Improved quality of life after lung volume reduction surgery.

Lung volume reduction surgery (LVRS) improves dyspnoea, pulmonary function, and physical performance in patients with severe pulmonary emphysema. This study investigated the impact of LVRS on health-related quality of life (HRQL) over a 2-yr period following surgery. Thirty-nine consecutive patients were prospectively assessed before LVRS, and followed over 24 months postoperatively. The assessments included pulmonary function, dyspnoea (Medical Research Council (MRC) dyspnoea score), 6-min walking distance (6MWD) and HRQL using the Short Form 36-item questionnaire (SF-36). Several domains of SF-36 improved considerably over 2 yrs after surgery: Physical Functioning: 39 +/- 4 (mean +/- SEM) versus 16 +/- 2 (p<0.01); Vitality: 51 +/- 3 versus 32 +/- 3 (p<0.01); Social Functioning: 72 +/- 4 versus 51 +/- 5 (p<0.01). Also, improvements in pulmonary function (forced expiratory volume in one second (FEV1): 27 +/- 1% predicted, residual volume (RV)/total lung capacity (TLC): 0.65 +/- 0.01), 6 MWD (274 +/- 16 m) and dyspnoea (MRC: 3.9 +/- 01) were sustained for up to 2 yrs after LVRS (FEV1 36 +/- 2% pred, RV/TLC: 0.58 +/- 0.02; 6 MWD: 342 +/- 19 m; MRC: 2.0 +/- 0.2; p<0.05). In patients with severe emphysema, lung volume reduction surgery had positive effects on health-related quality of life and pulmonary function over 2 yrs.

Thoracoscopic lobectomy for benign disease--a single centre study on 64 cases.

OBJECTIVE: Chronic lung infection is the main indication for lobectomy in benign pulmonary disease and may be technically demanding due to inflammatory changes such as adhesions, lymph node enlargement and neovascularization. The role of the thoracoscopic operation in these indications is yet ill-defined. METHODS: We retrospectively analyzed the results of patients who underwent thoracoscopic lobectomy (TL) between 1992 and June 1999 and compared this study group with patients who underwent open lobectomy (OL), all for benign disease. Data were not normally distributed, therefore, the median and range is given and nonparametric statistical analysis was applied. RESULTS: A total of 117 lobectomies for benign disease (64 TL) were analyzed. Indications included bronchiectasis (36 TL; 18 OL), chronic infections (13 TL; eight OL), tuberculosis (five TL; 15 OL), emphysema (five TL; one OL), AV-malformations (two TL; one OL), severe haemoptysis (four OL), and others (three TL; six OL). Twelve conversions to thoracotomy were necessary due to severe adhesions. One patient in the open lobectomy group died within 30 days postoperative. Drainage time was 5.0 (1-32) days in TL and 6.0 (3-21) days in OL, hospital stay was 8.5 (4-41) days and 10.0 (5-52) days, respectively. Blood loss was 0 (0-2000) ml in TL and 300 (0-6000) ml in OL. Operation time for thoracoscopic lobectomies significantly decreased from 2.5 (1-6) h for cases between 1992 and 1997 (n=49) to 1.5 (0.5-2.5) h for recent cases (n=15) (P<0.01). In addition, a trend towards less blood loss was noted (100 (0-2000) ml vs. 0 (0-400) ml; P=0.06). Drainage time and hospital stay did not differ significantly. CONCLUSIONS: Thoracoscopic lobectomy in chronic inflammatory disease can be performed safely in selected patients, especially with bronchiectasis. Conversion rate to thoracotomy is low. Operation time with this approach declined significantly over time.

Survival and graft function in a large animal lung transplant model after 30 h preservation and substitution of the nitric oxide pathway.

