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Annals of Clinical & Laboratory Science 38:221-227 (2008)
© 2008 Association of Clinical Scientists

Influence of Nrf2 Genotype on Pulmonary NF-{kappa}B Activity and Inflammatory Response after Traumatic Brain Injury

Wei Jin1, Lin Zhu1, Qun Guan2, Gang Chen1, Qing Feng Wang1, Hong Xia Yin1, Chun Hua Hang1, Ji Xin Shi1 and Han Dong Wang1
1 Departments of Neurosurgery and 2 Obstetrics & Gynecology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China

Address correspondence to Dr. Han Dong Wang, Department of Neurosurgery, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, P. R. China; tel 86 25 8481 7581; fax 86 25 8481 7581; e-mail hdwang_nj{at}yahoo.com.cn.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Inflammatory response plays an important role in the pathogenesis of acute lung injury (ALI) after traumatic brain injury (TBI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that plays a crucial role in cytoprotection against inflammation. The present study explored the influence of Nrf2 genotype on the production of cytokines and on activation of transcription factors in a murine TBI model. Wild-type Nrf2 (+/+) and Nrf2 (–/–) deficient mice were subjected to a moderately severe weight-drop impact-acceleration head injury. Lung wet/dry weight ratio, tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-1β (IL-1β), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and nuclear factor kapp–aB (NF-{kappa}B) were investigated at 24 hr after TBI. Nrf2 (–/–) mice were shown to have a greater increase in the lung wet/dry weight ratio compared to their wild-type Nrf2 (+/+) counterparts after TBI. This exacerbation of lung injury in Nrf2 (–/–) mice was associated with increased levels of TNF-{alpha}, IL-1β, IL-6, ICAM-1, and their mediator, NF-{kappa}B. The results suggest that Nrf2 plays an important protective role in attenuating the pulmonary inflammatory response and NF-{kappa}B activation after TBI.

Keywords: traumatic brain injury, lung, Nrf2, NF-{kappa}B, cytokines, pulmonary inflammatory response


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The association between traumatic brain injury (TBI) and subsequent pulmonary dysfunction has been increasingly recognized [1,2]. Development of acute lung injury (ALI) may not only influence the lung epithelium itself, but also impair brain oxygenation and enhance the neurogenic injury. Previous studies have demonstrated enhanced pulmonary inflammation after brain trauma [3,4]. This neurogenic pulmonary inflammatory response is associated with increased concentrations of inflammatory cytokines such as TNF-{alpha}, IL-1β, and IL-6, and upregulation of intercellular adhesion molecule-1 (ICAM-1) [5].

Nuclear factor erythroid 2-related factor 2 (Nrf2), a leucine zipper redox-sensitive transcription factor, is a pleiotropic regulator of cell survival mechanisms [6]. Under basal conditions, Nrf2 is sequestered in the cytoplasm by a cytosolic regulatory protein, Keap1. Under conditions of oxidative or xenobiotic stress, Nrf2 translocates from the cytoplasm to the nucleus, and sequentially binds to a promoter sequence called the antioxidant response element (ARE), resulting in the expression and upregulation of antioxidant and cytoprotective genes that attenuate tissue injury [7–10].

There is growing evidence for a protective role of Nrf2 in pulmonary diseases. Nrf2 protects lung from butylated hydroxytoluene-induced acute respiratory distress syndrome [11], hyperoxic injury [12], and bleomycin-mediated pulmonary fibrosis [13]. Furthermore, Nrf2 helps to counteract inflammation in various experimental models, including protection against allergen-mediated airway inflammation [14], cigarette smoke-induced emphysema [15], dextran sulfate sodium (DSS)-mediated colitis [16], inflammation-mediated colonic tumorigenesis [17], and inflammatory responses during skin wound healing [18]. Therefore, it is reasonable to postulate that Nrf2 might play an important role in limiting pulmonary inflammation secondary to TBI.

