only cells stained exclusively by annexin V-PE were considered apoptotic, whereas cells stained by both markers or exclusively by 7-amino actinomycin D (AAD) were considered dead. Absolute values were normalized to the values of control samples.

1.6. Colorimetric enzymatic assay Single-cell suspensions were processed according to the manufacturer's instructions and assessed for active caspase-3 activity (active caspase-3 colorimetric assay kit; R&D Systems, Minneapolis, MN). Briefly, cells were counted, pelleted, and resuspended in lysis buffer for 10 minutes. Cellular lysates were incubated with a reaction buffer and the active caspase-3 substrate Asp-Glu-Val-Asp-p-nitroanilide (DEVD-pNA) for 2 hours. The amount of the chromophore pNA released by the active caspase-3 was colorimetrically quantified on a 405-nm plate reader (Synergy HT; Biotek, Winooski, VT). Values were normalized to the activity of control samples.

1.7. Immunohistochemistry Liver samples were fixed in 10% neutral formalin solution and embedded in paraffin. Four-micron sections were immunostained using rabbit monoclonal antimouse-active caspase-3 antibody (Abcam Inc, Cambridge, MA) at a 1:50 dilution, overnight at 4°C, after quenching the endogenous

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peroxidase activity with 0.3% hydrogen peroxide in distilled water. After this, a horseradish peroxidase polymer conjugate was applied (Invitrogen, Carlsbad, CA) and samples developed with the ImmPACT-DAB horseradish peroxidase–specific chromogenic substrate (Vector Laboratories, Burlingame, CA). Finally, all samples were counterstained with Harris hematoxylin. Pictures were taken with an AXIO Imager-A1 microscope and AxioVision software (Carl Zeiss, Göttingen, Germany).

data from different sets, raw values from group 2 were always normalized to the values of group 1, and raw values from groups 4, 5, and 6 were always normalized to the values of group 3 within the same set. Immunohistochemical analysis is expressed as raw data. Statistical significance was accepted at P b .05.

2. Results 1.8. Statistical analysis Data were analyzed using a Kruskal-Wallis test (SPSS v15.0 software; SPSS, Chicago, IL) with treatment as the grouping variable. Post hoc testing was performed with a Mann-Whitney U test to identify significant differences between mean values. On each experimental day, flow cytometry and colorimetry data were collected from 1 mouse each of the 6 groups. Because of a wide intra-assay variability observed from one day to another, to compare

Approximately 80% of mice exposed to Rhesus rotavirus developed BA, evidenced by generalized jaundice, failure to thrive, choluria, and acholic stools. The first signs of cholestasis were noted around day of life 7 (jaundice), and by day of life 14, all the features were present, including profound failure to thrive compared with age-matched controls (Fig. 1A). All the histologic features of human BA were identified in these animals: bile duct obliteration and proliferation, lymphocyte infiltration of the periportal areas,

Fig. 1 (A) Naive Balb/c mouse (left) and mouse with BA (right) at day 18 of life. The failure to thrive and general jaundice are evident in the mouse with BA. (B) Liver histology from a mouse with rotavirus-induced BA. The features that characterize human BA are present in this animal model: fibrosis (black arrow), inflammatory infiltration (arrowhead), and bile duct obliteration and proliferation (white arrow). (C) A mouse with BA under general inhalation anesthesia (spontaneous ventilation), undergoing insufflation through a 16-gauge standard angiocath placed at the midline, secured with a 6.0 purse string suture. The abdominal cavity is clearly distended. (D) Active caspase-3–positive cells were uniformly distributed throughout the liver sections and not restricted to any particular region.

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1794

P. Laje et al. there were no statistically significant differences between groups 5 and 6 (CO2 versus air), which implies that it is not the CO2 that is responsible for the observed damage in livers with BA, but rather the pressure itself.

