Biomedical subjects

S Keshavjee

Publications and source records attributed to S Keshavjee.

At least 55 records · Page 3Linked to original sources

PubMed2000

Cell death in human lung transplantation: apoptosis induction in human lungs during ischemia and after transplantation.

OBJECTIVE: To examine the presence and extent of apoptosis as well as the affected cell types in human lung tissue before, during, and after transplantation. SUMMARY BACKGROUND DATA: Apoptosis has been described in various human and animal models of ischemia-reperfusion injury, including heart, liver, and kidney, but not in lungs. Therefore, the presence of apoptosis and its role in human lungs after transplantation is not clear. METHODS: Lung tissue biopsies were obtained from 20 consecutive human lungs for transplantation after cold ischemic preservation (1-5 hours), after warm ischemia time (during implantation), and 30, 60, and 120 minutes after graft reperfusion. To detect and quantify apoptosis, fluorescent in situ end labeling of DNA fragments (TUNEL assay) was used. Electron microscopy was performed to verify the morphologic changes consistent with apoptosis and to identify the cell types, which were lost by apoptosis. RESULTS: Almost no evidence of apoptosis was found in specimens after immediate cold and warm ischemic periods. Significant increases in the numbers of cells undergoing apoptosis were observed after graft reperfusion in a time-dependent manner. The mean fraction of apoptotic cells at 30, 60, and 120 minutes after graft reperfusion were 16.6%, 22.1%, and 34.9% of total cells, respectively. Most of the apoptotic cells appeared to be alveolar type II pneumocytes, as confirmed by electron microscopy. CONCLUSIONS: Programmed cell death (apoptosis) appears to be a significant type of cell loss in human lungs after transplantation, and this may contribute to ischemia-reperfusion injury during the early phase of graft reperfusion. This cell loss might be responsible for severe organ dysfunction, which is seen in 20% of patients after lung transplantation. Therefore, this work is of importance to surgeons for the future development of interventions to prevent cell death in transplantation.

Adolescent↗

PubMed2000

Alterations of nitric oxide synthase expression and activity during rat lung transplantation.

Decreased nitric oxide (NO) production has been reported during lung transplantation in patients. To study the effects of ischemia and reperfusion on endogenous NO synthase (NOS) expression, both an ex vivo and an in vivo lung injury model for transplantation were used. Donor rat lungs were flushed with cold low-potassium dextran solution and subjected to either cold (4 degrees C for 12 h) or warm (21 degrees C for 4 h) ischemic preservation followed by reperfusion with an ex vivo model. A significant increase in inducible NOS and a decrease in endothelial NOS mRNA was found after reperfusion. These results were confirmed in a rat single-lung transplant model after warm preservation. Interestingly, protein contents of both inducible NOS and endothelial NOS increased in the transplanted lung after 2 h of reperfusion. However, the total activity of NOS in the transplanted lungs remained at very low levels. We conclude that ischemic lung preservation and reperfusion result in altered NOS gene and protein expression with inhibited NOS activity, which may contribute to the injury of lung transplants.

Animals↗

PubMed2000

NO(+) but not NO radical relaxes airway smooth muscle via cGMP-independent release of internal Ca(2+).

We compared the effects of two redox forms of nitric oxide, NO(+) [liberated by S-nitroso-N-acetyl-penicillamine (SNAP)] and NO. [liberated by 3-morpholinosydnonimine (SIN-1) in the presence of superoxide dismutase], on cytosolic concentration of Ca(2+) ([Ca(2+)](i); single cells) and tone (intact strips) obtained from human main stem bronchi and canine trachealis. SNAP evoked a rise in [Ca(2+)](i) that was unaffected by removing external Ca(2+) but was markedly reduced by depleting the internal Ca(2+) pool using cyclopiazonic acid (10(-5) M). Dithiothreitol (1 mM) also antagonized the Ca(2+) transient as well as the accompanying relaxation. SNAP attenuated responses to 15 and 30 mM KCl but not those to 60 mM KCl, suggesting the involvement of an electromechanical coupling mechanism rather than a direct effect on the contractile apparatus or on Ca(2+) channels. SNAP relaxations were sensitive to charybdotoxin (10(-7) M) or tetraethylammonium (30 mM) but not to 4-aminopyridine (1 mM). Neither SIN-1 nor 8-bromoguanosine 3',5'-cyclic monophosphate had any significant effect on resting [Ca(2+)](i), although both of these agents were able to completely reverse tone evoked by carbachol (10(-7) M). We conclude that NO(+) causes release of internal Ca(2+) in a cGMP-independent fashion, leading to activation of Ca(2+)-dependent K(+) channels and relaxation, whereas NO. relaxes the airways through a cGMP-dependent, Ca(2+)-independent pathway.

