Biomedical subjects

G A Patterson

Publications and source records attributed to G A Patterson.

At least 73 records · Page 4Linked to original sources

PubMed1998

Pulmonary retransplantation: predictors of graft function and survival in 230 patients. Pulmonary Retransplant Registry.

BACKGROUND: Despite improving results in lung transplantation, a significant number of grafts fail early or late postoperatively. The pulmonary retransplant registry was founded in 1991 to determine the predictors of outcome after retransplantation. We hypothesized that ambulatory status of the recipient and center retransplant volume, which had been previously shown to predict survival after retransplantation, would also be associated with improved graft function postoperatively. METHODS: Two hundred thirty patients underwent retransplantation in 47 centers from 1985 to 1996. Logistic regression methods were used to determine variables associated with, and predictive of, survival and lung function after retransplantation. RESULTS: Kaplan-Meier survival was 47% +/- 3%, 40% +/- 3%, and 33% +/- 4% at 1, 2, and 3 years, respectively. On multivariable analysis, the predictors of survival included ambulatory status or lack of ventilator support preoperatively (p = 0.005; odds ratio, 1.62; 95% confidence interval, 1.15 to 2.27), followed by retransplantation after 1991 (p = 0.048; odds ratio, 1.41; 95% confidence interval, 1.003 to 1.99). Ambulatory, nonventilated patients undergoing retransplantation after 1991 had a 1-year survival of 64% +/- 5% versus 33% +/- 4% for nonambulatory, ventilated recipients. Eighty-one percent, 70%, 62%, and 56% of survivors were free of bronchiolitis obliterans syndrome at 1, 2, 3, and 4 years after retransplantation, respectively. Factors associated with freedom from stage 3 (severe) bronchiolitis obliterans syndrome at 2 years after retransplantation included an interval between transplants greater than 2 years (p = 0.01), the lack of ventilatory support before retransplantation (p = 0.03), increasing retransplant experience within each center (fifth and higher retransplant patient, p = 0.04), and total center volume of five or more retransplant operations (p = 0.05). CONCLUSIONS: Nonambulatory, ventilated patients should not be considered for retransplantation with the same priority as other candidates. The best intermediate-term functional results occurred in more experienced centers, in nonventilated patients, and in patients undergoing retransplantation more than 2 years after their first transplant. In view of the scarcity of lung donors, patient selection for retransplantation should remain strict and should be guided by the outcome data reviewed in this article.

Adolescent↗

PubMed1998

Outcome of Medicare patients with emphysema selected for, but denied, a lung volume reduction operation.

BACKGROUND: Lung volume reduction operation shows promise in relieving symptoms and improving function in highly selected patients with emphysema. Withdrawal of Medicare funding for patients selected for operation by standard criteria created a matched control group with which to compare lung volume reduction recipients. METHODS: A retrospective study was done comparing 22 volume reduction candidates denied operation with 65 contemporaneous and comparable volume reduction recipients. Baseline physiologic characteristics were compared and longitudinal measures of pulmonary function were followed up for 24 months. RESULTS: Patients denied operation were similar to volume reduction recipients in all baseline measurements. Patients denied operation experienced a progressive worsening of their function, whereas volume reduction patients experienced sustained improvements. Absolute survival to date is 82% for the surgical group and 64% for the medical group. CONCLUSIONS: The improvement seen in volume reduction patients cannot be attributed to the effects of patient selection or preoperative and postoperative rehabilitation.

Aged↗

PubMed1998

Recombinant Kunitz protease inhibitor ameliorates reperfusion injury in rat lung transplantation.