OBJECTIVE: Substitution of the nitric oxide- (NO-) pathway improves early graft function following lung transplantation. We previously demonstrated that 8-Br-cGMP (second messenger of NO) to the flush solution and tetrahydrobiopterin (BH4, coenzyme of NO synthase) given as additive during reperfusion improve post-transplant graft function. In the present study, the combined treatment with 8-Br-cGMP and BH4 was evaluated. METHODS: Unilateral left lung transplantation was performed in weight matched outbred pigs (24-31 kg). In group I, grafts were preserved for 30 h (n=5). 8-Br-cGMP (1mg/kg) was added to the flush solution (Perfadex, 1.5l, 1 degrees C) and BH4 (10mg/kg/h) was given to the recipient for 5h after reperfusion. In group II, lungs were transplanted after a preservation time of 30 h (n=3) and prostaglandin E(1) (250 g) was given into the pulmonary artery (PA) prior to flush. In all recipients 1h after reperfusion the contralateral right PA and bronchus were ligated to assess graft function only. Survival time after reperfusion, extravascular lung water index (EVLWI), hemodynamic variables, and gas exchange (PaO(2)) were assessed during a 12h observation period. RESULTS: All recipients in group I survived the 12h assessment, whereas none of the group II animals survived more than 4h after reperfusion with a rapid increase of EVLWI up to 24.8+/-6.7 ml/kg. In contrast, in group I EVLWI reached up to 8.9+/-1.5 ml/kg and returned to nearly normal levels at 12h (6.1+/-0.8 ml/kg). In two animals of group I the gas exchange deteriorated slightly. The other three animals showed normal arterial oxygenation over the entire observation time. CONCLUSION: Our data indicate that the combined substitution of the NO pathway during preservation and reperfusion reduces ischemia/reperfusion injury substantially and that this treatment even allows lung transplantation after 30 h preservation in this model.

Effects of linear polyethylenimine and polyethylenimine/DNA on lung function after airway instillation to rat lungs.

Lung transplantation is an acceptable treatment option for various end-stage pulmonary diseases, but long-term survival currently lags behind that after transplantation of other solid organs. We hypothesized that gene transfer to grafts before transplantation may be a useful method to deliver antioxidant and/or anti-inflammatory genes to modulate these processes. For this purpose, we assessed the efficiency of gene transfer and effects on lung function of the synthetic polycation, linear polyethylenimine (PEI), after airway instillation to the lungs of Fischer rats. Twenty-four hours after gene delivery, reporter gene activity in DNA/PEI treated rats was approximately 12-fold higher than that in rats treated with naked DNA, but by 72 hours there was no significant difference between groups and activity had decreased by at least 85%. Function of the transfected left lung was assessed by measuring arterial PaO(2) levels and was found to be significantly lower at 24 and 72 hours after gene transfer in the PEI/DNA group compared with the naked DNA group. The deterioration in lung function correlated with histological findings. Rats treated with PEI alone and sacrificed after 72 hours showed an impairment in lung function similar to that seen with PEI/DNA treatment. Our studies highlight the importance of assessing the functional capacity of a graft after gene transfer to determine suitability for subsequent transplantation.

Efficiency of non-viral gene delivery systems to rat lungs.

OBJECTIVE: Transient expression of therapeutic genes within lung allografts may modulate the pathological processes following allotransplantation. Whilst efficient gene transfer to lungs has been reported with viral vectors, their usefulness is limited on the grounds of safety. Since non-viral systems overcome many of these safety issues, our studies were designed to evaluate the efficiency of several non-viral gene delivery vectors for in vivo transfer of plasmid DNA to rat lungs via the airways. METHODS: Fischer rats (230--260 g) underwent a thoracotomy, right main bronchus occlusion and instillation of 300 microg naked or complexed DNA (pCIluci, luciferase gene/CMV promoter) to the left lung followed by ventilation for 10 min. Rats were divided into five treatment groups (n=5): (1) Glucose, (2) Naked DNA, (3) Linear polyethylenimine (PEI), (4) Branched PEI, (5) Lipid GL-67/DOPE and (6) DOTAP/cholesterol. Animals were sacrificed 24 h after gene delivery for measurement of reporter gene activity and gas exchange of the left lung. RESULTS: Linear PEI was the most efficient gene delivery vector and was significantly better than DOTAP/cholesterol (P=0.00002) and naked DNA (P=0.004). All gene delivery vectors impaired function of the transfected left lung compared with DNA alone. Of all the gene delivery vectors tested, lipid GL-67/DOPE exerted the least effect on lung function whilst DOTAP/cholesterol mediated the most adverse effect. CONCLUSION: Linear PEI was the most efficient vector for gene delivery to rat lungs in our experimental setting although it mediated a moderate impairment in lung function. Further studies are needed to evaluate whether this effect is transient.

