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Biomedical subjects

Thomas K Waddell

Publications and source records attributed to Thomas K Waddell.

At least 19 recordsLinked to original sources
PubMed2007

Impact of lymph node metastasis on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma.

OBJECTIVES: Extrapleural pneumonectomy is a therapeutic option for selected patients with malignant pleural mesothelioma. The impact of lymph node metastasis on the site of recurrence and the role of mediastinoscopy in the selection of patients for extrapleural pneumonectomy, however, remain unclear. METHODS: We reviewed 50 consecutive patients undergoing extrapleural pneumonectomy for malignant pleural mesothelioma in our institution between January 1993 and March 2005. RESULTS: The median survival was 11 months, with a 3-year survival of 24%. Survival was significantly worse for patients with N2 disease than for those with no lymph node metastasis (median survival 10 months vs 29 months, respectively, P = .005). Patient sex, histologic cell type, stage, and N2 disease, but not mediastinoscopy, had significant impacts on survival according to univariate analysis. In a multivariate analysis, however, only the presence of N2 disease remained a significant predictor of poor outcome. The proportion of patients with N2 disease and the long-term survival was similar regardless of whether preoperative mediastinoscopy yielded a negative result. The initial site of recurrence was determined in 28 patients (locoregional in 10 and distant in 18). The presence of N2 disease had no impact on the site of recurrence. Adjuvant hemithoracic radiation therapy, however, significantly decreased the risk of locoregional recurrence. CONCLUSIONS: The presence of N2 disease negatively affects the prognosis of patients with malignant pleural mesothelioma. Mediastinoscopy, however, seems to have a limited role in patient selection for extrapleural pneumonectomy. Adjuvant hemithoracic radiation therapy but not N2 disease affects the risk of locoregional recurrence.

Adult↗
PubMed2006

Cell-based tissue engineering for lung regeneration.

Emphysema is a chronic lung disease characterized by alveolar enlargement and tissue loss. Tissue engineering represents an attractive potential for regeneration of several organ systems. The complex three-dimensional architectural structure of lung parenchyma requiring connections of alveolar units to airways and the pulmonary circulation makes this strategy less optimistic. In the present study, we used Gelfoam sponge as a scaffold material, supplemented with fetal rat lung cells as progenitors, to explore the potential application of cell-based tissue engineering for lung regeneration in adult rats. After injection into lung parenchyma, the sponge showed porous structures similar to alveolar units. It did not induce severe local inflammatory response. Fetal lung cells in the sponge were able to survive in the adult lung for at least 35 days, determined by CMTMR [5-(and-6)-{[(4-chloromethyl)benzoyl]amino}tetramethylrhodamine] labeling. Proliferation of cells within the sponge was demonstrated in vivo by bromodeoxyuridine (BrdU) labeling. Cells formed "alveolar-like structures" at the border between the sponge and the surrounding lung tissue with positive immunohistochemical staining for epithelial and endothelial cells. Neovascularization of the sponge was demonstrated with India ink perfusion. The sponge degraded after several months. This study suggests that cell-based tissue engineering possesses the potential to regenerate alveolar-like structures, an important step towards our ultimate goal of lung regeneration.

Absorbable Implants↗
PubMed2006

Phospholipase C, calcium, and calmodulin are critical for alpha4beta1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants.

