Single lung allotransplantation in pigs. A morphologic study of tissue preservation with modified Euro-Collins and fluorocarbon solutions.

In the present study the functional and morphologic effects of two pulmoplegic solutions are evaluated. Single left-lung allotransplantation with ligation of the right pulmonary artery was performed in 15 piglets (13-20 kg). The lungs were preserved after donor prostaglandin E-1 treatment with single pulmonary artery flush with either modified Euro-Collins solution (mECS) (9 pigs) or oxygenated fluorocarbon emulsion (FC-43) (6 pigs) and transplanted after 6-hr storage in cold Physiosol solution. Tidal volumes of 15 ml/kg x fr (18) with 40% inspired oxygen were used for ventilation during reperfusion. Function of the transplanted lung was monitored for 4 hr postoperatively by determining pa CO2 and pa O2 levels from arterial samples and by noninvasive monitoring of end-tidal CO2 values and arterial oxygen saturations. Sequential morphologic changes in pulmonary artery flow surface and lung tissue were studied after 6-hr storage and 4-hr reperfusion, using light, scanning, and transmission electron microscopy (LM, SEM, TEM). There was no mortality. After transplantation the mECS group experienced significant hypoxia and hypercarbia and had low end-tidal CO2 values as signs of defective oxygenation and gas exchange, whereas the FC-43 group was normoxic and normoventilated without disturbed elimination of carbon dioxide. After storage and reperfusion, LM showed signs of increased vascular permeability and reperfusion damage--more evident in the mECS group compared with the FC-43 group--while the lymphoid cell population was more intensely activated in the latter group. Electron microscopy after storage showed good overall preservation of structures in both groups. After reperfusion preservation of pulmonary artery flow surface and lung tissue was estimated to be moderate in the mECS group, whereas it was good-to-moderate in the FC-43 group by SEM (NS). TEM of lung tissue, however, showed significantly better-preserved alveolar epithelial lining in the FC-43 group compared with the mECS group. In conclusion, oxygenated fluorocarbon (FC-43) pulmoplegia gave better functional and morphologic preservation of lung grafts compared with modified Euro-Collins solution.

Immune cells and immunosuppression in a porcine bronchial model of obliterative bronchiolitis.

BACKGROUND: To study obliterative bronchiolitis (OB), we have developed a porcine heterotopic bronchial model. Allografts obliterate within 3 weeks, the immunosuppression cyclosporine (CsA)-azathioprine (AZA)-methylprednisolone (MP) delays OB, but OB is prevented when AZA is switched to 40-0-(2-hydroxyethyl)-rapamycin (RAD). To characterize our model, we studied immune cells under various immunosuppressive conditions. METHODS: The groups studied were autografts (U), allografts (A), and allografts given either CsA-RAD-MP (R), or CsA-AZA-MP (C). The implants were harvested at 3, 7, 10, 14, 21, 30, 60, and 90 days after transplantation. Epithelial damage and obliteration were graded histologically, and the number of CD4, CD8, MHC class II expressing cells, macrophages, and B lymphocytes were counted (mean+SEM)/high-power visual field. RESULTS: In group U, normal epithelium was regained with no obliteration and only few immune cells. In group A, consistent with initially acute ejection, an influx of CD4 (105+23), CD8 (166+23), and class II (92+20) cells was seen up to day 21, when total obliteration preceded by epithelial destruction had already developed. Some macrophages were seen and B cells were scarce. In group R, epithelial damage and obliteration were insignificant, but moderate numbers of CD4, CD8, and class II cells were seen. In group C, epithelial damage and obliteration were only delayed, but the immune cell response was clearly blunted. CONCLUSIONS: In our model, rejection with significant immune cell influx was still active when obliteration was total in nontreated allografts. In immunosuppressed allografts, decrease in the number of immune cells alone did prevent OB. These results support OB being T-cell mediated. RAD may have additional important effects on growth factors and proliferation in prevention of OB.

Obliterative lesions in a heterotopic bronchial xenograft model--a preliminary study.