Fas ligand gene transfer combined with low dose cyclosporine A reduces acute lung allograft rejection.

The interaction between Fas and its ligand (FasL) induces apoptosis in the Fas-expressing cell. We hypothesized that liposome-mediated FasL gene transduction to the lung allograft, in addition to low-dose immunosuppression, might reduce acute rejection. Orthotopic left lung allotransplantation was performed in male rats (Brown Norway to Fischer F344). FasL gene transfer was performed by use of the plasmid pBCMGSNeo carrying the gene coding for murine FasL and the cationic liposome GL#67:DOPE. Six hundred and sixty micrograms of DNA in 250 microl H2O and 0.5 micromol GL#67 in 250 microl H2O were diluted to 5 ml with saline solution. This emulsion (20 degrees C) was instilled retrogradely through the left pulmonary vein after flushing with LPD solution (20 ml, at 4 degrees C). Subsequently, the graft was stored at 10 degrees C for 3 h. A single dose of cyclosporine A (CsA; 2.5 mg/kg i.m.) was given to all groups 48 h after the transplantation. In group 1 (n = 6), FasL/GL#67 was instilled as described. In group 2 (n = 5), GL#67 was given without DNA. Group 3 (n = 5) animals received CsA only. Five days after transplantation, gas exchange was assessed after exclusion of the contralateral native lung (FiO2 = 1.0). Grafts were flushed with saline solution and fixed in formaldehyde for histological evaluation. No statistical difference in gas exchange (PaO2) between the two control groups 2 (6.4 +/- 0.4 kPa) and 3 (7.4 +/- 0.4 kPa) could be detected 5 days postoperatively (P = 0.9). In contrast, grafts transduced with FasL (group 1) had significantly better gas exchange on postoperative day 5 (PaO2: group 1 37.0 +/- 10.6 kPa vs group 2 6.4 +/- 0.41 kPa; P = 0.002). Two animals in group 1 revealed no or only minimal improvement in gas exchange. Histologically, all lung specimen of all groups showed signs of acute rejection (A2). Leukocyte infiltrates, rated by two independent observers, were less severe in all group 1 animals. Liposome-mediated FasL gene transfer at the time of harvest in combination with low-dose CsA reduces acute rejection in four out of six animals in this model of rat lung allotransplantation.

sCR1sLe ameliorates ischemia/reperfusion injury in experimental lung transplantation.

BACKGROUND: The nonspecific immune response with activation of the complement system and polymorphonuclear leukocytes is important for the mediation of reperfusion injury after lung transplantation. In this study, we investigated the combined blockade of the complement system and leukocyte adhesion by a novel drug combining soluble complement receptor type 1 (sCR1, CD35) with the selectin ligand sialyl Lewis X (sLe(X), CD15s) synthesized to sCR1sLe(X). Both sCR1 and sCR1sLe(X) were supplied by AVANT Immunotherapeutics, Inc, Needham, Massachusetts. METHODS: Orthotopic allogeneic single left lung transplantation was performed in male rats (Brown Norway to Fischer F344; n = 5 in all groups) after a total ischemic time of 20 hours. Recipients received either no specific treatment (control) or administration of sCR1 (10 mg/kg) or sCR1sLe(X) (10 mg/kg) 15 minutes before reperfusion by intracardiac injection. Twenty-four hours after reperfusion, the native contralateral lung was occluded to assess gas exchange of the graft only. In additional animals (5 per group), lung tissue was frozen 24 hours after reperfusion and assessed for myeloperoxidase activity as a measurement of neutrophil migration into the graft and thiobarbituric acid reactive substances to quantify lipid peroxidation. RESULTS: Graft function as assessed by arterial PO (2) in recipients treated with sCR1sLeX was superior not only to that of controls (383 +/- 53 vs 56 +/- 7 mm Hg, P =. 000095) but also to that of animals treated with sCR1 (243 +/- 45 mm Hg, P =.031). This improvement was confirmed by significant reduction of neutrophil migration (0.33 +/- 0.05 vs control, 1.0 +/- 0.09 DeltaOD/mg/min, P =.0000024) and lipid peroxidation (6.2 +/- 0. 38 vs control, 10.6 +/- 0.54 pmol/g, P =.00021). CONCLUSIONS: Our data indicate that combined inhibition of complement activation and leukocyte adhesion with sCR1sLe(X) reduces reperfusion injury significantly and that both mechanisms are effectively inhibited in this model.