BACKGROUND: Recombinant Kunitz protease inhibitor (rKPI-BG022) is more homologous to human Kunitz protease inhibitor than is aprotinin. Because aprotinin has been reported to inhibit free radicals, we hypothesized that rKPI would ameliorate reperfusion injury caused by free radicals. We examined its effect and the timing of administration in an in vivo rat lung transplantation model. METHODS: All lungs were flushed with low-potassium dextran-1% glucose solution and stored for 24 hours at 4 degrees C, then orthotopic left lung transplantations were performed. Rats were divided into 4 groups (n=6) as follows: group 1 served as control; in Group 2, rKPI was added to the flush solution (10 micromol/L); in group 3, rKPI (5 mg/kg) was administered intravenously to the recipient just after reperfusion; and in group 4, rKPI was added to the flush solution (10 micromol/L) and rKPI (5 mg/kg) was administered intravenously to the recipient just after reperfusion. Twenty-four hours after transplantation, the right main pulmonary artery and right main bronchus were ligated, and the rats were ventilated with 100% O2 for 5 minutes. Peak airway pressure, blood gas analysis, serum lipid peroxide level, tissue myeloperoxidase activity, and wet-dry weight ratio were measured. RESULTS: The partial oxygen tension values of group 2 were higher than those of groups 1 and 4 (groups 1, 2, and 4: 104.8+/-15.8, 245.1+/-49.0, 101.4+/-4.5 mm Hg, respectively; p < 0.01). The partial carbon dioxide tension values of groups 3 and 4 were lower than those of group 1 (groups 1, 3, and 4: 74.5+/-5.7, 42.0+/-11.0, 46.0+/-8.4 mm Hg, respectively; p < 0.05). Peak airway pressures were lower in groups 2 and 3 than in groups 1 and 4 (groups 1, 2, 3, and 4: 22.5+/-0.5, 18.2+/-0.5, 19.2+/-0.8, 22.5+/-1.1 mm Hg; p < 0.01). Serum lipid peroxide levels in groups 2 and 3 were lower than those of groups 1 and 4 (groups 1, 2, 3, and 4: 0.793+/-0.037, 0.577+/-0.069, 0.560+/-0.029, and 0.785+/-0.053 nmol/mL, respectively; groups 2 and 3 vs group 1, and group 3 vs group 4: p < 0.01; group 2 vs group 4: p < 0.05). There were no differences in wet-dry weight ratio and tissue myeloperoxidase activity between the groups. CONCLUSION: Recombinant Kunitz protease inhibitor ameliorates reperfusion injury caused by free radicals in an in vivo rat lung transplantation model. Administration of rKPI through the flush solution and intravenous injection after reperfusion were effective separately, but the combination of the two administrations was not effective.

Animals↗

PubMed1998

Isolated lung liposome-mediated gene transfer produces organ-specific transgenic expression.

BACKGROUND: Gene therapy is a promising strategy for the treatment of inoperable pulmonary tumors and rejection after lung transplantation. However, unlike ex vivo administration, intravenous in vivo transfection lacks organ specificity and has a limited duration of expression. The objectives of this study were to limit transfection to a single lung and to increase the duration of gene expression in vivo. METHODS: Sixteen male Fisher rats were anesthetized and divided into two groups. Animals in group I (n = 7) received an intrajugular administration of 1,320 microg of chloramphenicol acetyl transferase (CAT) complementary DNA complexed with cationic liposomes. Animals in group II (n = 9) received 660 microg of CAT complementary DNA complexed with cationic liposomes into the pulmonary artery of an isolated left lung over 10 minutes. After 40 minutes of incubation, the lung was flushed with 10 mL of normal saline solution, and the perfusate was suctioned through a left pulmonary venotomy. The circulation to the left lung was then restored. After 48 hours, the animals were divided into subgroups (a and b) and CAT activity was assessed in the lungs, hearts, livers, and kidneys of groups Ia (n = 3) and IIa (n = 5). After 21 days, CAT activity was assessed in the left lungs of groups Ib (n = 4) and IIb (n = 4). RESULTS: After 48 hours, animals that had received intravenous administration of CAT cDNA showed strong expression in the lungs and hearts and negligible expression in the livers and kidneys. In contrast, animals in group IIa, which had received isolated left lung perfusion of CAT cDNA showed expression only in the left lung. After 21 days, the left lungs of animals in group Ib, which had received intravenous administration of CAT complementary DNA, showed no CAT expression, but the left lungs of animals in group IIb, which had received isolated left lung perfusion of CAT complementary DNA, exhibited strong CAT expression. CONCLUSIONS: Compared with intravenous administration, isolated lung liposome-mediated gene transfer provides prolonged organ-specific gene expression. This provides a useful model to study the effects of gene therapy on pulmonary tumors, which may have further application when gene therapy is used in clinical practice.

