Interact CardioVasc Thorac Surg 2008;7:1114-1120. doi:10.1510/icvts.2007.170456
© 2008 European Association of Cardio-Thoracic Surgery
Negative results - Thoracic general |
Occult injury in the residual lung after pneumonectomy in mice
Atsushi Tajimaa,
Mitsutomo Kohnob,*,
Masazumi Watanabeb,
Yotaro Izumib,
Sadatomo Tasakac,
Ikuro Maruyamad,
Taku Miyashoe and
Koichi Kobayashib
a Department of Surgery, Saiseikai Utsunomiya Hospital, Tochigi, Japan
b Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
c Department of Medicine, Keio University School of Medicine, Tokyo, Japan
d Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
e Department of Veterinary Biochemistry, Rakuno Gakuen University, Hokkaido, Japan
Received 19 October 2007;
received in revised form 20 May 2008;
accepted 17 July 2008
 This study was partly supported by the Ministry of Education, Science, Sports and Culture, Grant-in-Aid for Scientific Research, 18120101, 2006, for I. Maruyama and K. Kobayashi.
Corresponding author. Tel.: +81-3-5363-3806; fax: +81-3-5363-3499.
E-mail address: kohno{at}1993.jukuin.keio.ac.jp (M. Kohno).
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Abstract
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Objectives: We aimed to determine the acute phase impact of pneumonectomy with respect to injury in the remaining lung using a murine model, and to investigate the profiles of inflammatory mediators including high mobility group box 1 protein (HMGB1) following surgery and administration of low dose intratracheal lipopolysaccharide. Methods: Mice received left pneumonectomy with intratracheal administration of either saline or lipopolysaccharide. Lung permeability index, lung wet-to-dry weight ratio, pathological findings, HMGB1 levels in bronchoalveolar lavage fluid (BALF) and plasma, and cytokine profiles in BALF were assessed 24 h after surgery. Results: Index of capillary permeability, lung water content, and neutrophil and macrophage counts in BALF were significantly increased by pneumonectomy. These parameters were highest in the mice with pneumonectomy with intratracheal administration of lipopolysaccharide. On lung pathology, neutrophil infiltration was prominent in the residual lung after pneumonectomy. HMGB1 levels were significantly higher in both BALF and plasma in the mice with pneumonectomy, and were highest in those with pneumonectomy and intratracheal administration of lipopolysaccharide. Pro-inflammatory cytokine levels including interferon- significantly increased in BALF in the mice with pneumonectomy. Conclusions: It was suggested that pneumonectomy itself may cause occult lung injury in the acute phase (24 h) of post-surgery which could be enhanced by inflammatory stimulus, such as bacterial component, leading to significant lung injury. HMGB1 might be involved in the pathogenesis of the occult lung injury.
Key Words: Pneumonectomy; Lung injury; Endotoxin; HMGB1
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1. Introduction
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Lung cancer remains the leading cause of cancer death in Japan and many other developed countries [1]. Surgical resection, with or without adjuvant chemotherapy and radiotherapy, is currently the treatment of choice for early stage non-small cell lung cancer [2]. Although major advances in thoracic surgery have led to a significant reduction in postoperative complications following lung resection, it is always important for surgeons to try to reduce perioperative mortality [1, 3].
The major cause of morbidity and mortality following lung resection is respiratory complications. Acute lung injury (ALI), which develops in approximately 5% of patients undergoing lung resection, is responsible for the vast majority of respiratory-related deaths following thoracic surgery [4]. ALI following thoracotomy and lung resection has a grave prognosis, with overall hospital mortality rates over 20%. In some series limited to pneumonectomy, the mortality rates rose as high as 100% [5, 6]. The mortality rate of ALI following lung resection is higher than the mortality rate of ALI from all causes [7].