4-Aminopyridine↗

PubMed2000

Mechanical stretch stimulates macrophage inflammatory protein-2 secretion from fetal rat lung cells.

Ventilation-induced lung injury has been related to cytokine production. Immaturity and barotrauma are important contributors to the development of bronchopulmonary dysplasia in infants. In the present study, stretch of organotypic cultured fetal rat lung cells was used to simulate ventilation of preterm newborns. Cells were stimulated with lipopolysaccharide (LPS; 100 ng/ml) and/or mechanical stretch. After 4 h, stretch enhanced LPS-induced macrophage inflammatory protein (MIP)-2 production in a force- and frequency-dependent manner. The maximal effect of stretch was seen with 5% elongation at 40 cycles/min. In contrast, after 1 h of stimulation, stretch alone significantly increased MIP-2 production, which was not blocked by cycloheximide, an inhibitor of protein synthesis. At both the 1- and 4-h time points, only LPS increased MIP-2 mRNA levels. Stretch-induced MIP-2 release was associated with cell injury as measured by lactate dehydrogenase release and was not inhibited by gadolinium, a stretch-activated ion channel blocker. Taken together, these results suggest that the major effect of stretch on MIP-2 production from fetal rat lung cells is to stimulate its secretion.

Animals↗

PubMed2000

A novel cell culture model for studying ischemia-reperfusion injury in lung transplantation.

Many cell culture models have been developed to study ischemia-reperfusion injury; however, none is specific to the conditions of lung preservation and transplantation. The objective of this study was to design a cell culture model that mimics clinical lung transplantation, in which preservation is aerobic and hypothermic. A549 cells, a human pulmonary epithelial cell line, were preserved in 100% O(2) at 4 degrees C for varying periods in low-potassium dextran glucose solution, simulating ischemia, followed by the introduction of warm (37 degrees C) DMEM plus 10% fetal bovine serum to simulate reperfusion. Cultures were assayed for cell attachment and viability. Sequential extension of ischemic times to 24 h showed a time-dependent loss of cells. There was a further decrease in cell number after simulated reperfusion. Cell detachment was due mainly to cell death, as determined by cell viability. The effects of chemical components such as dextran 40 and calcium in the preservation solution and various preservation gas mixtures were examined by use of this model system. With its design and validation, this model could be used to study mechanisms related to ischemia-reperfusion injury at the cellular and molecular level.

Cell Adhesion↗

PubMed2000

Targeting the angiotensin system in posttransplant airway obliteration: the antifibrotic effect of angiotensin converting enzyme inhibition.

The angiotensin system plays a role in the pathogenesis of fibrotic diseases. We used a rat heterotopic tracheal transplant model of bronchiolitis obliterans (BO) to examine the role of angiotensin converting enzyme (ACE) in development of the fibroproliferative lesion of BO. Isograft and allograft tracheal transplants were performed. Allograft rats received either no treatment (control) or captopril (100 mg/kg/d) in their drinking water. The drug treatment given to the recipient rats was begun 5 days before transplantation, on postoperative Day 1, or on postoperative Day 5. The treatment was continued until postoperative Day 21, when tracheal specimens were harvested and subjected to histologic, immunohistologic, and morphometric analyses. We noted heavy staining for ACE in the obliterated portion of the tracheas of allograft control animals. This area was not present in nontransplanted or isograft tracheas. Captopril administration begun 5 d before transplantation and on postoperative Day 1 resulted in a significant attenuation in the percent airway obliteration (45% and 26%, respectively) as compared with that in control allografts (83%; p < 0.05). This study demonstrates the presence of ACE in the fibroproliferative lesion in a rat model of BO, and shows that inhibition of ACE can limit development of airway obliteration.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

Dynamic changes in apoptotic and necrotic cell death correlate with severity of ischemia-reperfusion injury in lung transplantation.