Animals↗

PubMed1998

Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome.

OBJECTIVE: A retrospective analysis was performed to examine the role of HLA antibodies and cytomegalovirus mismatch on the development of bronchiolitis obliterans syndrome and survival after lung transplantation. METHODS: Of 339 consecutive lung transplantations performed over a 102-month interval, 301 patients survived at least 3 months. There was a minimum follow-up period of 13 months. Bronchiolitis obliterans syndrome was defined as a decline in forced expiratory volume in 1 second less than 80% of posttransplantation baseline and/or histologic presence of obliterative bronchiolitis and was defined as occurring "early" if documented within 3 years of transplantation. Variables analyzed included preoperative donor and recipient cytomegalovirus status and the development of antibodies to human leukocyte antigens after transplantation. Microcytotoxicity was used to determine the presence of antibodies to human leukocyte antigens. Variables were subjected to Kaplan-Meier analysis to determine their impact on freedom from bronchiolitis obliterans syndrome and survival. RESULTS: The development of antibodies to human leukocyte antigens after transplantation correlated significantly with bronchiolitis obliterans syndrome (P = .02). The development of antibodies to human leukocyte antigens did not affect survival (P = .33) unless they were detected within 2 years of transplantation (P = .04). There was greater frequency of early bronchiolitis obliterans syndrome in cytomegalovirus seronegative patients who received allografts from seropositive donors compared with all other combinations (P = .02). There was also a trend toward worse survival of cytomegalovirus seronegative patients who received allografts from seropositive donors (P = .13). CONCLUSION: These data suggest that bronchiolitis obliterans syndrome is the result of an immune-mediated process in which HLA antibodies and cytomegalovirus may play a significant role.

Actuarial Analysis↗

PubMed1998

Effect of soluble complement receptor type 1 on reperfusion edema and neutrophil migration after lung allotransplantation in swine.

OBJECTIVE: Soluble complement receptor type 1 inhibits complement activation by blocking C3 and C5 convertases of the classical and alternative pathways. We evaluated the effect of soluble complement receptor type 1 on lung allograft reperfusion injury. METHODS: Left lung transplantation was performed in 13 weight-matched pigs (25 to 31 kg) after prolonged preservation (20 hours at 1 degree C). One hour after reperfusion the recipient contralateral right lung was excluded to assess graft function only. Complement activity and C3a levels were measured after reperfusion and at the end of the assessment. Extravascular lung water index, intrathoracic blood volume, and cardiac output were assessed during a 5-hour observation period. Gas exchange and hemodynamics were monitored. At the end of the 5-hour assessment period, myeloperoxidase assay and bronchoalveolar lavage were performed to assess neutrophil migration, and C5b-9 (membrane attack complex) deposits in the allograft were detected by immunohistochemistry. Two groups were studied. In group II (n = 6) recipient animals were treated with soluble complement receptor type 1 (15 mg/kg) 15 minutes before reperfusion. Group I (n = 7) served as the control group. RESULTS: Serum complement activity was completely inhibited in group II. In contrast to group I, C5b-9 complexes were not detected in group II allograft tissue samples. C3a was reduced to normal levels in group II (p = 0.00005). Extravascular lung water index was higher in group I animals throughout the assessment period (p = 0.035). No significant difference in allograft myeloperoxidase activity (p = 0.10) and polymorphonuclear leukocyte count of the bronchoalveolar lavage fluid (p = 0.057) was detected. CONCLUSION: Inhibition of the complement system by soluble complement receptor type 1 blocks local complement activation in the allograft and reduces posttransplantation reperfusion edema but does not improve hemodynamic parameters.

Animals↗

PubMed1998

Pediatric and adult lung transplantation for cystic fibrosis.