2.1. Flow cytometry

Fig. 2 Annexin V–positive/7-AAD–negative cells within the liver samples. The Balb/c-CO2 group raw values were normalized to the values of the Balb/c group, and the raw values of the BAsham, BA-CO2, and BA-Air groups were normalized to the values of the BA group.

and progressive bridging liver fibrosis (Fig. 1B). All operated mice tolerated the surgical procedure and survived until euthanasia (Fig. 1C). We observed a generally higher rate of apoptosis in livers with BA that were exposed to a prolonged, high-pressure CO2 or air-PP (groups 5 and 6) compared with livers in all control groups; however, livers with BA had a baseline rate of apoptosis higher than livers without BA. Thus, to adequately compare groups and truly assess whether livers with BA are more susceptible to PP damage than healthy livers, the Balb/c-CO2 group (#2) was always compared with the Balb/c group (#1), and the BA-sham, BA-CO2 and BAair groups (#4, #5, and #6, respectively) were always compared with the BA group (#3). The differences between groups 1 and 2 were never statistically significant, whereas the differences between groups 3 versus 5 and 3 versus 6 individually were always statistically significant. In addition,

Samples were stained with annexin V-PE and 7-AAD (dead cells) according to the manufacturer's instructions. A gate was drawn on the side scatter/forward scatter dot plot in order include all liver cell types in the sample but exclude cellular fragments and debris. Groups 5 and 6 had a significantly higher percentage of annexin V–positive/7AAD–negative cells than all control groups. P values were as follows: Balb/c CO2 versus Balb/c: .152, BA-sham versus BA: .11, BA-CO2 versus BA: b.001, BA-air versus BA: b.001, and BA-CO2 versus BA-air: .848. We found some disparity in the raw values obtained from set to set because of intra-assay variability, but the normalized proportions within each set were consistent throughout all sets (Fig. 2).

2.2. Immunohistochemistry All samples were examined by a reviewer blinded to the source of each slide. Active caspase-3–positive cells were counted in 10 random high-power fields (40×) from each slide and averaged for each treatment group. Livers in groups 5 and 6 had a remarkably higher number of active caspase-3–positive cells than livers in all other groups. The differences between groups 5 or 6 and their control group (#3) were statistically significant (Figs. 3 and 4). P values

Fig. 3 Immunohistochemistry for active caspase-3 (peroxidase). Positive cells are more abundant in mice with BA exposed to CO2 or Air (slides 5 and 6, respectively) compared with all other groups. Although positive cells were barely detectable in samples from healthy livers (slide 1), samples from livers with BA (slide 3) showed scattered positive cells in every high-power field.

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3. Discussion

Fig. 4 Mean number of active caspase-3–positive cells per highpower field (40×) in each treatment group. Ten random high-power fields were examined in each slide. The difference between groups 5/6 (BA-CO2 and BA-air, respectively) and the rest of the groups is more prominent than the differences observed by flow cytometry or colorimetry.

were as follows: Balb/c CO2 versus Balb/c: .068, BA-sham versus BA: .831, BA-CO2 versus BA: .012, BA-air versus BA: b.009, and BA-CO2 versus BA-air: .917. The active caspase-3–positive cells were distributed uniformly throughout the liver and were not restricted to any particularly region (Fig. 1D).

2.3. Colorimetric assay Fresh cellular lysates from livers in groups 5 and 6 showed a significantly higher activity of the active caspase-3 enzyme than lysates from groups 1, 2, 3, or 4. P values were as follows: Balb/c CO2 versus Balb/c: .152, BA-sham versus BA: .633, BA-CO2 versus BA: .001, BA-air versus BA: b.001, and BA-CO2 versus BA-air: .338. Again, raw values were normalized to compare sets that were analyzed on different days. The Balb/c-CO2 group raw values were normalized to the values of the Balb/c group, and the raw values of the BA-sham, BA-CO2 and BA-Air groups were normalized to the values of the BA group. Normalized values are shown in Fig. 5.

