Case Report
Rat Cardiopulmonary Bypass Models to Investigate Multi- Organ Injury
Shingo Hirao, Hidetoshi Masumoto* and Kenji Minatoya
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
*Corresponding author: Hidetoshi Masumoto, Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University 54 Kawahara-cho, Shougoin, Sakyo-ku, Kyoto 606-8507, Japan
Published: 12 Jun, 2017
Cite this article as: Hirao S, Masumoto H, Minatoya K.
Rat Cardiopulmonary Bypass Models
to Investigate Multi-Organ Injury. Clin
Surg. 2017; 2: 1509
Abstract
Cardiopulmonary bypass (CPB) has been an essential modality in cardiovascular surgery. Although
the technique has since undergone dramatic refinement, prolonged CPB-related multi-organ
complications due to contact activation, ischemia–reperfusion injury, coagulation, endotoxemia
and/or production of oxygen free radicals still compromise the outcome of cardiovascular surgeries.
Animal models recapitulating the clinical usage of CPB help elucidate the pathophysiological
processes following CPB, and aid in the development of strategies aimed at preventing these
complications. Rat CPB models mimicking clinical situations in cardiovascular surgery have
been refined and have gradually taken the place of large-animal models because of greater costeffectiveness,
convenient experimental processes, abundant testing methods at the genetic or
protein levels, and genetic consistency. In the present review, we discuss various beneficial aspects
of rat CPB models for investigating CPB-related multi-organ injury and for mitigating the severity
of complications in an organ-specific manner (lung/kidney/brain/liver/myocardium/intestine). The
interventions established through basic research using rat CPB models may further improve the
safety of cardiovascular surgery in the future.
Keywords: Rat cardiopulmonary bypass; Multi-organ injury; Kidney
Introduction
In 1953, Gibbon successfully performed the first cardiac surgery in the world using
cardiopulmonary bypass (CPB) [1]. CPB subsequently became an essential modality in cardiovascular
surgery, and the technique has since undergone dramatic refinement. However, multi-organ
complications related to prolonged CPB still compromise the outcome of cardiovascular surgeries,
and may deteriorate postoperative morbidity and mortality [2]. CPB-related organ damage is caused
by contact activation, ischemia–reperfusion injury, coagulation, and endotoxemia during CPB,
leading to immune system activation and synthesis of proinflammatory cytokines, compliment
activation, and production of oxygen free radicals [2].
Animal models recapitulating the clinical usage of CPB enable us to clarify the pathophysiological
processes that occur after CPB, and facilitate pre-clinical studies to develop strategies protecting
against these complications. Because of similarities to humans in terms of body size and anatomy,
large animals were initially used in CPB models [3]. Since Popovic et al. first reported using a rat
CPB model in 1967 [4], rat CPB models have been refined, and have gradually taken the place of
large-animal models due to, among other reasons, greater cost-effectiveness, including the cost of
the animals and experimental devices, convenient experimental processes, and abundant testing
methods at the genetic or protein levels. Furthermore, inbred rats can be genetically identical,
reducing possible biological biases.
Various methods for simulating the clinical situations of CPB-related multi-organ injury have
been reported. Fabre et al. [5] first established a recovery model that allowed the study of the longterm
multiple organ sequelae of CPB. A cardiac arrest model, developed by de Lange et al. [6],
can be used to characterize the enzymatic, genetic, and histologic responses to myocardial injury,
and aid in forming protective strategies. Moreover, a deep hypothermic circulatory arrest model,
established by Jungwirth et al. [7], is suitable to further elucidate the mechanisms associated with
adverse cerebral outcome after cardiac surgery and deep hypothermic circulatory arrest (DHCA),
and allows us to investigate potential neuro protective strategies. These models are advantageous
for evaluating the various effects of CPB, closely mimicking clinical situations in cardiovascular
surgery.