High mobility group box 1 protein (HMGB1), originally identified as a DNA binding protein, is an abundant and highly conserved cellular protein, which stabilizes nucleosome formation and facilitates gene transcription [8, 9]. HMGB1 also has potent pro-inflammatory properties [9, 10]. Exposure of neutrophils or macrophages to HMGB1 induces nuclear translocation of NF- B and enhances production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)- and interleukin (IL)-1β, at least in part through the interaction of HMGB1 with Toll-like receptor (TLR)-2, TLR-4 and receptor for advanced glycation end products (RAGE) [11, 12]. Serum concentration of HMGB1 increased significantly 8–32 h after administration of lipopolysaccharide (LPS) or TNF- in mice [10]. Intratracheal injection of HMGB1 results in the development of acute pulmonary inflammation, and blockade of HMGB1 decreases the severity of LPS-induced ALI, implicating HMGB1 as a mediator of sepsis-associated lung injury [9, 10]. Systemic administration of recombinant HMGB1 is lethal in mice [9, 10]. HMGB1 is also an important mediator of mortality and organ system dysfunction including ALI in animal models of conditions such as bacterial peritonitis, lung transplantation, ventilator-induced lung injury and hemorrhage [13–18]. It has been suggested that HMGB1 contributes to the clinical course of ALI and postoperative complications [13, 19]. We therefore hypothesize that the postoperative HMGB1 level in plasma or organs may be useful as a parameter of surgical invasiveness and predictive of postoperative complication.
In this study, we aimed to determine the acute phase impact, meaning the impact of within 24 h, of pneumonectomy with respect to injury to the remaining lung in a murine model [20]. We administered a low dose of LPS to the residual lung as a model of ALI following lung resection. The profiles of inflammatory cytokines and HMGB1 were investigated to evaluate their roles in the pathogenesis of post-pneumonectomy lung injury.
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2. Materials and methods
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2.1. Experimental model
Specific pathogen-free inbred male C57BL/6 mice, eight-week-old and weighing 20–22 g were used. All experiments were conducted in accordance with protocols approved by the institutional review board for animal studies. Under general anesthesia, they were intubated with an 18-gauge intravenous catheter and connected to a rodent ventilator, which was adjusted to maintain normal ventilation (respiratory rate, 80 min; tidal volume, 10 ml/kg; positive end-expiratory pressure, 2 cm H2O; FiO2, 0.21). Mice were randomly assigned to one of four experimental groups. In the control group, 30 µl of saline was instilled into the lungs through the intratracheal tube. In the LPS group, 150 µg of LPS from Escherichia coli O55: B5 (Sigma, St Louis, MO) suspended in 30 µl of saline was instilled slowly into the lungs through the intratracheal tube, to create mild lung injury. In the pneumonectomy (PNX) group, 30 µl of saline was instilled into the lungs, followed by left pneumonectomy. In the LPS+PNX group, 150 µg of LPS diluted in 30 µl of saline was instilled into the lungs, followed by left pneumonectomy. The tidal volume was reduced from 10–6 ml/kg after the lung was removed. Human serum albumin (25 µg/100 µl; Buminate, Baxter Healthcare Corporation, Glendale, CA) was injected via tail vein 1 h before euthanasia to assess transvascular albumin leakage.
2.2. Parameters of lung injury
To investigate the impact of left pneumonectomy on the right lung, mice in the four groups were euthanized 24 h after surgery. The parameters to investigate lung injury were as follow: 1) lung wet-to-dry (W/D) weight ratio to estimate the severity of pulmonary edema; 2) ratio of human albumin concentrations in bronchoalveolar lavage fluid (BALF) to that in plasma (albumin B/P ratio) to assess transvascular albumin leakage (permeability index); 3) total and differential cell counts in BALF to assess inflammatory cell sequestration.
2.3. Histological examination
The degree of microscopic injury to the right lung was scored based on the following variables: hemorrhage, edema and neutrophil infiltration. The severity of injury was judged according to the following criteria: no injury=0; injury to 25% of the field=1; injury to 50% of the field=2; injury to 75% of the field=3, and diffuse injury=4 [21].
2.4. Micro-computed tomography
Lung images were obtained by a micro-computed tomography (CT) device, the LaTheta LCT-100A (ALOKA, Inc., Tokyo, Japan), to investigate the extent of lung infiltration 24 h after the intervention.
2.5. HMGB1 and cytokine measurements
ELISA was performed to detect HMGB1 levels in plasma and BALF using monoclonal antibodies to HMGB1 (Shino-Test. Co, Tokyo, Japan) [22]. To investigate cytokine profiles in BALF, we employed a Bio-Plex mouse cytokine assay (Bio-Rad Laboratories, Hercules, CA) for simultaneous quantitation of interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-, keratinocyte-derived chemokine (KC) and tumor necrosis factor (TNF)-.
