ABSTRACT
Transplantation of any organ into a recipient requires a donor. Lung transplant has a long history of an inadequate number of suitable donors to meet demand, leading to deaths on the waiting list annually since national data was collected, and strict listing criteria. Before the Uniform Determination of Death Act (UDDA), passed in 1980, legally defined brain death in the U.S., all donors for lung transplant came from sudden death victims [uncontrolled Donation after Circulatory Death donors (uDCDs)] in the recipient's hospital emergency department. After passage of the UDDA, uDCDs were abandoned to Donation after Brain Death donors (DBDs)-perhaps prematurely. Compared to livers and kidneys, many DBDs have lungs that are unsuitable for transplant, due to aspiration pneumonia, neurogenic pulmonary edema, trauma, and the effects of brain death on lung function. Another group of donors has become available-patients with a devastating irrecoverable brain injury that do not meet criteria for brain death. If a decision is made by next-of-kin (NOK) to withdraw life support and allow death to occur by asphyxiation, with NOK consent, these individuals can have organs recovered if death occurs relatively quickly after cessation of mechanical ventilation and maintenance of their airway. These are known as controlled Donation after Circulatory Death donors (cDCDs). For a variety of reasons, in the U.S., lungs are recovered from cDCDs at a much lower rate than kidneys and livers. Ex-vivo lung perfusion (EVLP) in the last decade has had a modest impact on increasing the number of lungs for transplant from DBDs, but may have had a larger impact on lungs from cDCDs, and may be indispensable for safe transplantation of lungs from uDCDs. In the next decade, DCDs may have a substantial impact on the number of lung transplants performed in the U.S. and around the world.
ABSTRACT
PURPOSE OF REVIEW: In this review, we discuss the current state of donation after circulatory death (DCD). We define the DCD donor and describe the current protocols in management of the DCD patient. We then discuss current techniques in organ procurement of the lung and abdominal organs. RECENT FINDINGS: Although donation after brain death is preferable to DCD, recent data have demonstrated acceptable early outcomes in both thoracic and abdominal organ transplant. In spite of advancements in surgical techniques and organ preservation, much has yet to be learned to minimize warm ischemia time and reperfusion injury in the DCD population. SUMMARY: In light of the continually growing disparity between organ supply and demand, DCD has regained traction as a means to increase the donor pool.
Subject(s)
Organ Preservation/methods , Tissue and Organ Procurement , Blood Circulation Time , Heart Arrest , Humans , Reperfusion Injury , Tissue Donors , Warm IschemiaABSTRACT
Lung transplantation is the only established therapeutic option for several end-stage respiratory diseases. Limited mostly by lack of suitable allografts, the results have measurably improved over the last decade. Numerous surgical and pharmaceutical improvements have had positive impact on outcomes. The potential for critical care issues and the need for interdisciplinary management remains paramount. Cardiac, renal, and metabolic complications are frequently encountered in the acute postoperative phase. Allograft rejection and infectious diseases as well as problems related to immunosuppressive regimen are seen later after lung transplantation. Neurologic manifestations with a range of etiologies are discussed here in this context.
Subject(s)
Lung Transplantation/adverse effects , Nervous System Diseases/etiology , Postoperative Complications/physiopathology , Graft Rejection , Immunosuppressive Agents/therapeutic use , Lung Transplantation/methods , Lung Transplantation/psychology , Nervous System Diseases/physiopathology , Nervous System Diseases/psychology , Patient Selection , Tissue and Organ Procurement , Treatment OutcomeSubject(s)
Bland White Garland Syndrome/diagnosis , Pulmonary Artery/abnormalities , Vascular Neoplasms/diagnosis , Adult , Bland White Garland Syndrome/surgery , Blood Vessel Prosthesis Implantation , Cardiac Surgical Procedures , Diagnosis, Differential , Diagnostic Errors , Female , Humans , Predictive Value of Tests , Pulmonary Artery/diagnostic imaging , Pulmonary Artery/surgery , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
BACKGROUND: Aspiration of gastroesophageal refluxate has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the progression of bronchiolitis obliterans syndrome after lung transplantation. The goals of the present study were to identify lung transplant patients at the greatest risk of aspiration and to investigate the causative factors. MATERIALS AND METHODS: From September 2009 to November 2011, 252 bronchoalveolar lavage fluid (BALF) samples were collected from 100 lung transplant patients. The BALF pepsin concentrations and the results of transbronchial biopsy, esophageal function testing, barium swallow, and gastric emptying scan were compared among those with the most common end-stage lung diseases requiring lung transplantation: IPF, chronic obstructive pulmonary disease, cystic fibrosis, and α1-antitrypsin deficiency. RESULTS: Patients with IPF had higher BALF pepsin concentrations and a greater frequency of acute rejection than those with α1-antitrypsin deficiency, cystic fibrosis, or chronic obstructive pulmonary disease (P = 0.037). Moreover, the BALF pepsin concentrations correlated negatively with a lower esophageal sphincter pressure and distal esophageal amplitude; negatively with distal esophageal amplitude and positively with total esophageal acid time, longest reflux episode, and DeMeester score in those with chronic obstructive pulmonary disease; and negatively with the upright acid clearance time in those with IPF. CONCLUSIONS: Our results suggest that patients with IPF after lung transplantation are at increased risk of aspiration and a greater frequency of acute rejection episodes, and that the risk factors for aspiration might be different among those with the most common end-stage lung diseases who have undergone lung transplantation. These results support the role of evaluating the BALF for markers of aspiration in assessing lung transplant patients as candidates for antireflux surgery.