In this review, we discuss recent basic research using rat models
to investigate therapeutic strategies aimed at preventing multi-organ
injury during CPB. An overview of the studies discussed in this
review is shown in Table 1.
Table 1
Lung Injury
Acute lung injury (ALI) induced by CPB, a common and
serious complication, is an important factor influencing morbidity
and mortality after cardiac surgery. It is caused by the activation of
several cellular immune responses resulting from contact activation
and ischemia–reperfusion injury [2]. Acute respiratory distress
syndrome (ARDS) is a rare but serious complication associated
with significant mortality. The incidence and mortality of ARDS in
patients undergoing CPB were reported to be 0.4%–0.6% and 15%–
41.5%, respectively [8,9].
Inflammation
Numerous studies on CPB-related lung injury have been
conducted in rat models because of the usefulness of these models
for investigating protective strategies in the context of systemic
inflammatory responses.
The proinflammatory cytokines tumor necrosis factor-α (TNF-α),
interleukin-6 (IL-6), and IL-8play a pivotal role in the pathogenesis
of CPB-induced lung injury, and nuclear factorkappa B (NF-κB),a
major regulator of proinflammatory cytokine induction, has been
recognized as a key factor in the inflammatory reaction after CPB
[10]. Shao et al. [11] reported that pretreatment with simvastatin,
a statin, attenuated inflammatory cell infiltration in the lungs, and
reduced proinflammatory cytokine expression in serum, lung tissues,
and bronchoalveolar lavage fluid. They additionally showed effects on
down regulation of toll-like receptor 4 (TLR4) and NF-κB expression,
indicating potential protective mechanisms of simvastatin. Liu et
al. [12] also reported that a polyphenol, curcumin, attenuated CPBrelated
lung injury by suppressing NF-κB activation via inhibition of
the TLR4-mediated MyD88-dependent signaling pathway.
Wang et al. focused on matrix metalloproteinase-9 (MMP-9), a
subgroup of zinc endopeptidases, which has been found to degrade
basement membrane components[13]. MMP-9 is therefore thought
to be essential for polymorphonuclear neutrophil granulocyte
migration and alveolar capillary leakage activity in CPB-related lung
injury[14]. Wang et al. [15] also showed increased MMP-9 activity
and gene expression in CPB-related lung injury. In addition, the
authors showed that doxycycline, a tetracycline derivative, might
have a therapeutic effect on the lung injury process by suppressing
MMP-9 during CPB.
Lisle et al. [16] focused on the adenosine A2Areceptor (AA2AR),
which increases intracellular cyclic adenosine monophosphate
(cAMP). They reported that ATL313, an agonist of AA2AR, attenuated
inflammatory lung injury through inactivation of inflammatory cells,
decreased proinflammatory cytokine production, and suppressed
neutrophil recruitment and activation.
In addition to strategies involving bioactive chemical components
or molecules, approaches using stem cells are emerging. We
previously reported that intravenous administration of allogeneic
mesenchymal stem cells from fetal membrane (FM-MSCs)
attenuated systemic inflammation and lung injury after CPB in a rat
model [17]. Administration of FM-MSCs suppressed the production
of proinflammatory cytokines, alleviated ALI, inhibited neutrophil
infiltration to interstitial spaces of the lung, and protected alveolar
structure by stimulating secretion of organ-protective humoral factors.
Neutrophil activation
CPB-induced ALI is also thought to be associated with neutrophil
activation [2]. To evaluate neutrophil excitation, two signal intensity
of adhesion molecules, CD11b and CD62L, expressed on the cell
surface, have been reported to be crucial. CD11b contributes to the
tight adherence between neutrophils and endothelial cells, and this
binding plays an important role in the further activation of neutrophils
[18]. CD62L is highly expressed on inactivated neutrophils and
participates in the initial weak adherence between neutrophils and
endothelial cells, while activated neutrophils promote rapid shedding
of CD62L along with the progression of inflammatory responses [19].