OBJECTIVE: This paper was undertaken to review the experience at our institution with bilateral sequential lung transplantation for cystic fibrosis. METHODS: Since 1989, 103 bilateral sequential lung transplants for cystic fibrosis have been performed (46 pediatric, 48 adult, 9 redo); the mean age was 21 +/- 10 years. Cardiopulmonary bypass was used in all but one pediatric (age <18) transplant, and in 15% of adults. RESULTS: Hospital mortality was 4.9%, with 80% of early deaths related to infection. Bronchial anastomotic complications occurred with equal frequency in the pediatric and the adult populations (7.3%). One- and 3-year actuarial survival are 84% and 61%, respectively (no significant difference between pediatric and adult age groups; average follow-up 2.1 +/- 1.6 years). Mean forced expiratory volume in 1 second increased from 25% +/- 9% before transplantation to 79% +/- 35% 1 year after transplantation. Acute rejection occurred 1.7 times per patient-year, with most episodes taking place within the first 6 months after transplantation. The need for treatment of lower respiratory tract infections occurred 1.2 times per patient in the first year after transplantation. Actuarial freedom from bronchiolitis obliterans was 63% at 2 years and 43% at 3 years. Redo transplantation was performed only in the pediatric population and was associated with an early mortality of 33%. Eight living donor transplants (four primary transplants, four redo transplants) were performed with an early survival of 87.5%. CONCLUSION: Patients with end-stage cystic fibrosis can undergo bilateral lung transplantation with morbidity and mortality comparable to that seen in pulmonary transplantation for other disease entities.

Actuarial Analysis↗

PubMed1998

Lobectomy combined with volume reduction for patients with lung cancer and advanced emphysema.

OBJECTIVE: Early-stage lung cancer is best treated by anatomic pulmonary resection. Patients with lung cancer and severe emphysema are often denied resection or are offered only limited, nonanatomic resections when established pulmonary function criteria for lobectomy are not met. Recently, with the introduction of the volume reduction operation, selected patients with disabling emphysema have undergone excision of approximately 30% of the most destroyed lung tissue and have subsequently demonstrated subjective and objective improvement in pulmonary function. Using these principles, we elected to combine anatomic lobectomy with volume reduction in a select group of patients with both emphysema and lung cancer who would not otherwise be candidates for pulmonary resection. METHODS: Five patients with severe emphysema and suspected or proven lung cancers, who were poor candidates for anatomic lobectomy by traditional criteria but were good candidates for volume reduction, underwent lobectomy combined with volume reduction of one or more additional lobes. RESULTS: All five patients having lung volume reduction and anatomic lobectomy for early-stage primary lung cancer did well postoperatively. Furthermore, each patient has demonstrated subjective and objective improvement in respiratory function on serial postoperative studies. CONCLUSIONS: Selected patients with disabling emphysema and suitable anatomy for volume reduction, who have a lung cancer situated in destroyed lung tissue, may benefit from combined lobectomy and volume reduction. The introduction of the volume reduction operation has added a new factor in the algorithm for the evaluation and treatment of lung cancer in selected patients with advanced emphysema.

Aged↗

PubMed1998

Ex vivo liposome-mediated gene transfer to lung isografts.

OBJECTIVE: Gene therapy is a promising strategy to modify ischemia-reperfusion injury and rejection after transplantation. We evaluated variables that may affect ex vivo gene transfer to rat lung isografts. METHODS: Left lungs were harvested and perfused via the pulmonary vein with chloramphenicol acetyltransferase complementary deoxyribonucleic acid complexed with cationic liposomes. Several variables were examined: (1) Influence of temperature: In group I (n = 4), grafts were stored for 4 hours at 23 degrees C and transplanted. Chloramphenicol acetyltransferase activity was assessed on postoperative day 2. In groups II and III (n = 4), grafts were stored at 10 degrees and 4 degrees C, respectively. Arterial oxygen tension and inflammatory infiltrate were also determined. (2) Influence of storage time: Grafts were preserved at 10 degrees C for 1, 2, 3, 4 (n = 4), and 10 hours (n = 5). chloramphenicol acetyltransferase activity was assessed on postoperative day 2. (3) Rapidity and duration of transgene expression: Grafts were preserved at 10 degrees C for 1 hour and then transplanted. Chloramphenicol acetyltransferase activity was assessed 2, 4, 6, 12, and 24 hours and 2, 7, 14, 21, and 28 days after implantation. RESULTS: Chloramphenicol acetyltransferase expression was apparently less in lungs transfected at 4 degrees C than in those transfected at 10 degrees and 23 degrees C. Storage for 1 hour at 10 degrees C was sufficient to yield significant expression. Increasing the exposure time to 10 hours did not increase toxicity. There were no differences in arterial oxygen tension between transfected and nontransfected lungs. Chloramphenicol acetyltransferase expression was detected for at least 28 days. CONCLUSION: Ex vivo liposome-mediated transfection of lung isografts can be achieved after a short time of cold storage, with minimal toxicity.