Ischemia-reperfusion (IR) injury is a major cause of organ dysfunction following lung transplantation. We have recently described increased apoptosis in transplanted human lungs after graft reperfusion. However, a direct correlation between ischemic time, cell death, and posttransplant lung function has not yet been demonstrated. We hypothesized that an increased ischemic period would lead to an increase in cell death, and that the degree and type of cell death would correlate with lung function. To investigate this, we preserved rat lungs at 4 degrees C for 20 min and 6, 12, 18, and 24 h, and then transplanted the lungs and reperfused them for 2 h. Cell viability was determined with a triple staining technique combining trypan blue, terminal deoxynucleotidyl transferase-uridine nucleotide end-labeling, and propidium iodide nuclear staining. Percentages of apoptotic and necrotic cells were calculated from total cell numbers. Following 20 min and 6 and 12 h of cold preservation, less than 2% of graft cells were dead, whereas after 18 and 24 h of cold preservation, 11% and 27% of cells were dead (p < 0.05), the majority of which were necrotic. After transplantation and reperfusion, the mode of cell death changed significantly. In the 6- and 12-h groups, approximately 30% of cells were apoptotic and < 2% were necrotic, whereas in the 18- and 24-h groups, 21% and 29% of cells, respectively, were necrotic and less than 1% were apoptotic. Lung function (Pa(O(2))) decreased significantly (p < 0.05) with increasing preservation time. The percentage of necrotic cells was inversely correlated with posttransplant graft function (p < 0.0001). The study demonstrates a significant association among cold preservation time, extent and mode of cell death, and posttransplant lung function, and suggests new potential strategies to prevent and treat IR injury.

Animals↗

PubMed2000

RANTES plays an important role in the evolution of allograft transplant-induced fibrous airway obliteration.

Although lung transplantation is a widely applied therapeutic modality for end-stage pulmonary disease, the long-term survival following this procedure is limited by the development of bronchiolitis obliterans (BO). We investigated the role of RANTES, a C-C chemokine, in the evolution of fibrous airway obliteration (FAO) using a rat heterotopic tracheal transplant model. RANTES was highly expressed in infiltrating mononuclear cells in both allogeneic and isogeneic grafts as revealed by immunohistochemistry. Using a miniosmotic pump, neutralizing anti-RANTES antibody was locally and continuously infused to allografts, whereas recombinant rat RANTES was administered to isografts. Anti-RANTES antibody treatment decreased the number of CD4(+) infiltrating cells in allotracheas and preserved luminal patency compared with those of allocontrols. However, RANTES infusion in isografts did not induce FAO, even though CD4(+) cell migration was increased by this treatment. It appears that RANTES is relevant to the recruitment of CD4(+) cells and the development of FAO in the process of allorejection. Local administration of anti-RANTES might be a therapeutic option for BO following lung transplantation.

Animals↗

PubMed2000

Excitatory and inhibitory actions of isoprostanes in human and canine airway smooth muscle.

Isoprostanes are generated nonenzymatically during free radical-mediated lipid peroxidation, and are used clinically and experimentally as markers of oxidative stress. However, their biological effects are poorly understood. We examined the effects of seven different 8-isoprostanes in human and canine airway smooth muscles. In large order airways (carina) of the human, several isoprostanes evoked powerful contractions, with 8-iso-prostaglandin (PG) E(2), 8-iso-PGF(1 alpha), and 8-iso-PGF(2 alpha) being the most efficacious (and with logEC(50) values of 7.0, 5.9, and 6.2 microM, respectively). These contractions were sensitive to the prostanoid TP receptor antagonist ICI 192,605 (0.1-1 microM), but not the EP prostanoid receptor antagonist AH-6809 (50 microM), or the leukotriene receptor antagonists monteleukast or ICI 198,615 (both 1 microM). Qualitatively similar results were obtained in small order human airways (<2 mm o.d.), except that the isoprostanes were generally slightly less potent. None of the isoprostanes had any marked excitatory effect in canine airways. In carbachol-preconstricted tissues (pretreated with ICI 192,605 to block any potential contraction), several isoprostanes completely relaxed canine airways: 8-iso-PGE(1), 8-iso-PGE(2), and 8-iso-PGF(3 alpha) were the most potent, with logIC(50) values of 6.9, 6.9, and 5.7, respectively. Only 8-iso-PGF(3 alpha) relaxed human airways (logIC(50) = 4.9). Our results show that several 8-isoprostanes are highly biologically active in human and canine airways, evoking both excitatory and/or inhibitory effects, and that these effects are compound, species, and tissue dependent.

Animals↗

PubMed1999

Transgene expression after adenovirus-mediated retransfection of rat lungs is increased and prolonged by transplant immunosuppression.