Yamazaki et al. reported that administration of activated protein
C inhibits neutrophil activation and attenuates proinflammatory
cytokine production through increased CD11b and decreased CD62L
expression in the lungs. They also showed increased lung content
of macrophage inflammatory protein-2 [20]. Hamamoto et al. [21]
reported that rolipram, a selective phosphodiesterase type 4 inhibitor,
attenuates the intracellular stimulatory signaling of neutrophils
after CPB by blocking the decrease in levels of cAMP associated
with neutrophil activation. Furthermore, Xing et al. [22] suggested
that new therapeutic approaches based on manipulating immature
CD14lowCD16- monocytes, which contribute to blood-circuit contactinduced
ALI by generating TNF-α-producing, mature monocytes,
might help minimize CPB-related lung injury.
Oxidative stress
During CPB, a large number of oxygen free radicals are generated,
exceeding the oxidant scavenging capacity of the endogenous
antioxidant enzymes and thus causing cellular injury [2]. Several stress
proteins and antioxidant enzymes are activated to limit the damage
at the cellular level. Heme oxygenase1 (HO-1) plays an important
role in removing harmful free radicals [23]. Liu et al. [24] examined
the potential effects of curcumin on the expression of oxidative stress
markers like malondialdehyde (MDA) and myeloperoxidase (MPO),
and its impact on the activation of the HO-1 protein. Wang et al. [25]
reported that an antioxidant, pyrrolidine dithiocarbamate, improves
pulmonary function after CPB.
Kidney Injury
Although considerable progress has been made in surgical
techniques and perioperative intensive care, kidney injury remains a
serious complication of cardiac surgery. Kidney injuries are reported
to affect approximately 5%–31% of patients undergoing cardiac
surgery with CPB. Acute kidney injury (AKI) requiring hemodialysis
occurs in approximately 1% of cases, with a mortality rate as high as
64% [26].
Wang et al. reported that erythropoietin (EPO) protected against
CPB-induced renal injury and exerted anti-inflammatory effects on
rat renal tissues. They showed that EPO lessened renal histological
injury, and decreased levels of inflammatory markers like TNF-α, IL-
1β, and IL-6 in renal tissues. Furthermore, they found a potent downregulation
of NF-κB p65, ICAM-1 protein, and mRNA in EPOtreated
rat kidneys. The authors concluded that EPO may act as an
anti-inflammatory factor via suppression of NF-κB p65 expression,
leading to attenuation of CPB-induced kidney injury [27]. In another
report using EPO, Liu et al. [28] showed that recombinant human
EPO suppressed the canonical transient receptor potential channel
6, which plays crucial roles in hereditary glomerular dysfunction, by
down regulating nuclear factor of activated T-cells pathways induced
by CPB.
Wang et al. reported that melatonin (N-acetyl
5-methoxytryptamine), a powerful antioxidant, exerted a
renoprotective effect evidenced by biochemical and histopathologic
results through antioxidant functions. Melatonin reduced MPO and
MDA, while antioxidant enzymes such as catalase and superoxide
dismutase were significantly increased. In addition, HO-1 transcript
and protein levels in the kidneys were dramatically increased in
melatonin-treated rats during CPB [29].
We previously reported on the renoprotective effect observed
with preoperative oral administration of epigallocatechin-3-gallate
(EGCG), a major component of the polyphenolic fraction of green tea
[30]. We used a specific animal model consisting of multigenetic rats
with type 2 diabetes mellitus, which would be at increased risk for AKI
after CPB [31]. In our study, EGCG attenuated tubular injury, reduced
serum creatinine and neutrophil gelatinase-associated lipocalin
levels, and decreased mRNA expression of kidney injury molecule-1
and 8-hydroxy-20-deoxyguanosine, indicating attenuated oxidant
stress. This simple method could be applied in a clinical setting as
prophylactic renal protection against AKI after CPB, especially in
high-risk patients with diabetes mellitus [30].