Animals↗

PubMed1998

Technical aspects of adult lung transplantation.

This article describes the authors' current technical preferences for the performance of isolated single lung transplantation and bilateral sequential single lung transplantation. The current techniques are the result of lessons learned in the performance of over 400 lung transplant operations at Washington University School of Medicine since 1987.

Adult↗

PubMed1998

Surgeons' concern and practices of protection against bloodborne pathogens.

OBJECTIVE: To evaluate surgeons' concern regarding risk awareness and behavioral methods of protection against bloodborne pathogen transmission during surgery. METHODS: A 29-item questionnaire was sent to 914 surgeons from two universities and two surgical societies. RESULTS: The questionnaire was returned by 768 active surgeons. Slight or moderate concern about contracting human immunodeficiency virus (HIV) was reported by most surgeons; 8% reported extreme concern and 4% reported no concern. In total, 605 surgeons reported having been vaccinated against hepatitis B; surgeons in practice <7 years were most likely to be vaccinated. Most surgeons did not routinely use double gloves: 92 of 768 surgeons reported that they always use double gloves when performing surgery, and 83 reported that they usually use double gloves. There was a statistically significantly higher proportion of surgeons who always or usually use double gloves who also had hepatitis B vaccinations. Most surgeons incorrectly estimated the seroconversion rates with exposure to a patient with HIV (66% incorrect), hepatitis B (88% incorrect), or hepatitis C (84% incorrect). Most surgeons never or rarely report needle-stick injuries, and only 17% always report needle-stick injuries. CONCLUSIONS: Most surgeons underestimate the risk of bloodborne pathogens and do not routinely use double gloves.

Attitude of Health Personnel↗

PubMed1998

Increased expression of HDJ-2 (heat shock protein 40) and heat shock protein 70 in biopsy specimens of transplanted human lungs.

BACKGROUND: Heat shock proteins are expressed during several forms of stress and inflammation. This study was done to determine whether the expression of heat shock protein HDJ-2 (heat shock protein 40), heat shock protein 60, and heat shock protein 70 are increased during rejection in human pulmonary allografts. METHODS: Thirty-five transbronchial biopsy specimens were obtained from adult lung transplant recipients. Histologic analysis and assessment of heat shock protein HDJ-2, heat shock protein 60, and heat shock protein 70 mRNA expression was performed. Total RNA was extracted, reverse transcribed, and amplified by polymerase chain reaction with oligonucleotide primers specific for the heat shock proteins. The identity of the amplified message was verified by Southern blot and slot blot analysis. RESULTS: The expression of heat shock protein HDJ-2 was significantly higher in samples from lung transplant recipients undergoing rejection when compared with recipients without rejection or infection. Heat shock protein 70 expression was also increased in rejection. Expression of heat shock protein 60 did not show any increase in recipients with no evidence of rejection and infection or transplant recipients with rejection or infection. Serial analysis of heat shock protein HDJ-2 and heat shock protein 70 obtained in biopsy specimens during and after rejection showed a decrease of heat shock protein HDJ-2 and heat shock protein 70 expression after resolution of lung rejection. CONCLUSION: Our data demonstrate that the expression of heat shock protein HDJ-2 and heat shock protein 70 increases during lung rejection. However, only heat shock protein HDJ-2 was able to differentiate between rejection and infection. Measurement of heat shock protein HDJ-2 in transbronchial biopsy specimens may assist in the differential diagnosis between rejection and infection in lung transplant recipients.