BACKGROUND: We further developed our heterotopic pig model of obliterative bronchiolitis to study airway obliteration in xenografts. METHODS: Four domestic piglets each received 40 bronchial xenografts s.c. from a donor lamb. Piglet X was not immunosuppressed. The other animals received daily oral cyclosporine, 15 mg/kg (XC), or SDZ RAD, 1.5 mg/kg (XR), or both (XCR). Five implants at a time were serially removed from each animal during 17 days for histological assessment. RESULTS: In contrast to the grafts of the others, the xenografts of XCR recovered after initial ischemic damage. No epithelial damage (P<0.01) or mural necrosis occurred on day 7. Airway obliteration developed in all, but was significantly delayed in XCR. CONCLUSIONS: Invariably developing airway obliteration in nontreated xenografts was delayed by immunosuppression, making the model useful, especially in testing the efficacy of immunosuppressive drugs in a xenogeneic system.

Alloimmune injury preceding airway obliteration in porcine heterotopic lung implants: a histologic and immunohistologic study.

BACKGROUND: Obliterative bronchiolitis (OB), the major long-term complication of lung transplantation, has thus far lacked a good large-animal model. Our goal was to develop such a model on the basis of previous rodent models with tracheal implants. METHODS: Fragments of pulmonary tissue with structures of terminal bronchi were subcutaneously transplanted to four random-bred domestic piglets. Each animal received 10 autograft and 10 allograft implants. The histologic findings were graded from 0 to 3 for implants harvested repeatedly over 2 months. RESULTS: In autografts, partial destruction of the respiratory epithelium and gradual luminal obliteration as well as mild damage to the cartilage and the bronchial wall underwent rapid reversal after initial ischemic injury. In the allografts, epithelial destruction and gradual obliteration were total within 14 days, the difference being statistically significant (P<0.05) in both. The histologic features of the obliterative plug were similar to those of human OB. In the allografts, cartilaginous destruction and pericartilaginous inflammation increased gradually to severe levels, significantly worse than in the autografts (P<0.05). Necrosis and inflammation of the bronchial wall were also more severe in the allografts (P<0.05). CONCLUSIONS: At the end of follow-up, all autografts were vital, whereas the allografts were almost totally rejected and were without native structures. All bronchi in the allografts exhibited accelerated obliteration with histologic features characteristic of human OB, thus providing a model for research into OB and its prevention.

Endothelin content of bronchoalveolar lavage fluid from allotransplanted pigs is increased during unmodified rejection.

To find a new method for detection of rejection of allotransplanted lungs, we studied the endothelin content of bronchoalveolar lavage fluid by radioimmunoassay. Left-sided lung allotransplantation was performed in pigs. One group of animals received no treatment with immunosuppressive drugs (rejection group), the other group of animals (treated group) was treated with a triple-drug immunosuppressive regimen (cyclosporine, azathioprine, and methylprednisone), and nontransplanted lungs were controls. The endothelin content in bronchoalveolar lavage fluid was significantly elevated in the group of pigs with unmodified rejection (29.20 +/- 1.96 pg/ml) compared with that in the immunosuppressed group (15.3 +/- 2.4 pg/ml) and control group (4.27 +/- 1.23 pg/ml). The measurements were made from 5, 33, and 11 samples of bronchoalveolar lavage fluid from the rejection, treated, and control groups, respectively. These results suggest that endothelin content of bronchoalveolar lavage fluid could be a marker of lung allograft rejection.

Bioabsorbable self-reinforced poly-L-lactide, metallic, and silicone stents in the management of experimental tracheal stenosis.

The aim of the present study was to compare, in rabbits, the biocompatibility and suitability of a bioabsorbable spiral stent made of self-reinforced poly-L-lactide (SR-PLLA) in the management of experimental tracheal stenosis with stents made of metal and silicone. Tracheobronchial stenosis, and its management, is still problematic because stenoses are not always amenable to surgical resection and reconstruction, especially concerning anastomotic problems and stenosis after lung transplantation. Stenosis can be handled with stenting, although the ideal stent has yet to be developed; all the stents available have their disadvantages. Because stenting of the airways can be only temporary, stents made of bioabsorbable materials, theoretically, offer benefits. Tracheal stenosis was created in rabbits by the extramucosal resection of cartilaginous arches of the cervical trachea. After a few weeks, the animals were operated on again, and those stenoses that had developed were dilated with a balloon. Stents then were implanted in the area of stenosis to keep the dilated trachea open. All the animals in the group with silicone stents had to be killed because of respiratory difficulties: their stents had a tendency to occlude because of internal encrustation, and they developed a hyperplastic polyp at the ends of the stents. The SR-PLLA and metallic stents were tolerated well, and after follow-up ended the animals were put to death. This experimental study showed that silicone stents had a tendency to occlude and that stents made of metal and of SR-PLLA were well tolerated and can be used in the management of airway stenosis.