Apoptosis induced by ischemia and reperfusion in experimental lung transplantation.

BACKGROUND: Apoptosis is a distinct form of single-cell death in response to injury. Time course of apoptosis in lung parenchymal cells during posttransplant reperfusion and the influence of oxygen content during preservation on apoptosis of parenchymal cells are studied. METHODS: Orthotopic syngenic single left lung transplantation was performed in male Fischer (F344) rats after 18 hours of cold ischemia (n = 5 in all groups). Apoptotic cells were stained by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) technique. Strictly TUNEL-positive pneumocytes were counted on anonymized slides by a pathologist on 100 fields (x400) per specimen (mean +/- SEM). RESULTS: The peak of apoptotic pneumocytes occurred 2 hours after reperfusion (16.8 +/- 2.2 pneumocytes/100 fields [p/100f]; p = 0.000012 vs controls, lungs fixed after 18 hours of ischemia), whereas the lowest level of apoptotic pneumocytes was seen in lungs fixed after harvest (1.4 +/- 0.51 p/100f) and lungs not undergoing reperfusion (2.8 +/- 0.49 p/100f). Four hours after reperfusion, the number of apoptotic pneumocytes was lower than 2 hours after reperfusion (13.6 +/- 3.1 p/100f; p = 0.00032 vs controls), with a further decline at 8 hours (6.4 +/- 1.5 p/100f) and 12 hours after reperfusion (4.0 + 1.2 p/100f). Interestingly, lungs inflated with N2 before storage revealed a significantly lower level of TUNEL-positive pneumocytes 2 hours after reperfusion (8.8 2.0 p/100f) compared with lungs inflated with 100% O2 (p = 0.0052). CONCLUSIONS: Apoptosis of pneumocytes after posttransplant lung reperfusion is a very early event. Prolonged hypothermic preservation without reperfusion, however, does not lead to an elevated rate of apoptotic pneumocytes in lung grafts.

Early and long-term complaints following video-assisted thoracoscopic surgery: evaluation in 173 patients.

OBJECTIVE: Minimal invasive surgical techniques have gained high acceptance in thoracic surgery during the last 10 years. However, up to now, only scant information exists on chronic postoperative pain and discomfort in patients who underwent video-assisted thoracoscopy. Therefore, a retrospective study was performed with the aid of a self-reported questionnaire. METHODS: Two hundred and thirteen patients (of whom 79 females) with a mean age of 48 (range 15-88) years were operated on for a total of 225 procedures. Thoracoscopy was performed for pneumothorax (n=70), pulmonary nodules (n=44), interstitial lung diseases (n=20), pleural effusion (n=20), and empyema (n=19). Various indications included therapeutic or diagnostic procedures in bullous disease, mediastinal tumors, carcinoma, inflammatory lung disease, hyperhidrosis mani and bronchiectasis. RESULTS: Mean drainage time was 6.0+/-4.7 days and hospital stay 8.4+/-6.6 days. One patient died on the ninth postoperative day after lobectomy for bronchial carcinoma due to cardiac failure, five patients needed a short period of reintubation due to acute respiratory failure. In two patients, thoracoscopic reoperation was necessary for closure of bronchopleural fistula. The self-reported questionnaire was returned by 173 (81%) of all patients within a mean follow-up of 18 (3-38) months. More than half of the patients (53%) reported no thoracic pain as early as 2 weeks after the procedure. At 2 weeks after the operation, 13% of patients suffered from localized pain and 31% from diffuse discomfort. Twelve percent needed pain medication regularly, and 3% occasionally. At 6 months postoperatively, three quarters of the patients had no complaints, 5% suffered from scar pain, and 20% had diffuse chest discomfort. One year after the procedure, 86% of the patients had no complaints, 9% suffered from minimal pain, and 5% from moderate pain. Two years after the procedure, 96% of the patients had no complaints at all. One hundred and twenty-five of the 140 patients (89%) working preoperatively went back to work within 2 weeks after the operation. Fifteen patients did not work between 3 and 16 weeks; 14 due to chest pain, one due to shoulder pain. CONCLUSION: Video-assisted thoracoscopy permits very early recovery with rapid reintegration into the working process. Long-term complaints after videothoracoscopy are rare.