Carrier Proteins↗

PubMed1998

Vasoactive intestinal peptide ameliorates reperfusion injury in rat lung transplantation.

BACKGROUND: Vasoactive intestinal peptide (VIP) has been reported to have some properties that provide protection from lung injury. Furthermore, its protective effect in cold storage of donor lungs has been confirmed. We examined its effect and the timing of administration in an in vivo rat lung transplantation model. METHODS: All lungs were flushed with low-potassium dextran-1% glucose solution, and orthotopic left lung transplantations were performed. Rats were divided into four groups (n = 6). Group I received no preservation or storage. Groups II, III, and IV grafts were stored for 18 hours at 4 degrees C. Group II received no VIP. Group III received VIP (0.1 g/ml) via the flush solution. Group IV recipients received VIP (3 microg/kg) intravenously just after reperfusion. Twenty-four hours after transplantation, the right main pulmonary artery and right main bronchus were ligated, and the rats were ventilated with 100% O2 for 5 minutes. Mean pulmonary arterial pressure, peak airway pressure, blood gas analysis, serum lipid peroxide level, tissue myeloperoxidase activity, and wet-dry weight ratio were measured. RESULTS: The partial O2 tension values of groups III and IV were better than group II (groups II, III, and IV: 147.4 +/- 71.4, 402.1 +/- 64.8, 373.4 +/- 81.0 mm Hg; p < 0.05). Peak airway pressure was lower in groups III and IV than in group II (groups II, III, and IV: 19.7 +/- 0.8, 16.7 +/- 0.9. and 16.3 +/- 1.0 mm Hg; p < 0.05). Mean pulmonary arterial pressure in group III was lower than group II (groups II and III: 36.3 +/- 3.0 and 22.1 +/- 2.2 mm Hg; p < 0.01). Wet-dry weight ratio in group III was lower than in groups II and IV (group II, III, and IV: 5.2 +/- 0.2, 4.4 +/- 0.2, and 5.2 +/- 0.3; II vs III; p < 0.05, III vs IV; p < 0.01). Serum lipid peroxide levels in groups III and IV were significantly lower (groups II, III, and IV: 2.643 +/- 0.913, 0.455 +/- 0.147, and 0.325 +/- 0.124 nmol/ml; p < 0.01). CONCLUSION: VIP ameliorates reperfusion injury in an in vivo rat lung transplantation model. Either administration of VIP via the flush solution or systemically just after reperfusion was associated with improved pulmonary function.

Airway Resistance↗

PubMed1998

Delayed administration of low-dose NPC18915 ameliorates lung ischemia-reperfusion injury.

BACKGROUND: NPC18915, a member of new antiinflammatory agent called nactins (neutrophil activation inhibitors), has been shown to reduce reperfusion injury in rat lung transplantation at high dosage. In vitro studies have demonstrated effectiveness of this compound even at low dosage. We hypothesized that this compound ameliorates lung ischemia reperfusion injury even at low dosage levels if administration is optimally timed. The aim of this study was to determine the efficacy and the best timing for administration of low-dose NPC18915. METHODS: Forty syngeneic rat left lung transplantations were performed. All isografts were flushed with low-potassium dextran-1% glucose solution 20 ml and preserved for 18 hours at 4 degrees C. Animals were divided into four groups. Group I animals (n = 10) served as control subjects. In groups II (n = 10), III (n = 10), and IV (n = 10), NPC18915 (0.04 mg) was added to the flush solution and was administered intravenously (0.4 mg/kg) immediately before reperfusion (group II) and 60 minutes (group III) and 120 minutes (group IV) after reperfusion. Pulmonary function was assessed 24 hours after reperfusion. RESULTS: In group III, oxygenation improved in comparison to group I (247.2 +/- 59.8 versus 76.6 +/- 16.0 mm Hg, p < 0.002). Wet-to-dry weight ratio and graft myeloperoxidase activity were significantly improved (group III versus group I, 6.02 +/- 0.21 versus 7.19 +/- 0.41, p = 0.013) (group III versus group I, 0.093 +/- 0.019 versus 0.207 +/- 0.023 delta optical density/min/mg, p < 0.002). There were no significant differences in CD11b expression. CONCLUSION: These data suggest that delayed administration of NPC18915, 60 minutes after reperfusion, dramatically improves pulmonary graft function.