OBJECTIVES: Adenovirus-mediated gene therapy has been proposed as a potential treatment modality in lung transplantation. However, to date its utility has been limited by an inflammatory host immune response that not only limits the amount and duration of transgene expression but also obviates successful retransfection. Having previously shown that by administering triple-immunosuppression, as is routine in lung transplantation, we could increase and prolong transgene expression after initial transfection, we hypothesized that transgene expression after retransfection could also be increased and prolonged. METHODS: Lewis rats underwent intratracheal adenovirus-mediated transfection with the beta-galactosidase gene and were randomized to either the immunosuppression group, receiving daily cyclosporine (INN: ciclosporin), azathioprine, and methylprednisolone, or the control group (no immunosuppression). Five weeks later, rats were similarly retransfected and transgene expression and post-transfection inflammation were evaluated 1, 7, and 14 days after retransfection. RESULTS: After retransfection, immunosuppressed rats had significantly higher levels of transgene expression (P <.001), whereas control rats had virtually no detectable levels. On histologic sections of the lungs, immunosuppressed rats had overall lesser grades of post-transfection inflammation. CONCLUSIONS: Transplant immunosuppression attenuates the severe immune response to gene transfer and permits increased, prolonged, and repeated transfection. Retransfection is now achievable in the immunosuppressed lung transplant setting to allow for chronic, repeated administration of gene therapy.

Adenoviridae↗

PubMed1999

Alveolar recruitment prevents rapid-reperfusion-induced injury of lung transplants.

BACKGROUND: Physical factors play an important role in ischemia-reperfusion-induced injury of lung transplants. For example, rapid restoration of reperfusion resulted in severe pulmonary edema and deterioration of pulmonary function of lung explants in an ex vivo reperfusion system. This type of injury can be prevented by a stepwise increase in the perfusion flow rate, or by adding prostaglandin E1 (PGE1) to the blood perfusate during the first 10 minutes. However, the mechanisms of these protective effects are unknown. We noted a dramatic decrease in airway pressure rather than pulmonary arterial pressure in these studies, suggesting that lung recruitment may be an important factor in minimizing injury. METHODS: In the present study, we examined the importance of alveolar recruitment in preventing rapid-reperfusion-induced lung injury. Rat lungs were flushed preserved with low potassium dextran solution for 12 hours at 4 degrees C. Lung explants were randomly divided into three groups: 1) untreated control; 2) lungs inflated to total lung capacity for 2 minutes; and 3) lungs ventilated for 10 minutes prior to reperfusion. Postpreservation lung function was assessed in an isolated rat lung reperfusion model. RESULTS: Rapid initiation of reperfusion led to severe pulmonary edema and significant pulmonary dysfunction. In inflation or ventilation groups, the injury was significantly attenuated. The PaO2 and shunt fractions in these lungs were comparable to normal lungs. A significant drop in airway pressure was observed in these two groups and the lung compliance in the inflation group was significantly better than other two groups. CONCLUSIONS: These results suggest that overcoming alveolar collapse with inflation or ventilation, may protect the lung from mechanical-stress-induced injury during reperfusion.

Animals↗

PubMed1999

Transtracheal gene transfection of donor lungs prior to organ procurement increases transgene levels at reperfusion and following transplantation.

BACKGROUND: Gene therapy's potential to modify donor organs to better withstand the process of transplantation has yet to be realized. To determine whether gene transfection is feasible to treat the early post-transplant injury of ischemia-reperfusion, we compared transfection of lungs in the donor prior to organ procurement with transfection of harvested ex vivo lungs in a rat single lung transplant model. METHODS: Lewis rats (donor transfection [DT]; n = 4) underwent transtracheal adenoviral-mediated transfection with 10(9) plaque forming unit of the beta-galactosidase reporter gene. Donor lungs were harvested following 6 hours of in vivo post-transfection ventilation, and then preserved for 6 hours at 4 degrees C prior to left single-lung transplantation. Ex vivo transfection was performed following organ retrieval; lungs were then preserved at 4 degrees C for 6 hours (EVT6h; n = 6) and 12 hours (EVT12h; n = 6) prior to transplantation. Lung transgene expression was measured by chemiluminescence at reperfusion, and at 2 hours following lung transplantation. RESULTS: Donor transfection lungs showed significantly higher levels of transgene expression as compared with EVT lungs at the time of reperfusion (DT = 3,408+/-1,301 relative light units/mg protein; EVT6h = 218+/-7; EVT12h = 213+/-26; p < 0.02) and at 2 hours after lung transplantation (DT = 2900+/-870; EVT6h = 62+/-27; EVT12h = 123+/-21; p < 0.005). Transgene expression measured in the heart, liver, kidney, and serum from DT rats demonstrated virtually no evidence of collateral transfection at 12 hours post-transfection (all <5.0). CONCLUSIONS: Gene transfection of donor lungs produces significantly higher levels of transgene expression in lungs at the critical time of reperfusion and in the early period following lung transplantation as compared to ex vivo transfection of cold preserved lungs. Transtracheal donor-lung transfection does not appear to result in collateral transfection of other transplantable organs. Local adenoviral-mediated transfection of the lungs is possible in the multiorgan donor prior to organ procurement and may provide the optimal strategy for gene therapeutic manipulations to address post-transplant ischemia-reperfusion injury.