During inflammation, monocytes roll on activated endothelium and arrest after stimulation by proteoglycan-bound chemokines and other chemoattractants. We investigated signaling pathways downstream of G protein-coupled receptors (GPCRs) that are relevant to alpha4beta1 integrin affinity up-regulation using formyl peptide receptor-transfected U937 cells stimulated with fMLP or stromal-derived factor-1alpha and human peripheral blood monocytes stimulated with multiple chemokines or chemoattractants. The up-regulation of soluble LDV peptide or vascular cell adhesion molecule-1 (VCAM-1) binding by these stimuli was critically dependent on activation of phospholipase C (PLC), inositol 1,4,5-triphosphate receptors, increased intracellular calcium, influx of extracellular calcium, and calmodulin, suggesting that this signaling pathway is required for alpha4 integrins to assume a high-affinity conformation. In fact, a rise in intracellular calcium following treatment with thapsigargin or ionomycin was sufficient to induce binding of ligand. Blockade of p44/42 and p38 mitogen-activated protein (MAP) kinases, phosphoinositide 3-kinase, or protein kinase C (PKC) signaling did not inhibit chemoattractant-induced LDV or VCAM-1 binding. However, activation of PKC by phorbol ester up-regulated alpha4beta1 affinity with kinetics distinct from those of GPCR signaling. A critical role for PLC and calmodulin was also established for leukocyte arrest and adhesion strengthening.

Calcium↗
PubMed2006

High-volume ventilation induces pentraxin 3 expression in multiple acute lung injury models in rats.

Pentraxin 3 (PTX3) is an acute-phase protein, which can be produced by a variety of tissue cells at the site of infection or inflammation. It plays an important role in innate immunity in the lung and in mediating acute lung injury. The aim of this study was to determine the effect of mechanical ventilation on PTX3 expression in multiple lung injury models. Male Sprague-Dawley rats were challenged with intravenous injection of lipopolysaccharide (LPS) or hemorrhage followed by resuscitation (HS). The animals were then subjected to either relatively higher (12 ml/kg) or lower (6 ml/kg, positive end-expiratory pressure of 5 cmH(2)O) volume ventilation for 4 h. High-volume ventilation significantly enhanced PTX3 expression in the lung, either alone or in combination with LPS or hemorrhage. A significant increase of PTX3 immunohistochemistry staining in the lung was seen in all injury groups. The PTX3 expression was highly correlated with the severity of lung injury determined by blood gas, lung elastance, and wet-to-dry ratio. To determine the effects of HS, LPS, or injurious ventilation (25 ml/kg) alone on PTX3 expression, another group of rats was studied. Injurious ventilation significantly damaged the lung and increased PTX3 expression. A local expression of PTX3 induced by high-volume ventilation, either alone or in combination with other pathological conditions, suggests that it may be an important mediator in ventilator-induced lung injury.

Acute Disease↗
PubMed2006

Human monocytes recognize porcine endothelium via the interaction of galectin 3 and alpha-GAL.

Monocytes are one of the key inflammatory cells recruited to xenografts and play an important role in delayed xenograft rejection. Previous studies have demonstrated the ability of monocytes to bind to the major xenoantigen Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R; however, the receptor that mediates this interaction has yet to be identified. We provide evidence that it is Galectin-3, a approximately 30-kDa lectin that recognizes beta-galactosides (Gal-beta(1-3/4)GlcNAc) and plays diverse roles in many physiological and pathological events. Human monocyte binding is strikingly increased on porcine aortic endothelial cells (PAEC), which express high levels of Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R, compared with human aortic endothelial cells. Human monocytes obtained from healthy donors bind to Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R at variable intensities. This variation of binding intensity was consistent and reproducible in individual donors. Galectin-3 is mainly expressed in human monocytes, not lymphocytes. Purified Galectin-3 is able to bind directly to Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R. Galectin-3 can also be affinity isolated from monocytes (and not lymphocytes) using an Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R-biotin/streptavidin-bead pull-down system. Soluble Galectin-3 binds preferentially to PAEC vs human aortic endothelial cells, and this binding can be inhibited by lactose, indicating dependence on the carbohydrate recognition domain of Galectin-3. Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R is at least partly responsible for this phenomenon, as binding decreased after digestion of PAEC with alpha-galactosidase. Furthermore, monocytes pretreated with a blocking anti-Galectin-3 Ab show decreased adhesion to PAEC when compared with isotype control in a parallel plate flow chamber perfusion assay. Thus, we conclude that Galectin-3 expressed in human monocytes is a receptor for the major xenoantigen (Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R), expressed on porcine endothelial cells.