Animals↗

PubMed1998

Tacrolimus therapy for persistent or recurrent acute rejection after lung transplantation.

BACKGROUND: Because the severity, frequency, and duration of acute rejection have been linked to the risk of chronic allograft rejection, controlling persistent or recurrent acute rejection is paramount. Tacrolimus has been effective in the management of recalcitrant rejection in other solid organ transplants, and the initial experience in lung transplantation has been favorable. In this study, the impact of changing from a cyclosporine-based to a tacrolimus-based immunosuppressive regimen in lung transplant recipients with persistent or recurrent acute rejection was analyzed. METHODS: The incidence and severity of acute rejection were retrospectively analyzed in 14 lung transplant recipients who were switched from cyclosporine to tacrolimus maintenance immunosuppression because of persistent or recurrent, biopsy-proven acute rejection. RESULTS: Recipients had been treated for acute rejection an average of 2.6 times before changing from cyclosporine to tacrolimus, and 3 recipients had a course of OKT3 therapy. Tacrolimus therapy was begun 238+/-180 days after transplantation, and the mean follow-up period on tacrolimus treatment was 330+/-201 days. After the changeover from cyclosporine to tacrolimus, the number of episodes of acute rejection per recipient decreased (4.3+/-2.1 to 0.4+/-0.5; p=.0001), the average histologic grade of rejection receded (1.3+/-0.4 to 0.3+/-0.4; p=.0001), and the incidence of acute rejection declined (2.4+/-1.5 to 0.1+/-0.3 episodes per 100 patient-days; p=.0001). CONCLUSIONS: Conversion from a cyclosporine- to a tacrolimus-based maintenance immunosuppressive regimen is an effective approach for managing persistent or recurrent allograft rejection after lung transplantation.

Azathioprine↗

PubMed1998

The impact of cytolytic therapy on bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the major cause of morbidity and death after lung transplantation. Therapy has focused on augmented immunosuppression with a variety of agents. Although transient responses are often achieved, sustained remission has been unusual. The outcome of cytolytic therapy for BOS at our center has been analyzed and is reported. METHODS: Between July 1988 and July 1994, 233 patients underwent lung transplantation at Barnes-Jewish Hospital. Among 207 recipients (88.8%) who survived more than 3 months, 81 recipients (39%) had development of BOS; 48 of these patients underwent 64 courses of treatment with a cytolytic agent (antilymphocyte globulin, antithymocyte globulin, or OKT3 monoclonal antibody). The cases of BOS were retrospectively analyzed to determine the impact of cytolytic therapy. RESULTS: The 4-year survival rate was significantly greater in recipients without BOS than in those with BOS (82.8% vs 46.0%; p < .05). Various clinical factors, including diagnosis, forced expiratory volume in 1 second at onset of BOS, presence or absence of pathologically proven bronchiolitis obliterans, type of transplant operation, cytomegalovirus serologic status, and cytomegalovirus pneumonia, were examined, but no significant predictor of survival after the development of BOS was discerned. The mean decrement in forced expiratory volume in 1 second was significantly reduced by cytolytic therapy (-23.5% +/- 2.3% in the 3 months before therapy vs -9.9% +/- 3.5% in the 3 months after the therapy; p < .002). Nevertheless, the stage of BOS progressed over time in spite of therapy in most cases, and only 4 recipients (4.9%) with BOS remained in a lower BOS stage 2 years after treatment. CONCLUSIONS: Recipients with BOS had a significantly lower survival rate than recipients without BOS. No predictor of survival after the onset of BOS was identified. Although cytolytic therapy decreased the rate of decline in pulmonary function in the 3 months after treatment, the stage of BOS ultimately progressed in most patients.