2.6. Statistical analysis
Comparisons of histological scores were examined by Kruskal–Wallis non-parametric analysis of variance for factorial experiments, followed by Dunn's procedure for post-hoc multicomparison analysis. Other results were analyzed by one-way ANOVA followed by a Scheffe's post-hoc test for multiple comparisons. Data are expressed as mean±S.D. A P-value of <0.05 was considered statistically significant.
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3. Results
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3.1. Lung W/D weight ratio was increased in the groups with pneumonectomy
There was a significant difference in the mean lung W/D weight ratio between the control group and the surgical groups (3.69±0.07 vs. 4.92±0.60, P<0.001, vs. 5.23±0.25, P<0.0001), but there was no significant difference between the control group and the LPS group, between the LPS group and the PNX group, or between the PNX group and the LPS+PNX group. There was, however, a significant difference between the LPS group and the LPS+PNX group (4.26±0.41 vs. 5.23±0.25, P<0.005) (Fig. 1a).
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Fig. 1. (a) Lung wet-to-dry (W/D) weight ratio. (b) Permeability index: Ratio of albumin concentration in bronchoalveolar lavage fluid to that in plasma (albumin B/P ratio). There were significant differences in the lung W/D ratio and permeability index between the control group and the two groups with pneumonectomy. Values are means±S.D.; n=6. *P<0.05. Scheffe's post-hoc test.
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3.2. Permeability index increased after pneumonectomy, and increased even more after pneumonectomy plus LPS administration
Although there was no significant difference in the permeability index between the control group and the LPS group (0.0034±0.0006 vs. 0.0060±0.0013, P=0.64), there was a significant difference in the permeability index between the control group and the PNX group (0.0034±0.0006 vs. 0.0105±0.0051, P<0.05) and between the control group and the LPS+PNX group (0.0034±0.0006 vs. 0.0127±0.0034, P<0.01). There was also a significant increase in the permeability index in the LPS+PNX group compared with the LPS group (0.0060±0.0013 vs. 0.0127±0.0034, P<0.05) (Fig. 1b).
3.3. Different cell accumulations in the pneumonectomy groups
The total cell counts in BALF increased significantly in all three experimental groups compared to the control group. The cell patterns differed between the groups. In the LPS group, only neutrophils were increased significantly. In the PNX group, neutrophils, lymphocytes and macrophages were all increased significantly (Fig. 2).
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Fig. 2. Cell counts in bronchoalveolar lavage fluid. Neutrophils, lymphocytes and macrophages were all increased significantly in the PNX group compared with the control group. In the LPS group, only neutrophils increased significantly, compared with the control group. Values are means±S.D.; n=6. *P<0.05. Scheffe's post-hoc test.
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3.4. Lung histology: significant neutrophil infiltrations
Pneumonectomy alone induced significant neutrophil infiltration, although there was no significant difference in scores for hemorrhage and edema between the control and PNX groups. Instillation of LPS induced significant neutrophil infiltration with hemorrhage and edema of the lung. The severity of damage was significantly greater following pneumonectomy plus instillation of LPS than the other groups (Figs. 3 and 4).
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Fig. 3. The degree of microscopic injury was scored based on the following variables: hemorrhage (a), edema (b) and neutrophil infiltration (c). The severity of injury was judged according to the following criteria: no injury=0; injury to 25% of the field=1; injury to 50% of the field=2; injury to 75% of the field=3 and diffuse injury=4. Values are means±S.D.; n=6. *P<0.05. Dunn's multiple post-hoc test.
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Fig. 4. Histopathological findings in the right lung of mice from the control group (a), the LPS group (b), the PNX group (c), and the LPS+PNX group (d). Remarkable cell infiltration is visible in the LPS group (b), and a similar but milder change is observed in the PNX group (c). The most severe damage is seen in the LPS+PNX group (d). Bars=100 µm.
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3.5. Micro-computed tomography: severe damage to the lungs of the LPS+PNX group
CT for small animals following left pneumonectomy showed extensive inflation of the right lung, protrusion of the diaphragmatic lobe into the left pleural cavity, and left-shifted mediastinum. Infiltration was observed in the right lungs of the groups with LPS instillation. The infiltration area was more extensive in the LPS+PNX group than in the LPS group (Fig. 5).