Fig. 5 Normalized activity of the active caspase-3 enzyme measured by 405-nm absorbance colorimetry. Water was used as a control for calibration. The Balb/c-CO2 group raw values were normalized to the values of the Balb/c group, and the raw values of the BA-sham, BA-CO2, and BA-air groups were normalized to the values of the BA group.

The detrimental effects of a prolonged high-pressure CO2 PP on cardiac, pulmonary, renal, and hepatic function are well known. Hypercarbia, acid-base imbalances, oliguria, hypotension, and alterations in liver function tests have been documented in previous studies [5-8,20-25]. The potential pathophysiologic mechanisms causing these effects are multiple and could include abdominal competition, direct carbon dioxide absorption, impaired systemic venous return, and others. In the liver, the pressurized PP is thought to decrease hepatic blood flow resulting in transient ischemia and subsequent reperfusion injury inducing inflammation, cell damage, and cell death [10-12,26]. Typically, these effects are transient and have minimal clinical significance in otherwise healthy patients. Furthermore, in patients with mild to moderate underlying liver damage, it has been shown that, overall, the adverse effects of high-pressure CO2 are not a contraindication for laparoscopy [27-30]. Because of the transient nature of these PP-induced perturbations in normal patients, there has been very little published regarding the long-term consequences of a single prolonged exposure to a high-pressure PP in patients with organ dysfunction or disease. Tsuboi et al [14] showed that a CO2 PP decreased the total hepatic blood flow to 91.9% of basal flow in healthy control rats, but to 71% of basal flow in cirrhotic rats (P b .05), and Jiao et al [31] showed in an animal model that the impaired hepatic microcirculation, oxygenation, and function of livers with extensive fibrosis drastically improve by increasing portal venous flow, the opposite of the effect of a PP. These reports support the idea that livers with severe ongoing cell damage and fibrosis could be particularly sensitive to high-pressure PP exposure. In this study, we measured the rate of liver cellular apoptosis 18 to 24 hours after 60 minutes of uninterrupted PP using either CO2 or air insufflation in mice with or without BA. We found that in healthy controls, there were no major changes after the PP, whereas in mice with BA, the rate of apoptosis increased significantly (P b .05) with either CO2 or air-PP. These findings reinforce the idea that exposing livers with advanced degeneration and fibrosis to a prolonged, high-pressure PP might be more harmful than what has been generally appreciated. In addition, it dispels the notion that the CO2 gas is somehow harmful but rather documents that it is the pressure in the peritoneal cavity that induces the detrimental effect. Unfortunately, because of the relatively short life span of mice with BA (19-21 days), this animal model has limitations for study of whether this acute injury results in acceleration of hepatic fibrosis or liver failure, a question that remains unanswered. Although we did not directly measure hemodynamic changes or blood flow in this study, it is likely that the reduction in portal, hepatic, and microvascular flow demonstrated in other studies combined with an ischemia/ reperfusion injury is likely to be involved. We feel that the most important observation in this study was the extreme

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1796 susceptibility of the BA liver to injury from a PP relative to normal controls. Although no randomized prospective studies have been conducted comparing the open Kasai portoenterostomy with MIS-Kasai, it is the consensus among centers with experience with MIS-Kasai that patients who underwent a MIS-Kasai had a poorer outcome, requiring liver transplantation at an earlier age, compared with the historical results with an open Kasai procedure [32]. Although this has been attributed by some to technical issues related to accurate and complete division of the fibrous plate, given the consensus among several talented MIS surgeons, a biologic reason is perhaps more likely. In this study, we have demonstrated that livers with BA are highly sensitive to the detrimental effects of a prolonged PP, with a marked increase in the rate of cell apoptosis relative to normal livers. We speculate that this increased sensitivity to PP may at least in part explain the relatively poor results with the MIS-Kasai, but further studies confirming a long-term effect are required.

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