As induction of certain inflammatory genes (eg, TNF-{alpha}, IL-1β, IL-6, and ICAM-1) is directly regulated by NF-{kappa}B [19], we undertook in this study to assess the pulmonary upregulation of inflammatory cytokines TNF-{alpha}, IL-1β, IL-6, and ICAM-1, and to evaluate the role that NF-{kappa}B plays in pulmonary inflammation secondary to TBI in the presence or absence of Nrf2 in mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals.  All procedures in animals conformed to the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health (USA) and were approved by the Animal Care and Use Committee of Nanjing University. Breeding pairs of Nrf2-deficient ICR mice were kindly provided by Dr. Thomas W. Kensler (Johns Hopkins University, Baltimore, MD, USA). Homozygous wild-type Nrf2 (+/+) mice and Nrf2 (–/–) deficient mice were generated from inbred heterozygous Nrf2 (+/–) mice [8]. Genotypes of Nrf2 (–/–) and Nrf2 (+/+) mice were confirmed by polymerase chain reaction (PCR) amplification of genomic DNA isolated from the blood. PCR amplification was carried out by using three different primers, 5'-TGGACGGGACTATTGAAGGCTG-3' (sense for both genotypes), 5'-CGCCTTTTCAGTAGATGGAGG-3' (antisense for wild type), and 5'-GCGGATTGACCGTAATGGGATAGG-3' (antisense for LacZ). Mice were housed at 23±1°C in humidity-controlled animal quarters with 12-hr light/dark cycle. The mice were allowed water and food ad libitum throughout the study.

Experiment protocol.  The Nrf2 (+/+) and Nrf2 (–/–) mice were separated into 4 groups: (a) sham wild-type (Nrf2 +/+); (b) injured wild-type (Nrf2 +/+); (c) sham deficient (Nrf2 –/–); and (d) injured deficient (Nrf2–/–). The mice of the sham and injured groups were subjected to anesthetia alone or to experimental TBI, respectively (n = 10 mice/group).

The mouse model of TBI was employed as described [20] with minor modifications [21]. Mice were anesthetized with sodium pentobarbital (50 mg/kg, ip). A Teflon impounder (round, flat, 6 mm diameter) was centered between the ears and eyes. TBI was induced by a 100 g weight dropped from a 12 cm height along a stainless steel wire; the force was equal to 1200 g/cm. Brain injury-induced apnea was then treated for 3 min with 100% oxygen administration and chest compression to stimulate respiration. This model is generally associated with 20% mortality within the first 5 min post-injury and with no delayed mortality thereafter. After the operation, the mouse was returned to its cage. Heart rate, arterial blood pressure, and rectal temperature were monitored, and the rectal temperature was kept at 37±0.5°C (with physical cooling if required) throughout the experiment.

At 24 hr following sham operation or TBI, the mice were sacrificed for sample collection. Five mice in each group were exsanguinated by cardiac puncture and their lungs were harvested for assays of wet/dry weight ratio, cytokines TNF-{alpha}, IL-1β, and IL-6 production and NF-{kappa}B activation. The other mice were perfused via left ventricular puncture with cold saline (4°C) followed by 4% neutral-buffered formalin. The lungs were excised, stored overnight in 4% neutral-buffered formalin, and then embedded in paraffin for assay of ICAM-1 expression.

Lung wet/dry weight ratio.  The lung wet/dry weight ratio was measured as previously described [22]. The lung tissue samples were weighed before and after drying in a desiccated oven for 72 hr at 80°C.

Enzyme-linked immunosorbent assay (ELISA).  Pulmonary levels of inflammatory cytokines were quantified using ELISA kits specific for mouse according to the manufacturers’ instructions (TNF-{alpha} from Diaclone Research, France; IL-1β,and IL-6 from Biosource Europe SA, Belgium) and a previous study of our laboratory [23]. The cytokine contents in the lung tissue were expressed as pg/mg protein.

Immunohistochemical staining.  The lung tissue sections (4 µm) were used for immunohistochemical staining, which was performed with goat anti-mouse ICAM-1(CD54) antibody (diluted 1:200, R&D Systems, Inc., Minnesota, USA), according to a previous study of our laboratory [24]. Immunoreactivity for ICAM-1 in each section was determined using light microscopy by an experienced pathologist blinded to the experimental groups. Evaluation of sections was undertaken by classifying the intensity of staining in 5 grades: "0" = no detectable positive cell; "1" = very low density of positive cells; "2" = moderate density of positive cells; "3" = higher, but submaximal, density of positive cells; and "4" = the highest density of positive cells.

