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Eur J Cardiothorac Surg 2005;27:23-27
© 2005 Elsevier Science NL

Attenuation of lung injury in allograft rejection using NF-{kappa}B decoy transfection—novel strategy for use in lung transplantation

Kenichi Ohmori*, Shin-ichi Takeda1, Shinichiro Miyoshi2, Masato Minami, Shigeru Nakane, Mitsunori Ohta, Yoshiki Sawa, Hikaru Matsuda

Department of Surgery (E1), Osaka University Graduate School of Medicine, Yamada-oka 2-2, Suita City, Osaka 565-0871, Japan

Received 20 June 2004; received in revised form 31 August 2004; accepted 3 September 2004.

* Corresponding author. Present Address: Department of General Thoracic Surgery, Kure Medical Center, Aoyamacho 1-3 Kure Hiroshima 737-0023, Japan. Tel.: +81 823 22 3111; fax: +81 823 21 0428. (E-mail: omorik{at}kure-nh.go.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
 References
 
Objective: Increased production of nitric oxide (NO) is known to be a marker of lung allograft rejection and lung injury. NO production is up-regulated directly or indirectly by nuclear factor-kappa B (NF-{kappa}B), a transcriptional factor of inflammatory cytokines and iNOS. We attempted to determine whether transfection of an NF-{kappa}B decoy into allografts could reduce NO production and ameliorate acute lung injury during allograft rejection. Methods: Left lung transplantation was performed in pairs of Brown Norway (RT1n) and Lewis (RT1) rats. In Group NF (n=6), the allografts were flushed with 20ml of PBS solution containing a hemagglutinating virus of Japan (HVJ) liposome-ODN complex as an NF-{kappa}B decoy and preserved for 60min at 4°C. A scramble decoy was used in the positive control (Group S, n=5) and simple PBS solution in the negative control (Group C, n=5). Five days after transplantation without use of immuno-suppressants, exhaled NO, gas exchange, and graft histological rejection score were determined. Results: The exhaled NO level was significantly reduced in Group NF as compared with Group S (445±162 vs 1305±123 ppb, P<0.02), while improvements in PaO2 (197±28 vs. 60±18mmHg, P<0.02) and rejection score (1.8±0.3 vs. 2.5±0.4) were also observed. There were no differences in these parameters between Groups S and C. Conclusions: Inhibition of NF-{kappa}B activation in the allograft by ODN decoy transfection into the donor lung ameliorated lung injury during acute allograft rejection. Our results imply a possible therapeutic target for the inflammation process in lung transplantation clinical settings.

Key Words: Allograft lung injury • Gene Transfer • Lung transplantation • NF-{kappa}B


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
 References
 
Problems encountered with clinical lung transplantation include early graft dysfunction [1], a high frequency of various degrees of acute rejection [2], and chronic lung dysfunction manifested by obliterative bronchiolitis (OB) [3]. Unlike cardiac transplantation recipients, various degrees of acute rejection occur in patients receiving a transplanted lung, despite the common use of cyclosporine [2], which leads to allograft pulmonary tissue injury.

Recently, increased levels of exhaled nitric oxide (NO) have been shown to reflect the degree of lung allograft rejection in experimental animals [4] and human transplant recipients [5]. Thus, inhibition of NO production may reduce its damaging role in acute rejection [6]. Lung injury during the rejection process is thought to be mediated through allo-dependent (rejection) and allo-independent (inflammation) pathways, and, more importantly, episodes of acute rejection may be a predominant risk factor for the development of OB [3].

Recent advancements in molecular biology and genetics have enabled application of gene manipulation in the field of thoracic organ transplantation [7]. The hemagglutinating virus of Japan (HVJ) liposome gene transfer system [8] is useful for clinical application because of its high transfection efficiency, short incubation time, ability to deliver oligonucleotides, no requirement of cell division, lack of toxicity, and low antigenicity. Using this novel technique, foreign genes have been successfully introduced into livers, kidneys, hearts [9,10], and lungs [7].