Animals↗
PubMed2006

The effect of gender combinations on outcome in human lung transplantation: the International Society of Heart and Lung Transplantation Registry experience.

BACKGROUND: In the current practice of lung transplantation, donor and recipient genders are neither directly considered nor matched. METHODS: We analyzed the potential effect of gender combinations on survival in 9,651 lung transplant recipients in the International Society of Heart and Lung Transplantation Registry (ISHLT) Registry. We compared the risk of overall and 90-day mortality by using statistical models that accounted for confounding variables. RESULTS: A Kaplan-Meier survival analysis revealed a significant difference of survival among gender combinations (log rank, p = 0.0009). The unadjusted odds ratio (OR) of 90-day mortality was significantly higher in female (F) donors to male (M) recipients (OR, 1.58; 95% confidence interval (CI), 1.22-2.04; p < 0.001) and lower in F to F (OR, 0.742; 95% CI, 0.61-0.90; p = 0.004) compared with the reference category of M to M. After adjusting for size mismatch and diagnosis in the multivariate logistic regression model, the OR of F to M was still statistically significant (F to M OR, 1.52l; 95% CI, 1.04-2.20; p = 0.028; F to F OR, 0.67; 95% CI, 0.53-0.91; p = 0.008) for 90-day mortality. A Cox proportional hazards analysis for overall survival also showed a significantly higher hazard ratio of 1.12 in F to M (95% CI, 1.01-1.23) and a lower hazard ratio of 0.92 in F to F (95% CI, 0.87-0.98). CONCLUSION: ISHLT Lung Transplant Registry data demonstrated a significant risk for F to M. Interestingly, F to F appears to be potentially beneficial in lung transplantation. Gender combinations do appear to significantly impact outcome after lung transplantation.

Adult↗
PubMed2006

Surgery for small-cell lung cancer.

Treatment of small-cell lung cancer (SCLC) is typically chemotherapy with or without radiation, depending on the extent of disease. There are several situations where surgery may have a role to play. Patients with clinical stage T1-2 N0 SCLC may benefit from surgery for confirmation of diagnosis and improved local control when combined with chemotherapy. Surgery itself rarely contributes to prolonged survival for N2 SCLC. In this view, mediastinoscopy is recommended to exclude N2 disease before surgery is considered. Patients with a combined histology tumor (mixtures of SCLC with non-SCLC components) may be offered surgery since the non-SCLC component is less sensitive to chemotherapy and resection may contribute to cure. Salvage surgery should be considered for patients having relapse only in the primary site or a localized chemotherapy-resistant tumor, which can occur because of an unrecognized mixed tumor. Recent evidence has shown that platinum-based chemotherapy with concurrent hyperfractionated radiotherapy followed by surgery is feasible and a promising strategy for highly selected patients with SCLC. Among patients with nodal disease, only those with negative nodes following induction chemo/chemoradiotherapy should be candidates for surgery, which may offer improved local control. Further evidence for this strategy will be obtained from ongoing randomized clinical trials.

Carcinoma, Small Cell↗
PubMed2006

Up-regulation of functional CXCR4 expression on human lymphocytes in sepsis.