Nuclear protein extraction and electrophoretic mobility shift assay (EMSA).  Nuclear protein of lung tissue was extracted and quantified as previously described [25]. EMSA was performed using a kit (Gel Shift Assay System; Promega, Madison, WI) as previously described [24]. A consensus oligonucleotide probe (5'-AGT TGA GGG GAC TTT CCC AGG C-3') was end-labeled with [{gamma}-32P]-ATP (Free Biotech, Beijing, China) with T4-polynucleotide kinase and NF-{kappa}B activity was measured by computer-assisted densitometry.

Statistics.  Software SPSS 13.0 was used for the statistical analyses. All data were expressed as mean ± SE. Student’s t-test was used to analyze the differences between the sham and TBI groups within a single genotype as well as between genotypes. Statistical significance was accepted at p <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The wet/dry weight ratio, which reflects the percentage of water content, is an index of tissue microvascular permeability. We examined the influence of Nrf2 on the lung wet/dry weight ratio of mice after TBI. TBI caused significant increases in the lung wet/dry weight ratio in Nrf2 (+/+) and Nrf2 (–/–) mice, compared to genotype-matched sham-operated mice (p <0.01). The increase of lung wet/dry weight ratio was greater in Nrf2 (–/–) mice compared to their wild-type Nrf2 (+/+) counterparts at 24 hr after TBI (p <0.05) (Fig. 1Go).


Figure 1
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  		Fig. 1. Lung wet/dry weight ratio in sham and injured Nrf2 (+/+) and Nrf2 (–/–) mice. The lung wet/dry weight ratio was significantly increased and was higher in Nrf2 (–/–) mice than in Nrf2 (+/+) mice after TBI (n=5 per group, data are mean ± SE). *p <0.01 vs sham control of the same genotype; #p <0.05 vs injured wild-type mice.

 
Acute pulmonary inflammation is a normal response to brain injury. As measured by ELISA, TBI produced upregulation of TNF-{alpha} (Fig. 2AGo), IL-1β (Fig. 2BGo), and IL-6 (Fig. 2CGo) in the lungs of mice. Although increased TNF-{alpha}, IL-1β, and IL-6 levels were evident in the lungs of both Nrf2 (+/+) and Nrf2 (–/–) mice at 24 hr after TBI (p <0.01), the Nrf2 (–/–) mice showed significantly greater increases in levels of pulmonary TNF-{alpha}, IL-1β, and IL-6 (p <0.05) compared to Nrf2 (+/+) mice.


Figure 2
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  		Fig. 2. Changes of inflammatory cytokines in the lung tissue of sham and injured Nrf2 (+/+) and Nrf2 (–/–) mice. Concentrations of TNF-{alpha} (A), IL-1β (B), and IL-6 (C) were determined by ELISA in the lung tissue of Nrf2 (+/+) and Nrf2 (–/–) mice at 24 hr after TBI. The figure indicates that pulmonary levels of TNF-{alpha}, IL-1β, and IL-6 were significantly increased and were greater in Nrf2 (–/–) mice than in Nrf2 (+/+) mice after TBI; (n = 5 per group, data are mean ± SE); *p <0.01 versus sham control of the same genotype; #p <0.05 versus injured wild-type mice.

 
As detected by immunohistochemical staining, ICAM-1 expression was concentrated mainly in the venular and arteriolar walls, capillary segments, and alveolar walls (Figs. 3A, 3B, 3C, 3DGo), which agrees with a previous report [26]. Quantification of ICAM-1 immunoreactivity showed that pulmonary expression of ICAM-1 was significantly increased (p <0.01) and was greater in Nrf2 (–/–) mice than in Nrf2 (+/+) mice after TBI (p <0.05) (Fig. 3EGo).