High-resolution CT in long-term follow-up after lung transplantation.

OBJECTIVE: Our aim was to evaluate the development of changes on high-resolution CT (HRCT) associated with chronic pulmonary rejection. MATERIALS AND METHODS: Repeated HRCT examinations were performed 140 times on 13 consecutive lung transplant recipients during a mean observation period of 26 months. The postoperative time interval to the first detection of each chronic change on CT was calculated and compared with the onset of chronic rejection. Bronchiolitis obliterans syndrome (BOS) or the histologic diagnosis of obliterative bronchiolitis was assessed by the published criteria of the International Society for Heart and Lung Transplantation. RESULTS: BOS developed in eight patients, on an average, within 11.6 (+/-5.0) months. Histologic diagnosis was available from five patients. On HRCT, among the first identifiable chronic changes were volume contraction, decreased peripheral vascular and bronchial markings, and thickening of septal lines, all of which appeared between 7 (+/-5.0) and 11 (+/-6.8) months postoperatively. The mean interval for appearance of bronchodilatation was 12.5 (+/-8.7) months. Hyperlucency and mosaic phenomenon were identified, on an average, 16 (+/-6.3) and 21 (+/-7.3) months after transplantation. CONCLUSION: On radiologic monitoring of lung recipients with HRCT, in addition to bronchodilatation. a special attention should be paid to the early chronic changes, including diminution of peripheral bronchovascular markings, thickening of septal lines, and volume reduction, which usually precede the establishment of the diagnosis of chronic rejection, whereas hyperlucency and mosaic phenomenon usually appear during more advanced BOS.

Polydioxanone and polypropylene suture material in free internal mammary artery graft anastomoses.

An experimental study with six beagle dogs was conducted to evaluate a new monofilamentous absorbable suturing material--polydioxanone. Free internal mammary artery grafts, 3 cm long, were harvested via a median sternotomy and were implanted as arterial bypasses in femoral arteries (12 end-to-end anastomoses) and as arteriovenous shunts in the carotid artery-contralateral jugular vein position (12 end-to-side anastomoses). Twenty-four anastomoses were made with monofilamentous nonabsorbable suturing material, polypropylene (12 arterial, 12 shunts), to serve as control grafts. At 6 months the grafts and anastomoses were explanted and studied with light and scanning electron microscopes. Macroscopically, the polydioxanone sutures had disappeared. The major histologic finding was the foreign body reaction around the polypropylene sutures. In the electron microscopic study the endothelial line covered the anastomotic site and in the polypropylene anastomoses the suture material was bulging up from the anastomoses. No aneurysms or dilatations were seen. According to this study, polydioxanone is a suitable suturing material for small luminal arterial anastomoses and is superior to polypropylene suturing material because it causes no tissue or other late changes on the flow surfaces.

Life-threatening complications of cardiac operations and occurrence of myocardial catecholamine bombs.

Myocardial catecholamine bombs (huge local intra-axonal accumulations of catecholamine, mainly norepinephrine, within cardiac tissue) were observed in (right auricular) myocardial biopsy specimens in 16 of 65 adult patients selected randomly from a series of elective cardiac operations. The occurrence of catecholamine bombs was in highly significant correlation (p less than 0.001) with the occurrence of life-threatening complications of cardiac operations (life-threatening arrhythmias [ventricular tachycardias, ventricular fibrillation, asystole], clinically evident perioperative myocardial infarction/postoperative low-output syndrome, death). There was a very close correlation between the occurrence of catecholamine bombs and life-threatening arrhythmias. Life-threatening arrhythmias occurred in 13 patients. Eight of them belonged to the group of 16 patients with catecholamine bombs and five belonged to the group of 49 patients with no bombs; the difference (8/16 versus 5/49) is very clear (p less than 0.001). It was our experience that dangerous arrhythmias related to catecholamine bombs may occur as late as during the second postoperative week. We believe our observations are of considerable clinical importance, because catecholamine bombs are easily identified by fluorescence microscopic examination of right auricular myocardial specimens retrieved intraoperatively, and patients at high risk can then be selected (during the operation) for more extensive and prolonged surveillance and possibly prophylactic treatment.