Brain Damage
Cardiac surgery involving CPB has been associated with a
frequent incidence of postoperative cognitive dysfunction [32]. The
etiology of cognitive impairment after cardiac surgery may include
cerebral microembolization, increased cerebral perfusion, systemic
and cerebral inflammation, cerebral temperature perturbations,
cerebral edema, and possible blood–brain barrier (BBB) dysfunction,
all of which may be superimposed on genetic influences that may alter
susceptibility to injury or repair from injury once it has occurred [33].
Recently, some neuroprotective strategies have been investigated
in rat CPB models. De Lange et al. reported that the combination of
hypothermic CPB coupled with limited rewarming and prolonged
postoperative hypothermia decreased postoperative cognitive
dysfunction after CPB. Rats were assessed by cognitive testing in
the Morris water maze 7 days after CPB [33]. Cao et al. reported the
effect of penehyclidine hydrochloride, an anti-cholinergic drug, on
regulatory mediators during the neuroinflammatory response and
cerebral cell apoptosis following CPB. They examined plasma levels
of neuron specific enolase and S-100B, a type of neuropeptide that
is highly expressed in blood serum in severe cerebral injury, and
evaluated mRNA expression levels of MMP-9, IL-10, caspase-3,
Bcl-2, and p38 in brain tissue. Additionally, the ultrastructure of
hippocampus tissue was examined under an electron microscope.
The authors found ultrastructural disorders of neuronal cells in the
vehicle group, with a nearly round nucleus, aggregated and edged
nuclear heterochromatin, a fuzzy nuclear membrane, and the
occurrence of endocytic vacuoles within swollen mitochondria [34].
Zhang et al. [35] showed that sufentanil pretreatment had
protective effects on cerebral injury during CPB by reducing water
content and total calcium of the brain tissue, and expression of
S-100B in serum. Ouk et al. performed assessments of spatial and
learning memory using a Y maze cognition experiment. To evaluate
short-term memory, they used the passive avoidance test and a test
based on fear memory consolidation. The authors demonstrated
that reduction of CPB-induced inflammation and endothelial
dysfunction by lipid-lowering drugs prevented cognitive impairment
and preserved neuronal integrity in hippocampal regions [36].
Bartels et al. presented results from a pilot study using magnetic
resonance imaging (MRI) and molecular analysis to assess BBB
characteristics in a rat CPB/DHCA model. The results indicated that
MRI successfully detected increased brain capillary permeability
to a commercially available low-molecular-weight contrast agent,
while no significant quantitative changes in select proteins relevant
for BBB structure were observed [37]. Wang et al. [38] showed that
inhibition of microR-29c attenuates neurologic injuries induced
by prolonged DHCA through a peroxisome proliferator-activated
receptor gamma co-activator 1-alpha pathway. Moreover, rat cardiac
arrest models are useful for studies in emergency preservation and
resuscitation [39,40]. These models serve as a valuable platform to
link basic biochemical disorders and organ dysfunction in an effort
to design better therapeutic applications for the treatment of cardiac
arrest [40].
An experimental model of stroke induced by middle cerebral
artery occlusion during CPB was established by Homi et al. [41].
The authors reported that a protinin, a nonspecific serine protease
inhibitor, decreased the systemic inflammatory response to CPB and
reduced functional neurologic injury in the short-term, but did not
reduce cerebral infarct size [42].
Hepatic Injury
In clinical settings of cardiac surgery, approximately 10% of
patients receiving CPB experience hepatic injury, which directly
influences their mortality. Shen et al. reported that CPB may induce
and aggravate hepatic injury by facilitating oxidative stress and the
systemic inflammatory response, based on a rat CPB model, and
with samples collected over a 24-hr period. In the CPB group, serum
liver transaminases and TNF-α, activity of inducible nitric oxide
synthase, MDA, and MPO in liver tissue were significantly increased.