Figure 3
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  		Fig. 3. Expression of ICAM-1 in the lung tissue of sham and injured Nrf2 (+/+) and Nrf2 (–/–) mice. Immunohistochemical staining for ICAM-1 was performed in the lung tissue sections of Nrf2 (+/+) and Nrf2 (–/–) mice at 24 hr after TBI. (A) Sham control Nrf2 (+/+) mice showing low ICAM-1 immunoreactivity. (B) Injured Nrf2 (+/+) mice showing increased ICAM-1 immunoreactivity. (C) Sham control Nrf2 (–/–) mice also showing low ICAM-1 immunoreactivity. (D) Injured Nrf2 (–/–) mice showing the strongest ICAM-1 immunoreactivity. (E) Pulmonary expression of ICAM-1 was significantly increased and was greater in Nrf2 (–/–) mice than in Nrf2 (+/+) mice after TBI; (n = 5 per group, data are mean ± SE); *p <0.01 versus sham control of the same genotype; #p <0.05 versus injured wild-type mice.

 
Because lungs of Nrf2 (–/–) mice showed more TNF-{alpha}, IL-1β, and IL-6 production and ICAM-1 expression after TBI, we assessed their mediator, NF-{kappa}B activity, which has been generally involved in pulmonary inflammation. At 24 hr after TBI, NF-{kappa}B activity was significantly increased in the lungs of both Nrf2 (+/+) and Nrf2 (–/–) mice (p <0.01), with Nrf2 (–/–) mice showing a greater increase in NF-{kappa}B activity after TBI compared to Nrf2 (+/+) mice (p <0.05) (Fig. 4Go).


Figure 4
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  		Fig. 4. NF-{kappa}B activity in the lung tissue of sham and injured Nrf2 (+/+) and Nrf2 (–/–) mice. (A) Nuclear protein of lung tissue of Nrf2 (+/+) and Nrf2 (–/–) mice was assayed for NF-{kappa}B DNA binding activity by EMSA at 24 hr after TBI. (B) Quantification of NF-{kappa}B DNA binding activity was performed by densitometry. The figure shows that pulmonary NF-{kappa}B activity was significantly increased and was greater in Nrf2 (–/–) mice than in Nrf2 (+/+) mice after TBI; (n = 5 per group, data are mean ±SE); *p <0.01 versus sham control of the same genotype; #p <0.05 versus injured wild-type mice.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The most important finding of this study is that disruption of Nrf2 in mice causes higher sensitivity to TBI-induced upregulation of tissue microvascular permeability, inflammatory cytokines TNF-{alpha}, IL-1β, IL-6, and ICAM-1, and inflammatory mediator, NF-{kappa}B, in the lung. Based on these results, it appears that, in mice after TBI, Nrf2 has an important role in inhibiting inflammatory cyto-kines and reducing pulmonary microvascular permeability via the NF-{kappa}B signaling pathway.

Pulmonary inflammatory response has been implicated in the pathogenesis of TBI-induced ALI. Many studies have focused on aspects of the proinflammatory cytokine network, which is believed to be central to the pathophysiology of inflammatory processes in the lung [5]. TNF-{alpha} is reported to be a major initiator of inflammation and is released early after an inflammatory stimulus [27]. IL-1β is regarded as the prototypic multi-functional cytokine and is induced in a multitude of cell types [28]. IL-6 is increased after TNF-{alpha} and is an important pro-inflammatory cytokine that contributes to morbidity and mortality in conditions of uncontrolled inflammation [29]. Excessive expression of these cytokines during trauma or other stress potentiates the inflammatory response through the subsequent induction of other inflammatory mediators.

A prevailing theory has been that dysregulation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system resulting from TBI stimulates cytokine expression, leading to an inflammatory process in the lung [4]. In the present study, we evaluated the influence of Nrf2 genotype in the TBI-induced upregulation of inflammatory cytokines TNF-{alpha}, IL-1β, and IL-6 in the lung. The lack of an active Nrf2 pathway in mice was shown to result in increased expression of pulmonary inflammatory cytokines after TBI. These findings illustrated the anti-inflammatory effect of Nrf2 genotype on cytokine production during pulmonary inflammation secondary to TBI.