Renal and vascular effects of atrial natriuretic factor during cardiopulmonary bypass.

STUDY OBJECTIVE: To evaluate renal and vasodilator effects of synthetic atrial natriuretic factor (ANF) in patients undergoing cardiopulmonary bypass (CPB) with special reference to the applicability of ANF as a diuretic and natriuretic. DESIGN: The study consisted of two parts. The first 15 consecutive patients in a university hospital received a pharmacologically effective bolus dose of 100 micrograms ANF, as demonstrated previously in other studies, or placebo. After analysis of the bolus data (see "Results" section below), the 12 subsequent patients were administered ANF 50 micrograms as a constant 30-min infusion at a rate of 1.67 micrograms/min or placebo. PATIENTS: The patients were scheduled for elective coronary artery bypass grafting operation. There was no evidence of congestive heart failure in any patient, and no one had an endocrine or renal disorder. INTERVENTIONS: After achievement of hypothermia (29 to 30 degrees C of rectal temperature) during CPB, a bolus dose of ANF 100 micrograms was given or an infusion of ANF 1.67 micrograms/min for 30 min, ie, a total dose of 50 micrograms was started. The control patients received placebo correspondingly. Intravenous fluids were administered according to a predetermined scheme. MEASUREMENTS AND MAIN RESULTS: For the pharmacologic effects of ANF urine volume, urinary sodium excretion and mean arterial pressure (MAP) were measured. Only three of the eight patients receiving the bolus dose of ANF had a diuretic and natriuretic response to the drug, and the responses were significantly related (r = 0.91, p less than 0.05 and r = 0.98, p less than 0.001, respectively) to the prevailing MAP at the time of the bolus administration. The bolus dose of ANF decreased MAP significantly (p less than 0.001 vs placebo) from 65 +/- 6 (mean +/- SEM) to 55 +/- 6 mm Hg within 5 min. The infusion of ANF did not affect MAP, but it increased urine output (16.1 +/- 5.0 ml/min, when the data obtained during the 30-min infusion and a 30-min period after the infusion were combined) and urinary sodium excretion (1,651 +/- 514 microEq/min) significantly (p less than 0.05 and p less than 0.01, respectively) as compared with the corresponding values of 3.3 +/- 1.1 ml/min and 386 +/- 141 microEq/min after placebo. CONCLUSIONS: Prevailing arterial pressure is an important determinant of the diuretic and natriuretic activity of synthetic ANF in patients undergoing CPB. A low-dose infusion of ANF (50 micrograms within 30 min) provides diuresis and natriuresis without significant changes in MAP in these patients.

Selective assessment of single-lung graft function with 133Xe radiospirometry in acute rejection and infection.

In single-lung transplant recipients, the usefulness of spirometric indexes in detecting acute events involving the lung graft is limited due to the bias caused by the native lung. Selective functional monitoring is needed for the proper evaluation of complications after transplantation, but thus far, to our knowledge, no clinically feasible methods for selective graft-function assessment have been presented. In ten single-lung recipients, of whom six had a parenchymal lung disease and four had pulmonary hypertension, the relative ventilation (Vtx), perfusion (Qtx), and ventilation/perfusion ratio of the transplanted lung (V/Qtx) were determined with multidetector 133Xe radiospirometry. Additionally, the fractions of FEV1, FVC, and diffusing capacity for carbon monoxide (Dco) of the transplant (FEV1tx, FVCtx, Dcotx, respectively) were determined by using corresponding radiospirometric parameters for the calculation of their distribution between the lungs. The analysis included seven episodes of acute rejection and nine episodes of infection. The Qtx decreased during acute rejection but did not change during infection (p=0.001). Compared with the figures during infection, the V/Qtx increased during acute rejection significantly (p<0.05) in patients with underlying fibrosis or emphysema, but not in those with pulmonary hypertension. In detection of acute events, the sensitivity of the selective parameters, ie, FEV1tx (86%) and FVCtx (73%), was higher than that of the sum-function parameters, FEV1 (66%) and FVC (40%). Moreover, the sensitivity of Dcotx (80%) was higher than that of Dco (60%) in detecting acute rejection. The findings indicate that, in single-lung recipients with a parenchymal lung disease, the assessment of Qtx, V/Qtx, and Dcotx with a radioactive tracer can help to distinguish acute rejection from infection. The graft-selective parameters, ie, FEV1tx, FVCtx, and Dcotx, tended to be more sensitive than the corresponding sum-function parameters in detecting acute events, thus providing a more accurate functional profile of the single-lung graft.