OBJECTIVE: Lymphocyte dysfunction has been documented in sepsis, and evidence suggests that lymphocyte infiltration contributes to tissue injury. The purpose of this study was to examine chemokine receptor expression and function in lymphocytes from septic patients and healthy donors. DESIGN: Observational study of septic patients and laboratory investigation of normal controls. SETTING: Tertiary care intensive care unit. PATIENTS AND SUBJECTS: Nine critically ill patients fulfilling criteria for the systemic inflammatory response syndrome and with a Sepsis Score of >/=3 were included in this study. Lymphocytes were also obtained from healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The total number of circulating leukocytes in septic patients was markedly increased; however, lymphocyte counts were decreased. Chemokine receptor expression on lymphocytes was examined by flow cytometry. CXCR4 expression on lymphocytes from septic patients was increased whereas CCR5 was decreased and CCR7 was unchanged. Lipopolysaccharide stimulation of normal lymphocytes increased CXCR4 expression but decreased CCR5 and did not change CCR7 expression. This lipopolysaccharide-stimulated CXCR4 expression required 20 hrs of stimulation and was accompanied by increased messenger RNA. Lymphocytes from septic patients or after lipopolysaccharide treatment demonstrated enhanced actin polymerization and migration in response to CXCL12. Taken together, sepsis and lipopolysaccharide up-regulated CXCR4 expression and enhanced lymphocyte activation and migration in response to CXCL12. CONCLUSIONS: Blocking CXCR4 and CXCL12 function may provide a novel therapeutic method for controlling systemic inflammation and tissue injury in sepsis.

Actins↗
PubMed2006

The early responses of VEGF and its receptors during acute lung injury: implication of VEGF in alveolar epithelial cell survival.

INTRODUCTION: The function of the vascular endothelial growth factor (VEGF) system in acute lung injury (ALI) is controversial. We hypothesized that the role of VEGF in ALI may depend upon the stages of pathogenesis of ALI. METHODS: To determine the responses of VEGF and its receptors during the early onset of ALI, C57BL6 mice were subjected to intestinal ischemia or sham operation for 30 minutes followed by intestinal ischemia-reperfusion (IIR) for four hours under low tidal volume ventilation with 100% oxygen. The severity of lung injury, expression of VEGF and its receptors were assessed. To further determine the role of VEGF and its type I receptor in lung epithelial cell survival, human lung epithelial A549 cells were treated with small interference RNA (siRNA) to selectively silence related genes. RESULTS: IIR-induced ALI featured interstitial inflammation, enhancement of pulmonary vascular permeability, increase of total cells and neutrophils in the bronchoalveolar lavage (BAL), and alveolar epithelial cell death. In the BAL, VEGF was significantly increased in both sham and IIR groups, while the VEGF and VEGF receptor (VEGFR)-1 in the lung tissues were significantly reduced in these two groups. The increase of VEGF in the BAL was correlated with the total protein concentration and cell count. Significant negative correlations were observed between the number of VEGF or VEGFR-1 positive cells, and epithelial cells undergoing cell death. When human lung epithelial A549 cells were pre-treated with 50 nM of siRNA either against VEGF or VEGFR-1 for 24 hours, reduced VEGF and VEGFR-1 levels were associated with reduced cell viability. CONCLUSION: These results suggest that VEGF may have dual roles in ALI: early release of VEGF may increase pulmonary vascular permeability; reduced expression of VEGF and VEGFR-1 in lung tissue may contribute to the death of alveolar epithelial cells.

Animals↗
PubMed2005

Donor lymphocyte infusion induces long-term donor-specific cardiac xenograft survival through activation of recipient double-negative regulatory T cells.

Previous studies have shown that pretransplant donor lymphocyte infusion (DLI) can enhance xenograft survival. However, the mechanism by which DLI induces xenograft survival remains obscure. Using T cell subset-deficient mice as recipients we show that CD4+, but not CD8+, T cells are necessary to mediate the rejection of concordant cardiac xenografts. Adoptive transfer of naive CD4+ T cells induces rejection of accepted cardiac xenografts in CD4-/- mice. This rejection can be prevented by pretransplant DLI in the absence of any other treatment. Furthermore, we demonstrate that DLI activates alphabeta-TCR+CD3+CD4-CD8- double-negative (DN) regulatory T (Treg) cells in xenograft recipients, and that DLI-activated DN Treg cells can inhibit the proliferation of donor-specific xenoreactive CD4+ T cells in vitro. More importantly, adoptive transfer of DLI-activated DN Treg cells from xenograft recipients can suppress the proliferation of xenoreactive CD4+ T cells and their ability to produce IL-2 and IFN-gamma in vivo. Adoptive transfer of DLI-activated DN Treg cells also prevents CD4+ T cell-mediated cardiac xenograft rejection in an Ag-specific fashion. These data provide direct evidence that DLI can activate recipient DN Treg cells, which can induce donor-specific long-term cardiac xenograft survival by suppressing the proliferation and function of donor-specific CD4+ T cells in vivo.