Modified technique for heterotopic rat heart transplantation under cardioplegic arrest.

The development of microsurgical techniques offers a valuable opportunity to use small animals for experimental studies of vascularized organ transplants. Availability of inbred strains, natural resistance to infection, and economy make the rat an ideal animal model to investigate the effects of heart transplantation. The recent high interest and substantial laboratory activity with regard to posttransplantory immunological tissue reactions and apoptotic tissue processes led us to optimize transplantation technique by improving myocardial protection during ischemia and thereby minimizing adverse effects of the transplantation procedure itself. Thus the present report details the technique of heterotopic heart transplantation in rats using cardioplegic arrest.

Redo lung volume reduction surgery in a patient with alpha1-antitrypsin deficiency.

Lung volume reduction surgery is a palliative procedure that improves dyspnea and pulmonary function in selected patients with advanced emphysema. Postoperative benefit is sustained for an individual period and depends on the emphysema morphology, the surgical technique, and other not yet well-defined factors. The question whether lung volume reduction surgery can be performed a second time on the same thoracic cavity is often raised but experience in this regard is lacking. We describe a patient who has undergone a successful redo operation 2 years after the initial lung volume reduction surgery.

8-Br-cyclic GMP given during reperfusion improves post-transplant lung edema and free radical injury.

UNLABELLED: Substitution of the NO-pathway reduces ischemia/reperfusion injury following lung transplantation. 8-Br-cGMP is a membrane permeable analogue of cGMP, the second messenger of NO. In this study the effect of continuous administration of 8-Br-cGMP on early graft function was evaluated. METHODS: Unilateral left lung transplantation was performed in 10 weight-matched pigs (23-30 kg). Donor lungs were flushed with 1.51 cold (1 degree C) LPD solution and preserved for 20 hours. In Group I (n = 5), 8-Br-cGMP (0.2 mg/kg/h) was given continuously over the entire observation time starting 15 min before reperfusion. Group II served as control, no 8-Br-cGMP was administered. In both groups, 250 microg PGE1 was injected into the pulmonary artery (PA) before flush. One hour after reperfusion the recipients contralateral right PA and bronchus were ligated to assess isolated graft function only. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, mean systemic arterial pressure and gas exchange were assessed during a 5-hour observation period. Lipid peroxidation as indicator for free radical mediated injury and neutrophil migration to the allograft were measured at the end of the assessment. RESULTS: EVLWI was significantly reduced in animals treated with 8-Br-cGMP (overall difference P = 0.024) with a peak 2 hours after reperfusion (Group I, 8.2+/-0.3 mg/ml vs Group II, 10.1+/-0.6 mg/ml; P = 0.039). Also in Group I the free radical mediated tissue injury was significantly lower when compared to Group II (Group I, 61.8+/-12.3 pmol/g vs Group II, 120.7+/-7.2 pmol/g; P = 0.006). A tendency towards a reduced neutrophil migration after 8-Br-cGMP infusion was shown; however, the changes in comparison to the control animals were not statistically significant (Group I, 1.0+/-0.2 deltaOD/mg/min vs Group II, 1.7+/-0.3 deltaOD/mg/min; P = 0.13). Pulmonary- and systemic hemodynamics, and allograft gas exchange did not differ between groups. CONCLUSIONS: The results indicate that substitution of the NO pathway by administration of the second messenger cGMP at the time of reperfusion improves post-transplant lung allograft function.