Emerging oligo-deoxynucleotide (ODN)-based strategies have shown immediate effects when used with HVJ liposomes [10], as compared to the other conventional transgene strategies, which require a time lag for protein synthesis.

Since NO production is up-regulated by NF-{kappa}B [10], a transcriptional factor of inflammatory cytokines and iNOS, a synthetic ODN used as a decoy against NF-{kappa}B has the potential to be a powerful inhibitor of NF-{kappa}B activation and downstream transgene activation in the inflammation cascade.

In the present study, we attempted to determine whether transfection of an NF-{kappa}B decoy ODN into the graft during harvest could reduce NO production and ameliorate allograft injury during the process of acute lung rejection.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Statistics
 4. Results
 5. Discussion
 References
 
2.1. Animals
Male inbred Brown Norway (RT1n) and Lewis (RT1) rats (Charles River Japan, Yokohama, Japan) weighting 280–320g were used. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH, publication 85-23, revised 1985).

2.2. Synthesis of ODN
An NF-{kappa}B decoy has been shown to bind to the NF-{kappa}B transcriptional factor. Sequences of the phosphorothioate ODN used in the present study have been described previously [10,11], and were double-stranded and phosphorylate-modified at both 3' and 5' (Nissin Seifun, Tokyo, Japan). The sequence of the NF-kB decoy sense strand was 5'-AGT TGA GGG GAC TTT CCC AGGC-3', and contained both the specific p50 (GGGGAC) and p65 (TCC) {kappa}B binding sites. As for the scrambled ODN, the nonsense sequence was 5'-TTG CCG TAG CTG ACT TAG CCGT-3'. The decoy ODN was labeled with fluorescein isothiocyanate (FITC).

2.3. Preparation of HVJ-liposomes
HVJ-liposomes were prepared as described previously [7,9,11]. Briefly, 10mg of mixed lipids [phosphatidylcholine (ePC), dioleoylphos-phatidylethanolamine (DOPE), egg yolk sphingomyelin (eSph), cholesterol (Chol), phosphatidylserine (PS)] was dried by reversed phase evaporation and hydrated in 200µl of balanced salt solution (BSS, 137mM NaCL/5.4mM KCL/10mM Tris–HCL, pH 7.6). The liposome suspension was incubated with UV-inactivated HVJ (15,000 hemagglutinating units [HAU]), first at 4°C and then at 37°C. Finally, 4mL of the top layer of the sucrose gradient containing the HVJ-liposome complex was collected for use.

2.4. Analysis of FITC ODN
The efficiency of the FITC-labeled ODN delivered by the HVJ liposome method was assessed histologically. The specimen was frozen at –80°C, and then cut and examined with fluorescence microscopy. The sections were stained with hematoxylin/eosin (H/E), and photographed under a light microscope to compare and semi-quantify the transfection efficiency, as described previously [12].

2.5. Experimental protocol
All rats were anesthetized by an intraperitoneal injection of pentobarbital (20mg/kg) followed by inhalation anesthesia, after which they were ventilated with room air with a tidal volume of 2.5–3.0ml and respiratory rate of 90–100breaths/min. In each, a left single lung transplantation was performed according to a method previously reported [4]. Briefly, following a median sternotomy, a 14-gauge tube was inserted via the right ventricle through the pulmonary artery, then the donor lungs were flushed with a cold (4°C) solution containing HVJ-liposome ODN and preserved for 1h at 4°C. The animals were divided into 4 groups. In Group NF (n=6), an FITC-labeled NF-kB decoy was added to the flushing solution. Groups S and C (n=5 in each) served as positive (scrambled decoy) and negative (PBS alone) controls, respectively.