Antilymphocyte Serum↗

PubMed1998

Heat shock pretreatment protects pulmonary isografts from subsequent ischemia-reperfusion injury.

BACKGROUND: Heat shock has been associated with the acquisition of tolerance to a wide variety of stressful conditions, including ischemia. This is partly mediated by the production of various heat shock proteins (HSP), including HSP70. One novel approach to the reduction of ischemia-reperfusion injury after lung transplantation is the induction of HSP70 by heat pretreatment of the donor. The purpose of this study was to investigate the feasibility of this approach in an animal model of lung transplantation. METHODS: Animals were divided into six main groups, with groups I to III representing transplanted animals: In groups I and II, donor animals were anesthetized and then underwent heat stress 6 and 12 hours before organ harvest, respectively. Control animals underwent general anesthesia but no heat stress. After harvest, left lungs from groups I to III were preserved for 18 hours at 40 degrees C and then implanted into isogeneic recipients, which were killed 24 hours after reperfusion to assess graft function. Group IV and V animals underwent heat stress followed by a recovery period of 6 and 12 hours, respectively. Lungs were collected both at the time of harvest (right lungs) and after 18 hours of cold preservation (left lungs). Group VI served as nontransplanted controls. Groups IV to VI did not undergo lung transplantation. RESULTS: At the time of harvest but before implantation, HSP70 was significantly increased in heat-shocked nontransplanted donor lungs (groups IV and V) compared with group VI controls. After 18 hours of cold preservation, HSP70 levels were higher in group IV compared with group V and group VI controls. At 24 hours after reperfusion, mean arterial oxygenation was significantly higher in group I compared with group II and group III controls (290.25+/-24.5 vs 154.5+/-23.9 and 119.6+/-11.3 mm Hg, respectively; P < .001). Myeloperoxidase activity was improved in group I compared with group III controls (0.048+/-0.018 vs 0.137+/-0.036 deltaOD/mg/min, respectively; P < .05). The wet/dry weight ratio was also improved in group I compared with group III controls (6.2+/-0.3 vs. 7.8+/-0.4, respectively; P < .05). CONCLUSIONS: Heat pretreatment of the donor 6 hours before harvest results in increased synthesis of HSP70, which offers a dramatic protective effect against subsequent ischemia-reperfusion injury in the lung isograft.

Animals↗

PubMed1997

Inhibition of inducible nitric oxide synthase ameliorates functional and histological changes of acute lung allograft rejection.

BACKGROUND: We recently demonstrated that inhibition of inducible nitric oxide synthase (iNOS) ameliorated severe acute lung allograft rejection. This study used a rat lung transplant model to determine (1) the time course and cellular localization of iNOS expression during the histological progression of unmodified acute rejection and (2) whether inhibition of iNOS prevented impaired gas exchange function of the allograft lung and/or ameliorated the histological changes of acute rejection. METHODS AND RESULTS: iNOS mRNA and enzyme activity were expressed in allograft lungs during mild, moderate, and severe acute rejection, but not in normal, isograft, or allograft lungs before histological changes of mild acute rejection. iNOS expression in allografts resulted in elevated serum nitrite/nitrate levels, indicative of increased in vivo nitric oxide (NO) production. In situ hybridization demonstrated iNOS mRNA expression in infiltrating inflammatory cells, but not in allograft parenchymal cells. Allografts had significantly impaired gas exchange, which was prevented with the selective iNOS inhibitor aminoguanidine (PaO2 of 566+/-19, 76+/-22, and 504+/-105 mmHg for isograft, allograft, and aminoguanidine-treated allograft, respectively; P<0.0002). Aminoguanidine also significantly improved the histological rejection scores. CONCLUSIONS: (1) iNOS expression and increased NO production occurred during the early stages of acute rejection, persisted throughout the unmodified rejection process, and localized to infiltrating inflammatory cells, but not allograft parenchymal cells; (2) aminoguanidine ameliorated the histological and functional changes of acute rejection; and (3) increased NO production, detected by the presence of iNOS mRNA, protein, or noninvasively by measuring serum nitrite/nitrate levels, may serve as an early marker of acute allograft rejection.

Acute Disease↗