In addition, swollen hepatocytes, vacuolization, and congestion
in sinusoids were observed. By contrast, the activities of liver
antioxidative enzymes and the concentration of glutathione (GSH)
remarkably decreased[43].
An et al. reported that recombinant human growth hormone
(rhGH) may prevent acute liver injury associated with CPB by
decreasing acute-phase reaction proteins, TNF-α and IL-1β,
and hepatocyte apoptosis, which is associated with increases in
constitutive hepatic proteins, total liver protein content, and
hepatocyte proliferation [44,45].
Huang et al. suggested that N-acetylcysteine (NAC) and exogenous
melatonin had protective effects on CPB-induced liver injury by
reducing oxidative stress and the systemic inflammatory response.
The Ca2+-ATPase activity of liver tissues was also determined. NAC
and melatonin reduced liver transaminases, TNF-α, liver inducible
nitric oxide synthase, MDA, and MPO, while the activity of liver
antioxidative enzymes and the concentration of GSH remarkably
decreased[46,47].
Myocardial Injury
Previous research focusing on cardio-protective strategies during
cardiac surgery has been performed in isolated heart models [48,49].
However, these models are not suitable to investigating the long-term
effects of therapeutic interventions on myocardial reperfusion injury
and systemic inflammation.
Günzinger et al. developed a cardioplegic arrest model with
the use of cold crystalloid cardioplegia after aortic cross clamping
through thoracotomy. The authors assessed left ventricular (LV)
function parameters by intraventricular conductance catheter.
Results indicated impaired LV function after cardiac arrest, and
increased myocardial TNF-α and IL-6 mRNA [50]. In another study,
the authors investigated MMP and TIMP expression with crystalloid
cardioplegia or blood cardioplegia [51]. They showed impaired LV
function and increased MMP-2/TIMP-4 ratio on the mRNA and
protein level in the crystalloid cardioplegia group. De Lange et al.
developed another method to administrate ante grade cardioplegia
with endoaortic cross-clamping, without thoracotomy, using a
balloon catheter via the carotid artery in a rat CPB model[6]. These
cardioplegic arrest models allow us to characterize myocardial injury
and investigate new cardio-protective strategies.
By contrast, Cao et al. [52] reported on the cardio-protective effect
of ghrelin in a rat CPB model without cardiac arrest. In this study,
ghrelin reduced inflammatory responses through the Akt-activated
pathway. Pulido et al. [53] demonstrated myocardial-protective
effects using pretreatment with inhaled carbon monoxide (CO).The
authors suggested that pretreatment with CO may have a modulatory
effect on the inflammatory response to CPB without compromising
hemodynamics or oxygen delivery.
Intestinal Injury
Mesenteric ischemia develops in 5%–27% of patients who
experience abdominal complications after CPB, with a mortality of
30%–93% [54]. In rat models, CPB was shown to induce mesenteric
endothelial dysfunction and cause a direct increase in the contractile
response to α1-adrenergic agonist. In addition, CPB was associated
with microcirculatory injury, decreased tight junction protein
expression of intestinal mucosa, and generalized inflammatory
responses [55-57].
Sun et al. demonstrated that penehyclidine hydrochloride, a
newly developed anticholinergic drug, exerts protective effects by
attenuating biochemical and histopathological changes in a dosedependent
manner, and by decreasing intestinal permeability
and bacterial translocation[58]. In another study, the authors
investigated the effects of pretreatment with probiotic preparations.
Pre-administration of probiotics effectively reduced intestinal
permeability and the bacterial translocation rate due to improvement
of local intestinal immune function, and increased expression of
intestinal epithelial tight junction proteins[59].
Conclusion
In the present review, we discussed various beneficial aspects of using rat CPB models to investigate CPB-related multi-organ injury and to mitigate the severity of the complications, which may contribute to improved surgical outcome. The interventions found through basic research using rat CPB models may increase the safety of cardiovascular surgery in the future.
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