Adoptive Transfer↗
PubMed2005

Targeted deletion of Fgl-2/fibroleukin in the donor modulates immunologic response and acute vascular rejection in cardiac xenografts.

BACKGROUND: Xenografts ultimately fail as a result of acute vascular rejection (AVR), a process characterized by intravascular thrombosis, fibrin deposition, and endothelial cell activation. METHODS AND RESULTS: We studied whether targeted deletion of Fgl-2, an inducible endothelial cell procoagulant, (Fgl-2-/-) in the donor prevents AVR in a mouse-to-rat cardiac xenotransplantation model. By 3 days after transplant, Fgl-2+/+ grafts developed typical features of AVR associated with increased levels of donor Fgl-2 mRNA. Grafts from Fgl-2-/- mice had reduced fibrin deposition but developed cellular rejection. Treatment with a short course of cobra venom factor and maintenance cyclosporine resulted in long-term acceptance of both Fgl-2+/+ and Fgl-2-/- grafts. On withdrawal of cyclosporine, Fgl-2+/+ grafts developed features of AVR; in contrast, Fgl-2-/- grafts again developed acute cellular rejection. Rejecting Fgl-2+/+ hearts stained positively for IgG, IgM, C3, and C5b-9, whereas rejecting Fgl-2-/- hearts had minimal Ig and complement deposition despite xenoantibodies in the serum. Furthermore, serum containing xenoantibodies failed to stain Fgl-2-/- long-term treated hearts but did stain wild-type heart tissues. Treatment of Fgl-2-/- xenografts with mycophenolate mofetil and tacrolimus, a clinically relevant immune suppression protocol, led to long-term graft acceptance. CONCLUSIONS: Deletion of Fgl-2 ameliorates AVR by downregulation of xenoantigens and may facilitate successful clinical heart xenotransplantation.

Animals↗
PubMed2005

Monocyte adhesion to xenogeneic endothelium during laminar flow is dependent on alpha-Gal-mediated monocyte activation.

Monocytes are the predominant inflammatory cell recruited to xenografts and participate in delayed xenograft rejection. In contrast to allogeneic leukocytes that require up-regulation of endothelial adhesion molecules to adhere and emigrate into effector tissues, we demonstrate that human monocytes adhere rapidly to unstimulated xenogeneic endothelial cells. The major xenoantigen galactosealpha(1,3)galactosebeta(1,4)GlcNAc-R (alpha-gal) is abundantly expressed on xenogeneic endothelium. We have identified a putative receptor for alpha-gal on human monocytes that is a member of the C-type family of lectin receptors. Monocyte arrest under physiological flow conditions is regulated by alpha-gal, because cleavage or blockade results in a dramatic reduction in monocyte adhesion. Recruitment of human monocytes to unactivated xenogeneic endothelial cells requires both alpha(4) and beta(2) integrins on the monocyte; binding of alpha-gal to monocytes results in rapid activation of beta(2), but not alpha(4), integrins. Thus, activation of monocyte beta(2) integrins by alpha-gal expressed on xenogeneic endothelium provides a mechanism that may explain the dramatic accumulation of monocytes in vivo.

Animals↗
PubMed2005

Risk of a right pneumonectomy: role of bronchopleural fistula.