Animals↗

PubMed1999

Upregulation of T-helper 1 cytokines and chemokine expression in post-transplant airway obliteration.

The major obstacle to long-term survival after lung transplantation is chronic graft dysfunction manifest as bronchiolitis obliterans. Since the early stages are characterized by proliferation of itinerant cells (lymphocytes and macrophages), we hypothesized that cytokines and chemokines may play a role in the development of the fibroproliferative process. In a heterotopic rat tracheal transplant model, we studied isografts and allografts 3, 7, and 21 d after transplantation as representative time points for the triphasic time course in the evolution of allograft airway obliteration. Using a semiquantitative RT-PCR technique, intragraft gene expression of T-helper 1 (Th1)- and Th2-type cytokines and of C-C and C-X-C chemokines was examined. The results of our study show a distinct pattern of cytokine and chemokine gene expression in the development of post-transplant airway obliteration. Allografts, in contrast to isografts, showed a strong and persistent Th1-type response (expression of interleukin-2 and interferon-gamma genes), even after fibrous airway obliteration was complete, suggesting an ongoing allo-immune process until late in the fibroproliferative stage. RANTES and MCP-1 were also upregulated late after transplantation, whereas MIP-2 upregulation occurred early post-transplant and was not restricted to allografts alone, which might reflect alloantigen-independent processes after transplantation that are present in both allografts and isografts.

Animals↗

PubMed1999

Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect.

Several problems limit the application of gene transfer to correct the cystic fibrosis (CF) Cl(-) transport defect in airway epithelia. These include inefficient transduction with vectors applied to the apical surface, a low rate of division by airway epithelial cells, failure of transgene expression to persist, and immune responses to vectors or vector-encoded proteins. To address these issues, we used a feline immunodeficiency virus-based (FIV-based) vector. FIV vector formulated with a calcium chelator transduced fully differentiated, nondividing human airway epithelia when applied to the apical surface. FIV-based vector encoding the cystic fibrosis transmembrane conductance regulator cDNA corrected the Cl(-) transport defect in differentiated CF airway epithelia for the life of the culture (>3 months). When this approach was applied in vivo, FIV vector expressing beta-galactosidase transduced 1-14% of adult rabbit airway epithelia. Transduced cells were present in the conducting airways, bronchioles, and alveoli. Importantly, gene expression persisted, and cells with progenitor capacity were targeted. FIV-based lentiviral vectors may be useful for the treatment of genetic lung diseases such as CF. This article may have been published online in advance of the print edition.

Animals↗

PubMed1998

Distinct regions of frequent loss of heterozygosity of chromosome 5p and 5q in human esophageal cancer.

Loss of heterozygosity (LOH) studies reported thus far suggest that tumor suppressor loci on chromosome 5q are important in esophageal cancer (EC) while little is known about the involvement of chromosome 5p. To investigate the potential existence of tumor suppressor gene(s) on chromosome 5 contributing to the development of EC, we performed LOH studies using a total of 24 polymorphic markers spanning the entire chromosome 5. Seventy primary esophageal cancers were microdissected and allelic deletions were detected by polymerase chain reaction (PCR)-single strand conformation polymorphism or by microsatellite analysis. LOH was observed in at least 1 of the loci in 47 of 70 (67%) esophageal tumors. Initially, 40 tumors [24 squamous cell carcinomas (SCC) and 16 adenocarcinomas (ADC)], each with matched histologically normal esophageal mucosa, were analyzed at 15 marker loci on 5p and 5q. A novel locus, D5S667 on 5p15.2, exhibited the highest frequency of LOH (44%) in these tumors along with another previously reported region of frequent deletion, irf-1 (5q31.1). In a series of 30 additional EC tumors (11 SCC and 19 ADC), a detailed LOH analysis of chromosome 5p15.2 region was conducted using 10 additional polymorphic markers, which mapped the frequently deleted region within 1 cM. Overall, LOH at the D5S667 locus was observed more frequently in SCC than in ADC (62% vs. 23%, p = 0.01). This significant rate of LOH of a distinct region of chromosome 5p implicates the existence of a putative tumor suppressor gene locus involved in EC.