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Fig. 5. Representative findings of the micro-computed tomography to evaluate the extent of lung infiltration from the control group (a), the LPS group (b), the PNX group (c), and the LPS+PNX group (d). Arrows indicate area of inflammatory infiltration in the lung. Computed tomography for small animals showed extensive inflation of the remaining right lungs, diaphragmatic lobe protrusion into the left pleural cavity, and left-shifted mediastinum in the groups with pneumonectomy (c and d). The area of lung infiltration was more extensive in the LPS+PNX group (d) than in the LPS group (b).
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3.6. HMGB1 increased in both BALF and plasma of the pneumonectomy group
HMGB1 increased significantly in both BALF and plasma of the PNX group (55.11±15.43 and 4.91±0.82 ng/ml, respectively) and of the LPS+PNX group (79.10±18.43 and 6.57±2.40 ng/ml, respectively), but not of the LPS group (44.42±5.94 and 2.43±2.09 ng/ml, respectively), compared to the control group (32.23±12.5 and 0.79±0.77 ng/ml, respectively). There was also a significant difference in HMGB1 in both BALF and plasma between the LPS and the LPS+PNX groups. In the LPS+PNX group, a significant increase in HMGB1 was observed in BALF, not in plasma, compared with the PNX group (P<0.05) (Fig. 6).
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Fig. 6. (a) High mobility group box 1 protein (HMGB1) concentration in bronchoalveolar lavage fluid (BALF). (b) HMGB1 concentration in plasma. HMGB1 increased significantly in both BALF and plasma of the PNX group compared to the control group. Values are means±S.D.; n=6. *P<0.05. Scheffe's post-hoc test.
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3.7. Increased cytokine levels in BALF after pneumonectomy and/or LPS instillation
Pneumonectomy and/or intratracheal LPS instillation induced significant increases in the levels of six cytokines examined in BALF at 24 h after the insults. Although the BALF level of IFN- was increased after pneumonectomy alone compared to the control group (0.47±0.32 vs. 1.24±0.24 pg/ml, P<0.05), there was no significant difference in the level of other five cytokines between the control and the PNX group. LPS instillation alone significantly increased BALF levels of IL-1β, IFN- and TNF- compared to the control group, but the increase in IL-6, IL-10 and KC levels were not significant. There were significant increases in the levels of IL-1β, IL-6, IL-10, IFN-, KC and TNF- in the LPS+PNX group compared to the LPS group and to the control group (Fig. 7).
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4. Discussion
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Although it is of great interest to a thoracic surgeon what is happening in the residual lung after pulmonary resection, little is known about this information. In the present study, pneumonectomy caused neutrophil and macrophage infiltration, capillary hyperpermeability and edematous changes in the residual lung, which was associated with a significant increase in the plasma and BALF levels of HMGB1, indicating occult injury to the residual lung. Pretreatment with a low dose of LPS induces a greater increase in HMGB1 in the BALF collected from the residual lung, resulting in more severe lung injury. BALF levels of pro-inflammatory cytokines were also increased significantly in a complex response to the combined insult of pneumonectomy and LPS administration. Although our model does not closely approximate the clinical situation, similar mechanisms may underlie ALI/ARDS after lung resection in patients complicated by bacterial infection.
Since, in preliminary experiment, mice recovered quickly after pneumonectomy, and survived long-term (data not shown), we hypothesized that the occult lung injury in the residual lung after pneumonectomy does not affect the outcome unless other factors such as infection take place. To test this hypothesis, we evaluated lung injury after pneumonectomy, with or without low dose LPS administration.
In our experiment, the amount of LPS administered into the lung was half the amount which has been described in previous reports of LPS-induced acute lung injury [13]. This was because, in our preliminary experiments, none of the mice in the LPS+PNX group survived for 24 h when using the same amount of LPS as in the previous reports. We therefore reduced the amount of LPS so that all the mice could survive for longer than 24 h after pneumonectomy and LPS instillation. This may be why in the LPS group neither the permeability index nor the W/D weight ratio increased significantly compared with the control group. However, this low dose of LPS caused a significant increase in both the permeability index and the W/D weight ratio when combined with pneumonectomy. The numbers of neutrophils, macrophages and total cells also increased significantly in the LPS+PNX group compared to the LPS group. Histologically, the most severe lung injury was observed in the LPS+PNX group.