Proper donor selection for heart-lung transplantation. The Stanford experience.

Clinical cardiopulmonary transplantation is currently limited by the availability of suitable heart-lung donors. Distant graft procurement, with pretreatment, of the donor by intravenous prostaglandin E1 and cooling of the graft with pulmonary artery perfusion, is now clinically established and should increase the number of available donors. Between March 1981 and September 1986, 40 heart-lung transplantations were performed. The characteristics of the donor pool were analyzed. Gram stain of the donor tracheal aspirate revealed gram-positive bacteria in 80% and gram-negative organisms in 35%. Yeast was present on stain in 25% of the patients. Donor arterial oxygen tension was less than 100 torr inspired oxygen concentration 40%) repeatedly in one patient; this recipient died of lung failure at operation. Severe deterioration of allograft lung function was seen in 11 (27.5%) recipients. The causes of deterioration were substantial postoperative bleeding in six patients, sepsis in two, and acute rejection, poor lung function, and allograft heart failure in one patient each. HLA-A locus mismatch, poor donor alveolar-capillary gas exchange, tracheal colonization with heavy polymorphonuclear cells, and heavy bacteria and fungus resulted in increased operative mortality. Donor pretreatment with prostaglandin E1 was associated with improved survival. Recipient selection, emphasizing adequate liver function and absence of previous thoracic operation, careful surgical technique with minimal bleeding, and brief perfusion time were factors associated with improved survival. Early morbidity and mortality were principally related to recipient risk factors, and the strict criteria observed for selection of heart-lung donors were valid. The importance of appropriate recipient selection is underscored.

Experimental piglet lung transplantation: histological bioptic changes and autopsy findings.

To investigate difficulties in diagnosing pulmonary rejection and to create a new model to observe long-term histological consequences, 21 piglets were subjected to left single lung transplantation. Five of these transplants served as targets for unmodified rejection in piglets without immunosuppression (Group I), 13 recipients were treated with cyclosporin A, azathioprine and methylprednisolone (Group II), and in 3 cases reimplantation of an autograft was performed (Group III). In the course of postoperative graft monitoring, transthoracic/bronchial biopsies were obtained on days 3, 5, 7, 10, 14, and 20, and thereafter less frequently up to 134 days. In the unmodified rejection group, grafts consolidated in one week and histologically presented perivascular mononuclear cell infiltrates, except for one case which showed vasculitis. Lymphocytic bronchiolitis and or peribronchiolar infiltrate was present in three of the four autopsied grafts. In Group II acute rejection was detected six times in three piglets, and all except one of these specimens had a peribronchiolar component. Although no incontestable bronchiolitis obliterans developed, mild to moderate chronic obliterative vascular lesions were detected in all immunosuppressed piglets (n = 3) surviving more than 80 days. Contralateral lungs and Group III autografts showed mild changes related to the operation itself and interstitial swine endemic pneumonia (SEP). Chronic changes related to rejection were limited to the vascular wall. The mainly inflammatory bronchiolar changes are thought to present an incipient phase leading to obliterative lesions.

Assessment of right and left atrial function in patients with transplanted hearts with the use of magnetic resonance imaging.

BACKGROUND: The purpose of this study was to determine the volumes and cyclic volume changes of the cardiac atria after heart transplantation in physically healthy recipients. METHODS: Ten heart transplant recipients (New York Heart Association grade I) entered the protocol. All operations had been made with classic biatrial anastomoses. Eight healthy volunteers were studied as controls. To measure the volumes of both atria and left ventricular cavity, we used a gradient-echo cine sequence. The 10 mm slices covered both atria over the total cardiac cycle. Images were planimetered, and simultaneous volumes were totalled to give the cavity volume at each time phase. RESULTS: The heart rate of the heart transplant recipients was faster than in controls, which resulted in higher cardiac output. The atrial minimum volumes were significantly larger, and fractional emptying was smaller in transplanted hearts when compared with controls. Reservoir and stroke volumes were smaller and conduit volumes were larger in transplanted hearts than in controls. The atrial filling and emptying rates were lower in heart transplant recipients than in controls. CONCLUSIONS: The classic surgical technique used in heart transplantation results in large atria with decreased volume changes and filling rates even in physically healthy transplant recipients. Magnetic resonance imaging is a reliable tool in assessment of atrial volumes and cyclic function after heart transplantation.