Adenocarcinoma↗

PubMed1998

Adenovirus-mediated interleukin-10 gene transfer inhibits post-transplant fibrous airway obliteration in an animal model of bronchiolitis obliterans.

Bronchiolitis obliterans, a form of chronic allograft rejection characterized by progressive fibrous obliteration of the airways, is the major obstacle limiting prolonged survival of lung transplant recipients. To date, no effective therapy against this fatal complication exists. Interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine, inhibits various T cell and antigen-presenting cell functions. We examined the effect of IL-10 in an animal model for bronchiolitis obliterans. A heterotopic tracheal transplant model was used. IL-10 was administered to the recipient either in its recombinant form by osmotic minipump or by adenoviral-mediated IL-10 gene transfer (Ad5E1mIL-10). Successful gene transfection and expression was confirmed by measuring circulating IL-10 protein. Tracheal allografts were assessed histologically based on a scoring system. IL-10 administration (in recombinant form or by gene transfer) inhibited the development of fibrous airway obliteration 3 weeks after transplantation in comparison to untreated controls (p < 0.05). This was demonstrated only if the delivery was initiated 5 days after transplantation and not if it was started at the time of transplantation. A single administration of the gene construct was sufficient to achieve the desired effect. We have shown that IL-10 can prevent the development of airway fibro-obliteration in this model. Gene transfection at a site distant from a graft can be used to produce a desired effect on the graft. IL-10 may be of major importance in the control of post-transplant bronchiolitis obliterans. The timing of its administration is critical and further studies are required to determine the mechanisms underlying the observed effects of IL-10.

Adenoviruses, Human↗

PubMed1998

Lung transplantation for chronic obstructive pulmonary disease.

Emphysema is the fifth leading cause of death in North America. It is now the most common indication for lung transplantation worldwide. Since 1986, evolution in operative techniques and improvements in organ preservation and post-operative immunosuppression have resulted in impressive long-term survival results. Significant problems remain in terms of inadequate organ supply and chronic rejection; many more candidates could be transplanted if not for these two major limitations. However, other options are now available for the surgical management of patients with end-stage emphysema. The decision making surrounding transplantation for emphysema has been radically altered by the advent of lung volume reduction surgery. This review will highlight new data that pertains to recipient and donor selection, choice of transplant procedure, either single or bilateral, and the role of lung volume reduction surgery. At the University of Toronto we generally favour bilateral lung transplantation for superior functional results and possibly enhanced long-term survival. We have been particularly interested in combining lung transplantation with synchronous lung volume reduction surgery and the rationale and results of this procedure are reviewed.

Female↗

PubMed1998

Exhaled nitric oxide in human lung transplantation. A noninvasive marker of acute rejection.

Acute allograft rejection in animals and humans has been associated with increased nitric oxide production in the graft. Exhaled nitric oxide (ENO) measurement is a noninvasive method of assessing inflammation in airway diseases, e.g., asthma, which might be applicable to lung transplant recipients. Over 12 months, ENO of lower respiratory origin was measured in 108 lung transplant recipients with a mean time after transplant of 1,083 d. ENO (mean +/- SEM; ppb) in stable patients (19.5 +/- 1.1; p < 0.001) was not different from that of healthy controls (23.8 +/- 3.2). ENO was significantly higher in episodes of clinical acute rejection (51.1 +/- 6.3) compared with stable patients but not elevated in bronchiolitis obliterans syndrome (18.6 +/- 1.5) or pulmonary infection (25.9 +/- 4.0). A retrospective analysis of bronchoscopy findings and concurrent ENO (n = 99) showed that ENO did not vary according to histological findings (normal, acute rejection grade I, nonspecific inflammatory change) or with a positive BAL culture. ENO was not correlated with differential lymphocyte and neutrophil counts. ENO appears to be a valid marker of clinical acute rejection in human lung transplantation as distinct from infection or bronchiolitis obliterans. Furthermore, bronchoscopic findings in the absence of a clinical illness were not associated with a rise in ENO.

Adult↗