The expression of the adhesion molecule, ICAM-1, is upregulated upon stimulation by many cytokines and mediators of the inflammatory process [30]. ICAM-1 mediates inflammation by promoting leukocyte adhesion to activated endothelium and subsequent leukocyte diapedesis through the pulmonary endothelial layer [31]. Excessive accumulation of leukocytes is believed to be responsible for injury to organs during inflammation. In the present study, we explored the influence of Nrf2 genotype in the expression of ICAM-1 in the pulmonary inflammation process secondary to TBI. The lack of an active Nrf2 pathway in mice was shown to upregulate the expression of ICAM-1 in the venular and arteriolar walls, capillary segments, and alveolar walls of lung tissue after TBI. These findings document the anti-inflammatory effect of Nrf2 genotype on ICAM-1 expression during pulmonary inflammation secondary to TBI.

Acute pulmonary inflammatory response is associated with epithelial expression of a wide variety of cytokines. Inflammatory cytokines, such as TNF-{alpha}, IL-1β, and IL-6, have cytotoxic effects that induce apoptosis of alveolar epithelium and destruction of intercellular tight junctions, resulting in increased tissue microvascular permeability and extravasation of vascular fluid [32,33]. The filling of alveolar spaces by edema fluid and inflammatory cells can lead to severe hypoxemia and respiratory failure [33]. In our study, the wet/dry weight ratio, an index of tissue microvascular permeability, was significantly increased in the lungs at 24 hr after TBI. Significantly greater increase in the wet/dry weight ratio was observed in Nrf2 (–/–) mice than in Nrf2 (+/+) mice. This suggests that Nrf2 plays a critical role in limiting the cascade of inflammatory cytokine expression leading to TBI-induced ALI.

Although many transcription factors are involved in the regulation of inflammatory gene expression, one mediator, NF-{kappa}B, appears to be of particular importance [34]. The induction of certain cytokine genes, including TNF-{alpha}, IL-1β, IL-6, and ICAM-1, is directly regulated by NF-{kappa}B [19]. NF-{kappa}B represents the unifying common pathway that links diverse inflammatory process and responses. In the present study, disruption of Nrf2 in mice caused greater sensitivity to TBI-induced activation of NF-{kappa}B in lungs. This observation may account for the influence of Nrf2 genotype in inflammatory cytokine expression. We postulate that Nrf2 plays an important role in inhibiting pulmonary inflammatory cytokine expression and reducing pulmonary microvascular permeability after TBI through the NF-{kappa}B signaling pathway. The interplay between Nrf2 and NF-{kappa}B signaling observed in our study corresponds well with the results of a study on experimental sepsis, which demonstrated that Nrf2-deficient mice displayed increased NF-{kappa}B activation in response to lipopolysaccharide (LPS) [35].

Although the precise mechanism underlying the network of inflammatory cytokines and their mediators is still unclear, several lines of evidence indicate that Nrf2 interferes with inflammatory signaling pathways by inhibiting NF-{kappa}B activation through the maintenance of cellular redox status. Oxidative stress from reactive oxygen species (ROS) is believed to be involved in the progression of acute lung injury secondary to TBI [36]. Activation of the NF-{kappa}B signaling pathway has been shown to be responsive to excess ROS and is important in the generation of inflammation [35]. The antioxidant transcription factor Nrf2 has been shown to play an important role in limiting ROS levels and thereby affects the redox-sensitive NF-{kappa}B signaling pathway involved in inflammation [8,37,38]. The protective function of Nrf2 is mainly mediated by a group of Nrf2-regulated antioxidant and detoxifying enzymes [7,9]. Augmentation of cellular antioxidative or detoxification systems via activation of Nrf2-regulated enzymes results in decreased inflammatory cytokine production via inactivation of NF-{kappa}B. This constitutes a possible anti-inflammatory mechanism for the attenuated inflammatory response and tissue damage seen in lungs from Nrf2 (+/+) mice but not Nrf2 (–/–) mice after TBI. Additional research is necessary to elucidate the entire mechanisms involved in these complicated networks.

In summary, the present study showed that Nrf2 plays a protective role in inhibiting pulmonary microvascular leakage, inflammatory cytokine expression, and NF-{kappa}B activation in mice with ALI secondary to TBI. These findings raise the possibility that Nrf2 might be a new therapeutic target for the treatment of ALI after TBI.


   Acknowledgments
 
This work was supported by grants from Jinling Hospital of China. The authors thank Dr. Bo Wu and Dr. Geng-bao Feng for technical assistance.


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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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