BACKGROUND: The purpose of this study is to compare the morbidity and mortality of right versus left pneumonectomy. METHODS: We used a retrospective review of pneumonectomies performed during the period 1990 to 2000 and included a meta-analysis of relevant literature. RESULTS: There were 187 pneumonectomies: 68 right, 119 left. The primary study end point was in-hospital death. There were 11 deaths: 7 (10.3%) right, 4 (3.3%) left (p = 0.10). Six deaths were attributable to bronchopleural fistula and its subsequent complications. The risk of bronchopleural fistula was higher on the right (9 [13.2%]) versus left (6 [5.0%]; p = 0.0472), as was the mortality associated with bronchopleural fistula (4 of 9 [44%] right versus 2 of 6 [33%] left). Right pneumonectomies were more likely to require an intrapericardial or extended dissection (p = 0.003), hand-sewn bronchial closure (p < 0.0001), or the closure buttressed (p < 0.0001). By univariate analysis, factors associated with an increased mortality were bronchopleural fistula (p < 0.0001), hand-sewn closure (p = 0.001), and a history of smoking (p = 0.01). By multivariate analysis, the most important factor was bronchopleural fistula (odds ratio, 43.3; 95% confidence limits, 4.2 to 441.9; p = 0.002). A meta-analysis combining our results with those from the literature found increased mortality of right pneumonectomy with a relative risk of 3.39 (95% confidence limits, 2.10 to 5.48; p < 0.00001). CONCLUSIONS: Right pneumonectomy is associated with a higher mortality even in the absence of induction therapy. This is primarily related to the increased risk of bronchopleural fistula on the right. The increased number of bronchopleural fistulas on the right may be attributable to more extensive resection. Addressing technical factors that contribute to early bronchopleural fistula may reduce the mortality of right pneumonectomy.

Adult↗
PubMed2005

Prevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplant.

BACKGROUND: Aspiration secondary to gastroesophageal reflux has been postulated to be a contributing factor in bronchiolitis obliterans after lung transplantation. It is not clear whether gastroesophageal reflux is a preexisting condition or secondary to intraoperative vagal injury or drug-induced prolonged gastric emptying. METHODS: The prevalence of gastroesophageal reflux was examined in 78 consecutive end-stage lung disease patients assessed for lung transplantation: emphysema, 21; cystic fibrosis, 5; idiopathic pulmonary fibrosis, 26; scleroderma, 10; and miscellaneous diseases, 16. All underwent esophageal manometry. Two-channel esophageal 24-hour pH testing was completed in 76 patients. Gastric emptying studies were conducted in 36 patients. RESULTS: Typical gastroesophageal reflux symptoms were documented in 63% of patients. The lower esophageal sphincter was hypotensive in 72% of patients, and 33% had esophageal body dysmotility. Prolonged gastric emptying was documented in 44%, and 38% had abnormal pH testing. The overall DeMeester score was above normal in 32% of patients, and 20% had abnormal proximal pH probe readings. CONCLUSIONS: Gastroesophageal reflux is highly prevalent in end-stage lung disease patients who are candidates for lung transplantation. Further investigation is needed to study the prevalence of gastroesophageal reflux after lung transplantation and its contribution to chronic allograft dysfunction.

Adult↗
PubMed2005

Pre-transplant panel reactive antibody in lung transplant recipients is associated with significantly worse post-transplant survival in a multicenter study.

BACKGROUND: The presence of antibodies to human leukocyte antigens (HLA) prior to transplantation has been linked to worse post-transplant outcomes in many solid organ transplants. The effect of these antibodies is less clear in lung transplant recipients, although previous studies have suggested an increased incidence of allograft dysfunction. METHODS: A retrospective study of all first lung transplant recipients from the University of Toronto (November 1983-July 2001, n = 380) and Duke University (April 1992-June 2000, n = 276) was performed. Demographic data, survival information, and level of last pre-transplant panel reactive antibody (PRA) were collected. PRA level was measured by the complement-dependent cell cytotoxicity assay at both centers. Survival analysis was performed using the Kaplan-Meier method, and groups were compared with the Wilcoxon rank sum test. RESULTS: Of 656 lung transplant recipients, 101 (15.4%) had a PRA greater than 0, 37 (5.6%) had a PRA greater than 10%, and 20 (3.0%) had a PRA greater than 25%. Patients with a PRA greater than 25% had decreased median survival than did the rest of the patients (1.5 vs 5.2 years) and at 1 month (70% vs 90%), 1 year (65% vs 76%), and 5 years (31% vs 50%), respectively (p = 0.006, Wilcoxon's rank sum test) test). CONCLUSION: Significant elevation of PRA prior to lung transplantation is associated with worse survival, especially in the early post-transplant period. This may be due to a direct effect of anti-HLA antibodies on the allograft. The effectiveness of treatments such as plasmapheresis and intravenous immunoglobulin prior to transplantation needs to be evaluated.