A new model for the assessment of lung allograft ischemia/reperfusion injury.

Lung edema is the main clinical manifestation of reperfusion injury following lung transplantation. The evaluation of strategies to prevent this injury is of high clinical importance. Therefore we developed a large-animal model to study the mechanisms of ischemia/reperfusion injury including dynamics of posttransplant reperfusion edema and their prevention. Left lung allotransplantation was performed in 6 weight-matched pigs (25-31 kg). Donor lungs were flushed with 1.5 L low-potassium dextran (LPD) solution (4 degrees C) and preserved for 20 h at 1 degrees C. One hour after reperfusion the recipient contralateral right lung was excluded from perfusion and ventilation to assess graft function only. Extravascular lung water index (EVLWI), intrathoracic blood volume (ITBV), and cardiac output (CO) were assessed (q = 30 min) with a lung water computer (Cold Z-021, Partig, Munich, Germany) by the thermo-dye technique during a 5-h observation period. Gas exchange (FIO2 = 1.0) was measured hourly, and hemodynamics were monitored continuously. The EVLWI of the recipient contralateral lung together with the donor left lung at the time of reperfusion was 6.5+/-1.1 ml/kg, increasing to 7.1+/-1.0 ml/kg at 60 min after reperfusion. After occlusion of the recipient right lung, EVLWI in the graft further increased within 80 min from 8.1+/-0.5 ml/kg to a peak of 11.4+/-1.3 ml/kg, followed by a decrease to 8.5+/-0.8 ml/kg at 5 h after reperfusion in 5 of 6 animals. In 1 animal a severe alveolar edema developed with subsequent deterioration of gas exchange and death 4.5 h after reperfusion. In this animal, peak EVLWI reached 16.8 ml/kg, PaO2 deteriorated from 60.1 to 7.8 kPa, and CO decreased from 3.1 to 1.4 L/min. In all other animals, ITBV (515+/-51 ml), left atrial pressure (LAP), central venous pressure (CVP), and CO (2.9+/-0.3 L/min) were stable during the 5-h assessment period. We conclude that EVLWI measurement is a reliable and very sensitive method to quantify lung allograft reperfusion edema. It may prove useful in early assessment of lung allograft reperfusion injury in the clinical setting and in experimental models.

Buttressing the staple line in lung volume reduction surgery: a randomized three-center study.

BACKGROUND: The intention of buttressing the staple line in lung volume reduction surgery is to reduce air leaks and to shorten the hospital stay. A randomized three-center study was carried out to test this hypothesis. METHODS: Sixty-five patients with a mean age of 59.2 +/- 1.2 years underwent bilateral lung volume reduction surgery by video-assisted thoracoscopy using endoscopic staplers (ET 45B; Ethicon Endo-Surgery, Cincinnati, OH) either without or with bovine pericardium for buttressing (Peri-Strips Dry; Bio-Vascular, Inc, Saint Paul, MN). There were no differences between the control and treatment groups in lung function, degree of dyspnea, and arterial blood gases before and 3 months after LVRS. RESULTS: Seven patients (3 in the treatment group) needed a reoperation because of persistent air leak. The median duration of air leaks was shorter in the treatment group (0.0 day [range, 0 to 28 days versus 4 days [range, 0 to 27 days); p < 0.001), confirmed by a shorter median drainage time in this group (5 days [range, 1 to 35 days] versus 7.5 days [range, 2 to 29 days); p = 0.045). Hospital stay was comparable between the two groups (9.5 days [range, 6 to 44 days] versus 12.0 days [range, 5 to 46 days]; p = 0.14). CONCLUSIONS: Buttressing the staple line significantly shortens the duration of air leaks and the drainage time. As hospital stay did not differ significantly between the two groups, cost-effectiveness may depend on the local situation.

Two years' outcome of lung volume reduction surgery in different morphologic emphysema types.