Heart transplant rejection treated with plasmapheresis.

The vascular element of a mixed type of rejection after orthotopic heart transplantation did not respond to steroid therapy in a 30-year-old man. Plasmapheresis was associated with the resolution of the clinical signs of rejection and the microscopic changes of vasculitis in the biopsy specimen. This case suggests that plasmapheresis may be useful in the treatment of acute vascular rejection in heart transplantation.

Assessment of forced expiratory volume in one second-fraction of the engrafted lung with 133-Xe radiospirometry improves the diagnosis of bronchiolitis obliterans syndrome in single lung transplant recipients.

BACKGROUND: Staging of bronchiolitis obliterans syndrome is based on the decline of forced expiratory volume in 1 second, a measure of overall ventilatory capacity. A single staging system is applied to all lung recipients, regardless of the bias which can be caused by the native lung after single lung transplantation. METHODS: We determined the decline of graft function in single lung recipients by a combination of two methods: 133-Xe radiospirometry and dynamic spirometry. The forced expiratory volume in 1 second fraction of the transplant (FEV1tx) was calculated from the proportion of ventilation of the transplant (Vtx) and forced expiratory volume in 1 second. Eight single lung recipients were followed up for a median observation period of 17 months; bronchiolitis obliterans syndrome developed in four of them. RESULTS: The fractional decline of forced expiratory volume in 1 second of the transplant was significantly greater than the decline of forced expiratory volume in 1 second (p = 0.016) in all patients during the follow-up. In the patients with bronchiolitis obliterans syndrome, the mean decline in forced expiratory volume in 1 second was 1.1 L (39.5%), and in forced expiratory volume in 1 second of the transplant it was 0.9 L (55.8%). The measurement of forced expiratory volume in 1 second of the transplant suggested stage 2a and 3a dysfunction in two grafts in which the assessment of forced expiratory volume in 1 second indicated stage 1a bronchiolitis obliterans syndrome. In one patient, decrease of forced expiratory volume in 1 second of the transplant was suggestive of chronic dysfunction 4 months before it was diagnosed by biopsy and declined lung function. CONCLUSIONS: The assessment of forced expiratory volume in 1 second seems to underestimate the severity of chronic dysfunction in single lung grafts. Instead, the determination of forced expiratory volume in 1 second of the transplant with radioactive tracers provides selective information of the graft function, which could be used for clinical evaluation of bronchiolitis obliterans syndrome in single lung recipients.

Small airway obliteration in a new swine heterotopic lung and bronchial allograft model.

BACKGROUND: We studied a heterotopic large-animal model with obliterative airway lesions caused by allograft rejection. METHODS: Lung fragments (1 cm3) with airways (LB), and 1 to 2 mm diameter bronchi alone (B) were implanted subcutaneously in 11 domestic piglets weighing 20 kg. Six animals each received 40 implants from nonrelated donors without immunosuppression (group A). Another 5 animals had autograft implants (group U). The implants were harvested consecutively for histologic analysis over 3 months in group A and 6 months in group U. RESULTS: In group U, the initial ischemia caused mild to moderate epithelial damage with moderate metaplasia but with a return to normal ciliary epithelium within 1 month. Transient mild luminal obliteration with granulation tissue and mononuclear cells was observed during the first weeks, but after 4 weeks the lumen was patent and filled with mucus. In the bronchial wall, moderate fibrosis developed in LB implants, whereas mild fibrosis was seen in B implants. In group A, the epithelium was totally absent by 2 weeks, and mild inflammation, fibrosis, and destruction of the cartilage with pericartilaginous mononuclear accumulation were observed in the bronchial wall. Small airways were gradually obliterated between days 7 and 21, initially by granulation tissue and mononuclear cells and later by progressive fibrosis. CONCLUSIONS: In this model, autografted airway implants stayed patent for at least 6 months, whereas total luminal obliteration histologically resembling obliterative bronchiolitis developed in allografts within 21 days. Because small airways, including bronchioli, can be transplanted with the use of this model, it may be useful for research into the causes of airway obliteration, which may be relevant to the pathogenesis of obliterative bronchiolitis in lung recipients.