Pulmonary function was assessed on postoperative day (POD)-5. The function of the isolated graft was assessed by clamping the right (contralateral) hilum and ventilation was provided with 100% oxygen (tidal volume 1.5ml, respiratory rate 100/min, positive end-expiratory pressure 0.5cm of H2O). We selectively measured of the exhaled NO of the left transplanted lung. Exhaled gas was collected by ligation of the right main bronchus, and the NO concentration was determined using a chemiluminescence analyzer (SIVERS NOA270B, Taiyo Toyo Sanso Co Ltd, Osaka, Japan) sensitive to NO at concentrations from 5 to 10,000ppb by volume 30min after collection [13,14] For histological study, the grafts were removed and fixed, and histologic rejection grades were scored by a blinded observer according to the international working formulation [15]: grade A0, no significant abnormality; A1, scattered infrequent perivascular mononuclear infiltration; grade A3, extension of mononuclear infiltration into alveolar septum/spaces; and A4 diffuse perivascular, interstitial. And air space infiltration of mononuclear cells.


   3. Statistics
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
4. Results
 5. Discussion
 References
 
Data are presented as means±standard error (SEM). Statistical comparisons between groups were made using a Newmann–Keuls multiple range test for significant differences between means. A P value of less than 0.05 was considered statistically significant.


   4. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
5. Discussion
 References
 
In our preliminary analysis, we sought to determine transgene distribution by in vivo transfection of the FITC-labeled decoy ODN into the lungs. In vivo gene transfer of the FITC-labeled ODN in the flushing solution after infusion into the pulmonary artery resulted in widely distributed fluorescence in alveolar epithelial cells, bronchiolar epithelial cells, and capillary endothelia (Fig. 1A–C). There was no immuno fluorescence in the PBS control or FITC-unlablled ODNs control.



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  		Fig. 1. FITC-labeled ODN in flushing solution infused through the pulmonary artery resulted in widely distributed fluorescence in pulmonary endothelial and bronchia-alveolar epithelial cells (A, x100). With the aid of HVJ-liposome, bronchial epithelium and alveolar macrophages were preferably transfected after 1h of preservation (B, x400), as was the vascular endothelium (C, x400).

 
There were no statistical differences in graft gas exchange function, exhaled NO, or histologic rejection score between groups S and C.

PaO2 levels in group NF were significantly higher than those in Groups S and C (Fig. 2) (91±35mmHg for Group C, 60±18mmHg for Group S, 197±29, mmHg for Group NF, P<0.02).



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  		Fig. 2. Graft function in the process of acute rejection. PaO2 levels for Group NF transfected with the NF-kB decoy were significantly higher than those in Groups C and S (P=0.045 and P=0.012, respectively).

 
In our previous studies [18,19], exhaled NO was sharply increased on POD-5 in untreated allografts (BN to LEW), whereas cyclosporine treated animals and isografts did not show a significant increase. In the present study, the exhaled NO level was significantly reduced in Group NF as compared to Groups C and S (1068±243 for Group C, 1305±123 for Group S, 445±162 ppb for Group NF, P<0.05) (Fig. 3). Further, the histologic rejection score was lower in Group NF than in Groups C and S (2.6±0.5 for Group C, 2.8±0.5 for Group S, 1.8±0.3 for Group NF, respectively), though the differences were not statistically significant (Fig. 4).



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  		Fig. 3. The level of exhaled NO was significantly reduced in group NF, who received NF-kB decoy transfection (445±1162 ppb), as compared with Group C (1068±243 ppb, NF vs. C P=0.014) and S (1305±123 ppb, NF vs. S P=0.003).

 


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  		Fig. 4. The histological grading of rejection was lower in group NF (1.8±0.3) than in Group C (2.6±0.5) and S (2.6±0.5), though the differences were not statistically significant (P=0.212 and P=0.12, respectively).

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
References
 
Gene therapy has emerged as a promising therapeutic modality for lung transplantation, though experimental efforts have been employed with only limited success [16–18]. Emerging ODN-based strategies with the HVJ liposome [10,11,19] have the advantage of immediate effects and high transfection efficiency, as compared to other conventional transgene strategies. This novel system shows potential for therapeutic intervention, as we have previously reported in large animal models [19]. Using an HVJ-liposome delivery system, ODNs can be easily delivered to the nucleus within 15–30min where it acts in an efficient manner [10], which may be applicable for therapeutic effects.