HMGB1 has been shown to play an important role in hemorrhagic shock and ventilator induced lung injury (VILI) [16, 18]. In the present study, the level of HMGB1 increased 1.5-fold in the lung and 5-fold in the plasma at 24 h after pneumonectomy. HMGB1 can be passively released by necrotic or damaged cells when the integrity of cytoplasmic membranes is lost [10]. Although it remains unclear whether mechanical stress induces the release of HMGB1, overinflation might be a stimulus to release HMGB1 in VILI and pneumonectomy models [16]. Overinflation may cause lung tissue damage with HMGB1 release into the bloodstream. HMGB1 in the lung may be released not only from the damaged cells but also from the increased numbers of activated neutrophils and macrophages [10]. Overinflation of the lung causes enlarged intercellular gaps between endothelial and/or epithelial cells, and neutrophils and macrophages may transmigrate into the alveolar space through the enlarged gaps. Otherwise, because pulmonary resection causes tissue damage at the hilar region and the chest wall, HMGB1 may be released into the bloodstream from the damaged cells, which may cause a catabolic state and a systemic inflammatory response in the mice [23, 24].
Although there was no significant difference in HMGB1 levels in BALF and plasma between the control and the LPS groups, HMGB1 levels increased significantly after the combined insults of LPS and pneumonectomy. Since both pneumonectomy and LPS instillation could be a stimulus that induces the release of HMGB1, they could cooperatively have a prominent role [10, 13].
Endotoxemia and severe hemorrhage are not routinely observed following surgical procedures such as pneumonectomy, indicating that other mediators may also contribute to the inflammatory response that may lead to ALI or multiple organ dysfunctions. HMGB1 has been demonstrated to be an important mediator of mortality and organ system dysfunction, including ALI [10, 13–17]. Suda et al. reported that, in a clinical setting of thoracic esophagotomy, postoperative serum HMGB1 level was higher in patients who developed complications than in those who did not [19]. They concluded that an elevated serum HMGB1 level may contribute to the development of postoperative organ system dysfunction. They also indicated that serum HMGB1 level before the operation may predict the postoperative clinical course. In our experiment, the increased HMGB1 could be one of the mediators which enhance the inflammatory response after pneumonectomy.
Pulmonary hyperpermeability was seen in the remaining lung after pneumonectomy, and the lung W/D weight ratio increased significantly. It has been reported that HMGB1 directly increases the permeability of enterocyte monolayers, and impairs intestinal barrier function through a mechanism that depends on the formation of nitric oxide and peroxynitrite [25]. Similar effects of HMGB1 on pulmonary epithelial tight junctions might develop interstitial pulmonary edema, besides the pro-inflammatory actions of HMGB1.
Our results showed increasing cytokine levels in the residual lungs 24 h after pneumonectomy. Comparison between the control group and the PNX group indicates a trend of increasing levels of six cytokines, suggesting that pro-inflammatory cytokines including TNF-, IL-1β, IL-6, IFN-, KC in BALF, might be involved in post-pneumonectomy occult lung injury. Moreover, comparisons between the four groups detected significant increases in the level of IFN- between the PNX group and the control group. Because IFN- is reported to stimulate macrophages in the presence of TNF- and IL-1β, to actively secrete HMGB1 [10], IFN- in particular may contribute to the complex response in the residual lung following the combined insults of LPS and pneumonectomy.
In conclusion, HMGB1, together with pro-inflammatory cytokines may play a prominent role in the establishment of occult lung injury after pneumonectomy, which has a potential to progress to ALI when an additional stimulus such as infection exists. This response of HMGB1 may not be unique to pneumonectomy. Other surgical procedures may also induce an increase in HMGB1 levels in the lungs as well as in other organs.
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Acknowledgements
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We wish to thank Dr Hiromi Sakai (Faculty of Science and Engineering, Waseda University) for his contribution to the statistical analyses and Dr Tokuhiro Kimura (Department of Pathology, Keio University School of Medicine) for his contribution to the pathological scoring.
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Abstract
1. Introduction