BACKGROUND: Lung volume reduction surgery (LVRS) improves dyspnea, pulmonary function, and quality of life in selected patients with severe emphysema. We investigated the role of emphysema morphology in 37 patients as an outcome predictor for up to 2 years after operation. METHODS: Patients selected for bilateral thoracoscopic LVRS were divided, according to a simplified emphysema morphology classification, into three groups (homogeneous, moderately heterogeneous, and markedly heterogeneous) based on a preoperative chest computed tomogram. Pulmonary function, walking distance, and dyspnea were assessed. RESULTS: Functional improvement after LVRS was best in markedly heterogeneous emphysema with an increase from preoperative forced expiratory volume in 1 second of 31% +/- 2% (mean +/- standard error of the mean) to 52% +/- 4% of predicted postoperatively. It was significantly higher than in homogeneous emphysema (from 26% +/- 1% to 38% +/- 2% predicted) and in intermediately heterogeneous emphysema (from 29% +/- 2% to 44% +/- 45% predicted). At 24 months postoperatively, forced expiratory volume in 1 second and dyspnea score continued to be significantly better than preoperative levels in all three morphologic groups. The survival rate was highest in patients with markedly heterogeneous emphysema. CONCLUSIONS: Functional and subjective improvements were maintained after LVRS for at least 24 months in patients with heterogeneous or homogeneous emphysema type.

Combined treatment with endothelin- and PAF-antagonists reduces posttransplant lung ischemia/reperfusion injury.

BACKGROUND: Pathophysiologic changes of posttransplant lung ischemia/reperfusion injury are mediated by redundant cellular and humoral mechanisms. We investigated the protective effect of combined administration of platelet activating factor (PAF) and endothelin (ET) antagonists after prolonged ischemia in a small animal lung transplantation model. METHODS: Orthotopic left lung transplantation was performed after 20 hours cold ischemia in male Fischer (F344) rats weighing 200-250 g. Group I served as control. In Group II, donors received 1 mg/kg body weight of the endothelin antagonist TAK-044, and recipients 2 mg/kg. Group III was treated with the PAF antagonist TCV-309 (donor: 50 microg/kg; recipient: 100 microg/kg) (Takeda Chemicals Ltd.). Group IV received a combined treatment with both substances at the same dosage. Twenty-four hours after reperfusion, the native contralateral lung was occluded to assess gas exchange of the graft only, and 5 minutes later the thoracic aorta was punctured for arterial blood gas analysis (n = 5). In other animals (n = 5), lung tissue was frozen 24 hours after reperfusion and assessed for myeloperoxidase activity (MPO) and thiobarbituric acid reactive substances. RESULTS: Combined inhibition of PAF and ET-1 at the receptor level resulted in significantly improved graft function as compared to controls (Group I), and to groups treated with either TAK-044 or TCV-309. This was determined by a higher arterial oxygen content (112 +/- 9 mmHg, p = .00061 vs control, 48 +/- 5 mmHg), reduced MPO activity (0.35 +/- 0.02 deltaOD/mg/min, p = .000002 vs control, 1.1 +/- 0.1 deltaOD/mg/min) and reduced lipid peroxidation (59.5 +/- 2.5 pmol/g, p = .011 vs control, 78.5 +/- 4.1 pmol/g). The improvement of arterial oxygen (Group II 77 +/- 10 mmHg, p = .027 vs control; Group III 84 +/- 8 mmHg, p = .0081 vs control) and reduction of MPO activity (Group II 0.85 +/- 0.061 deltaOD/mg/min, p = .017; Group III 0.92 +/- 0.079 deltaOD/mg/min, p = .058) in groups treated with either a PAF antagonist or an ET antagonist was significantly less than in Group IV. CONCLUSIONS: Combined donor and recipient treatment with an ET antagonist and a PAF antagonist results in superior posttransplant graft function 24 hours after reperfusion, suggesting a synergistic role of ET-1 and PAF in the mediation of reperfusion injury in this model. Single treatment with either of the antagonists revealed only a slight improvement compared to untreated controls.

The nitric oxide synthase cofactor tetrahydrobiopterin reduces allograft ischemia-reperfusion injury after lung transplantation.