Morishita et al. [10] developed a synthetic double-stranded ODNs as a decoy cis element to block the binding of nuclear factors at the promoter regions of the targeted genes. A decoy ODN may be more powerful than an antisense ODNs in multiple transcriptional factors that bind to the cis element. NF-{kappa}B is known to play a pivotal role in the activation of inflammatory cytokines, adhesion molecules, and iNOS genes [10] that contribute to acute allograft injury following lung transplantation, however, its decoy ODNs were easily delivered into the nucleus within 1h using the HVJ-liposome system and remained stable for 1–2 weeks [10,11]. Our preliminary experiments with lung ischemia-reperfusion showed beneficial effects [unpublished data], which were also seen in a heart transplant model [11]. The present study was designed to investigate the effect of an NF-{kappa}B decoy in a more severe lung injury model associated with acute rejection without immunosuppression.

Administration of an NF-kB inhibitor resulted in a decrease in NF-{kappa}B activity within transplanted hearts, as well as a decrease in NO production [20], supporting the notion of a role for NF-{kappa}B in the rejection process, mainly in the allo-dependent pathway. Further, optimal immuno-suppression was able to eliminate exhaled NO in an experimental lung transplant model [4]. Thus, we speculated that inhibition of NF-{kappa}B activity in the graft may act favorably toward the allo-independent (inflammation) pathway. In a heart transplant model, transfection of an NF-{kappa}B decoy resulted in a decrease of interleukin-8 (IL 8) and preserved heart function [10,11]. In addition, clinical evidence has revealed that an increased IL-8 level in the donor lung was a predictor of late graft failure and recipient mortality [21]. These results led to a hypothesis that therapeutic regulation of NF-{kappa}B is a possible means to modulate lung inflammation in the setting of acute lung injury [22]. Therefore, a synthetic ODN decoy against NF-{kappa}B has the potential to be a powerful inhibitor of NF-{kappa}B activation, as well as inhibit downstream transgene activation in the inflammation cascade.

We did not directly measure NF-{kappa}B activity or other cytokine expressions in the present study, only exhaled NO. The NO levels in the 2 control groups (S and C) were similar to that in our previous report [4]. This finding indicated that transfection of the NF-{kappa}B decoy decreased the level of NO level and improved allograft gas exchange in the acute rejection model without immunosuppression.

We focused on the effect of allograft NF-kB activation as well as NO production that may be related to the graft damage. The importance of plausible allo-independent disease processes has not been emphasized in the allograft rejection process until recently [7–23]. A role for treatment of NF-{kappa}B in rejection is attenuation of the initial event of acute lung injury, enabling recovery or regeneration of the allograft. As noted earlier, episodes of acute rejection may be a predominant risk factor for the development of OB [3,24] and clinical evidence supports the importance of non-immune acute lung injury [24] as another significant risk of OB development.

Acute rejection is evoked by host T-cell mediated host response. However, therapy for inflammatory lung tissue damage may emerge as a target in the clinical settings [24,25]. In the present experiments, inhibition of NF-{kappa}B activation in the allograft with an ODN decoy ameliorated lung injury in acute allograft rejection, and the technique used seemed to be feasible in the setting of lung transplantation. However, it is mandatory to prove these vectors to be safe for gene transfection in human subjects. Further understanding of the impact of these allo-independent components as well as development of novel approaches for these targets may function in combination with ordinal immuno-suppression to improve graft survival.


   Footnotes
 
1 Present Address: Department of Thoracic Surgery, Toneyama National Hospital, Toyonaka, Osaka 560-8552, Japan. Back

2 Present Address: Department of Thoracic Surgery Dokkyo Medical, College Tochigi 321-0293, Japan. Back


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistics
 4. Results
 5. Discussion
 References
 

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