Adult↗
PubMed2005

Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation.

BACKGROUND: Lung transplantation is an established treatment modality for a number of chronic lung diseases. Long-term survival after lung transplantation is limited by chronic allograft dysfunction, usually manifested by bronchiolitis obliterans syndrome. We describe a case series with upper lobe fibrosis, a novel presentation of chronic allograft dysfunction. METHODS: We reviewed lung transplants at the Toronto General Hospital and Duke University Hospital from 1990 to 2002 and identified patients with upper lobe fibrosis. RESULTS: Thirteen of 686 patients (6 women) developed upper lobe fibrosis (Toronto, 9; Duke, 4); 12 of 13 had bilateral transplants. The median age at diagnosis was 42 years (range, 19-70). Primary diagnoses were cystic fibrosis, 6; emphysema, 4; sarcoidosis, 1; and pulmonary fibrosis, 2 patients. Radiographic diagnosis was made at a median of 700 days post-transplant (range, 150-2,920). Pulmonary function tests demonstrated predominantly a progressively worsening restrictive pattern. Open lung biopsy specimens revealed dense interstitial fibrosis, with occasional features of obliterative bronchitis, bronchiolitis obliterans obstructive pneumonia, and aspiration. Nine patients died at a median follow-up of 2,310 days (range, 266-3,740), 8 due to respiratory failure. CONCLUSION: Upper lobe fibrosis is a novel presentation of chronic allograft dysfunction in lung transplant recipients and is differentiated from bronchiolitis obliterans syndrome on the basis of physiologic and radiologic findings.

Adult↗
PubMed2005

Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation.

BACKGROUND: Aspiration of gastroesophageal refluxate may contribute to lung transplant bronchiolitis obliterans syndrome (BOS). We investigated bile acids in bronchoalveolar lavage fluid (BALF) and studied its role in BOS. MATERIALS AND METHODS: Surveillance pulmonary function tests and BALF were evaluated in 120 lung recipients. BOS-(0p-3) was diagnosed after 6 months' survival. BOS was defined as "early" if diagnosed within 12 months after a transplant. BALF was assayed for differential cell count, bile acids, and interleukins 8 and 15. Bile acids were considered elevated if greater than normal serum levels ( or =8 micromol/L). RESULTS: Elevated BALF bile acids were measured in 20 (17%) of 120 patients. BOS was diagnosed in 36 (34%) of 107 patients and judged "early" in 21 (57%) of 36. Median BALF bile acid values were 1.6 micromol/L (range, 0-32 micromol/L) in BOS patients and 0.3 micromol/L (range, 0-16 micromol/L) in non-BOS patients ( P = .002); 2.6 micromol/L (range, 0-32 micromol/L) in early BOS patients and 0.8 micromol/L (range, 0-4.6 micromol/L) in late BOS patients, ( P = .02). Bile acids correlated with BALF IL-8 and alveolar neutrophilia (r = 0.3, P = .0004, and r = 0.3, P = .004, respectively), but not with IL-15. Freedom from BOS was significantly shortened in patients with elevated BALF bile acids (Cox-Mantel test, P = .0001). CONCLUSIONS: Aspiration of duodenogastroesophageal refluxate is prevalent after lung transplantation and is associated with the development of BOS. Elevated BALF bile acids may promote early BOS development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia.

Actuarial Analysis↗