OBJECTIVE: Exogenous nitric oxide reduces ischemia-reperfusion injury after solid organ transplantation. Tetrahydrobiopterin, an essential cofactor for nitric oxide synthases, may restore impaired endothelium-dependent nitric oxide synthesis. We evaluated whether tetrahydrobiopterin administration to the recipient attenuates lung reperfusion injury after transplantation in swine. METHODS: Unilateral left lung transplantation was performed in 15 weight-matched pigs (24-31 kg). Donor lungs were flushed with 1.5 L cold (1 degrees C) low-potassium-dextran solution and preserved for 20 hours. Group I animals served as controls. Group II and III animals were treated with a bolus of tetrahydrobiopterin (20 mg/kg). In addition, in group III a continuous infusion of tetrahydrobiopterin (10 mg/kg per hour over 5 hours) was given. One hour after reperfusion, the recipient right lung was occluded. Cyclic guanosine monophosphate levels were measured in the pulmonary venous and central venous blood. Extravascular lung water index, hemodynamic variables, lipid peroxidation, and neutrophil migration to the allograft were assessed. RESULTS: In group III a significant reduction of extravascular lung water was noted in comparison with the controls (P =.0047). Lipid peroxidation in lung allograft tissue was significantly reduced in group II (P =.0021) and group III ( P =. 0077) in comparison with group I. Pulmonary venous levels of cyclic guanosine monophosphate increased up to 23 +/- 1 pmol/mL at 5 hours in group II and up to 40 +/- 1 pmol/mL in group III (group I, 4.1 +/- 0.5 pmol/mL [I vs III]; P <.001), whereas central venous levels of cyclic guanosine monophosphate were unchanged in all groups. CONCLUSION: Tetrahydrobiopterin administration during lung allograft reperfusion may reduce posttransplantation lung edema and oxygen-derived free radical injury in the graft. This effect is mediated by local enhancement of the nitric oxide/cyclic guanosine monophosphate pathway.

8-Br-cGMP is superior to prostaglandin E1 for lung preservation.

BACKGROUND: Substitution of the nitric oxide (NO) pathway reduces ischemia/reperfusion injury after lung transplantation. 8-Br-cGMP is a membrane-permeable analogue of cGMP, the second messenger of NO. In this study, we evaluated the effect of administration of 8-Br-cGMP in the flush solution on early graft function. METHODS: Unilateral left lung transplantation was performed in 10 weight-matched pairs of outbred pigs (24 to 31 kg). Donor lungs were flushed with 1.5 L cold (1 degree C) low potassium dextrane (LPD) solution and preserved for 20 hours. In group I (n = 5), 8-Br-cGMP (1 mg/kg) was added to the flush solution. In group II (n = 5), 8 microg/kg prostaglandin E1 (PGE1) was injected into the pulmonary artery (PA) before flush. One hour after reperfusion, the recipients' contralateral right PA and bronchus were ligated to assess graft function only. cGMP levels in the PA and pulmonary vein were measured. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, and gas exchange (PaO2) were assessed during a 5-hour observation period. Lipid peroxidation (thiobarbituric acid-reactive substance) and neutrophil migration to the allograft (myeloperoxidase activity) were measured at the end of the assessment. RESULTS: In group I, a significant reduction of EVLWI (group I, 6.7 +/- 1.0 mL/kg vs group II, 10.1 +/- 0.6 ml/kg after 2 hours of reperfusion; p = 0.022), TBARS (group I, 65.6 +/- 10.0 pmol/g vs group II, 120.8 +/- 7.2 pmol/g, p = 0.0039), and MPO activity (group I, 0.8 +/- 0.1 change in optical density, (deltaOD)/mg/min vs group II, 1.7 +/- 0.3 deltaOD/mg/min, p = 0.036) was noted in comparison with group II. PaO2 levels tended to be higher in cGMP-treated animals, but the changes were not significant. Hemodynamic parameters did not differ between groups. CONCLUSIONS: In this large animal model of lung allograft ischemia/reperfusion injury, 8-Br-cGMP as additive to the flush solution improves posttransplant lung edema, lipid peroxidation, and neutrophil migration to the allograft. This effect is not attributable to improved flush by vasodilation, as we compared 8-Br-cGMP with PGE1 given before flush in control animals.