Value of high-resolution computed tomography in routine evaluation of lung transplantation recipients during development of bronchiolitis obliterans syndrome.

BACKGROUND: Chronic rejection is a major long-term complication after lung transplantation. The purpose of our study was to evaluate the role of repeated high-resolution computed tomographic examinations in monitoring the development of bronchiolitis obliterans syndrome after lung transplantation. METHODS: A total of 126 high-resolution computed tomographic examination in 13 lung transplant recipients was analyzed. During a mean follow-up period of 23 months, bronchiolitis obliterans syndrome developed in eight of the patients. A scoring system from 0 to 10 based on the number of chronic changes on high-resolution computed tomography was developed, and the score of each patient was compared with decline in the forced expiratory volume in 1 second and maximal forced expiratory flow rate of 50% of the forced vital capacity. RESULTS: The score of chronic changes, measured at 1 year after transplantation, correlated inversely with the values of forced expiratory volume in 1 second and maximal forced expiratory flow rate at 50% of the forced vital capacity (p < 0.05). Stage I bronchiolitis obliterans syndrome was associated with scores of 4 to 6 (mean 5.0), stage 2 with scores of 6 to 9 (mean 7.0), and stage 3 with scores of 6 to 9 (mean 7.7). The sensitivity of high-resolution computed tomography was 93% and its specificity was 92% when five chronic changes were used as a cutoff level. CONCLUSIONS: The progress of chronic changes on high-resolution computed tomography occurs concurrently with the development of bronchiolitis obliterans syndrome. High-resolution computed tomography may provide additional morphologic information for noninvasive evaluation of chronic lung rejection.

Prevention of small airway obliteration in a swine heterotopic lung allograft model.

BACKGROUND: In our swine model of obliterative bronchiolitis preventing obliteration by the standard immunosuppression with cyclosporine, methylprednisolone, and azathioprine was not successful. The purpose of this study was to test the ability of a new immunosuppressive regimen to prevent alloimmune reaction and obliteration of the allografts. This regimen includes the novel macrolide SDZ RAD, i.e., 40-O-(2hydroxyethyl)-rapamycin. METHODS: Donor lung allografts of 1 cm3 were implanted sub-cutaneously into 11 random-bred non-related domestic pigs receiving daily oral cyclosporine (10 mg/kg) and methylprednisolone (20 mg). In addition, the animals received either oral azathioprine (2 mg/kg) (Group 1) or oral SDZ RAD (1.5 mg/kg) (Group 2). Histologic alterations were graded from 0 to 3 based on repeatedly removed implants during a follow-up period of 3 months. RESULTS: Total epithelial destruction and permanent luminal obliteration occurred within 37 days in Group 1. After an initial grade of 2.3+/-0.3 destruction, epithelial recovery was evident in Group 2 (P < 0.01), and the bronchi stayed patent. Cartilaginous destruction was milder in Group 2 (P < 0.05) than in Group 1, but chondrocytic proliferation was more intense (P < 0.05). Alveolar tissue and native structures of the bronchial wall were destroyed in Group 1, but preserved in Group 2 with total recovery after a mild-grade initial necrosis. CONCLUSIONS: Unlike the standard triple therapy, SDZ RAD combined with cyclosporine and methylprednisolone preserves the pulmonary allografts and prevents epithelial destruction and subsequent luminal obliteration. This suggests that this regimen might efficiently suppress obliterative bronchiolitis and improve long-term results in lung transplant recipients.

Endothelial cell damage following crystalloid cardioplegic solution infusion. Scanning electron microscope study of coronary bypass grafts.

Scanning electron microscope studies of coronary bypass grafts were carried out in six routine bypass operations. Infusion of the initial crystalloid cardioplegic medium into the aortic root after aortic cross clamping was performed in every case. In two cases, pieces of aorta below and above the cross-clamped site, le, having and not having had contact with the crystalloid cardioplegic medium, were studied. The endothelial lining of the veins showed normal structure following distention with blood. Following infusion with a crystalloid cardioplegic solution, the endothelial cells had almost completely vanished and the flow surface was composed mainly of collagen fibers. The aortic samples taken from below the cross-clamp site showed similar destruction of the endothelium that was observed in vein grafts after crystalloid cardioplegic solution infusion, whereas the aortic samples taken from above the cross-clamp site disclosed normal endothelium.