Subject(s)
Bronchoalveolar Lavage Fluid/chemistry , Idiopathic Pulmonary Fibrosis/etiology , Idiopathic Pulmonary Fibrosis/metabolism , Lung Transplantation/adverse effects , Pepsin A/metabolism , Bronchiolitis Obliterans/epidemiology , Bronchiolitis Obliterans/etiology , Bronchiolitis Obliterans/metabolism , Female , Gastroesophageal Reflux/epidemiology , Gastroesophageal Reflux/etiology , Gastroesophageal Reflux/metabolism , Humans , Hydrogen-Ion Concentration , Idiopathic Pulmonary Fibrosis/epidemiology , Male , Manometry , Middle Aged , Pepsin A/analysis , Pneumonia, Aspiration/epidemiology , Pneumonia, Aspiration/etiology , Pneumonia, Aspiration/metabolism , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/metabolism , Risk FactorsABSTRACT
BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.
Subject(s)
Cytomegalovirus Infections/epidemiology , Cytomegalovirus Infections/prevention & control , Immunosuppressive Agents/therapeutic use , Lung Transplantation , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Sirolimus/therapeutic use , Female , Humans , Incidence , Male , Middle Aged , Prospective StudiesABSTRACT
Tumors that develop in lymphangioleiomyomatosis (LAM) as a consequence of biallelic loss of TSC1 or TSC2 gene function express melanoma differentiation antigens. However, the percentage of LAM cells expressing these melanosomal antigens is limited. Here, we report the overexpression of ganglioside D3 (GD3) in LAM. GD3 is a tumor-associated antigen otherwise found in melanoma and neuroendocrine tumors; normal expression is largely restricted to neuronal cells in the brain. We also observed markedly reduced serum antibody titers to GD3, which may allow for a population of GD3-expressing LAM cells to expand within patients. This is supported by the demonstrated sensitivity of cultured LAM cells to complement mediated cytotoxicity via GD3 antibodies. GD3 can serve as a natural killer T (NKT) cell antigen when presented on CD1d molecules expressed on professional antigen-presenting cells. Although CD1d-expressing monocyte derivatives were present in situ, enhanced NKT-cell recruitment to LAM lung was not observed. Cultured LAM cells retained surface expression of GD3 over several passages and also expressed CD1d, implying that infiltrating NKT cells can be directly cytotoxic toward LAM lung lesions. Immunization with antibodies to GD3 may thus be therapeutic in LAM, and enhancement of existing NKT-cell infiltration may be effective to further improve antitumor responses. Overall, we hereby establish GD3 as a suitable target for immunotherapy of LAM.
Subject(s)
Biomarkers, Tumor/metabolism , Gangliosides/metabolism , Lung Neoplasms/metabolism , Lymphangioleiomyomatosis/metabolism , Animals , Antigens, CD1d/metabolism , Biomarkers, Tumor/immunology , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Gangliosides/immunology , Humans , Lung/immunology , Lung/metabolism , Lung/pathology , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lymphangioleiomyomatosis/immunology , Lymphangioleiomyomatosis/pathology , Mice , Natural Killer T-Cells/metabolism , Tumor Cells, CulturedABSTRACT
BACKGROUND: Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. METHODS: We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients. RESULTS: A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection. CONCLUSIONS: These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.
Subject(s)
Biopsy/methods , Graft Rejection/diagnosis , Lung Transplantation/pathology , Lung/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Bronchoscopy , Female , Graft Rejection/pathology , Humans , Immunosuppression Therapy/methods , Male , Middle Aged , Observer Variation , Prospective Studies , United StatesABSTRACT
IL-2 is a growth factor for activated T cells and is required for maintenance of naturally arising regulatory T cells (nTregs). Mice defective in IL-2/IL-2 receptor signaling pathways have impaired nTregs and suffer from lymphoproliferative disorders, suggesting that IL-2 is present and functional in healthy animals. However, the cellular source of IL-2 is currently unknown. To determine which cells produce IL-2 in healthy animals, we established mice carrying cre gene knock in at the il-2 locus (termed IL-2(cre)). When IL-2(cre) mice were crossed with EGFP reporter mice, EGFP was exclusively expressed by a fraction of CD4 T cells present in both lymphoid and non-lymphoid tissues. Live imaging of IL-2(cre) mice that carry the luciferase reporter showed concentrated localization of luciferase(+) cells in Peyer's patches. These cells were not observed in new born mice but appeared within 3days after birth. Reduction of antigen receptor repertoire by transgene expression reduced their number, indicating that recognition of environmental antigens is necessary for generation of these IL-2 producers in healthy animals. A substantial fraction of EGFP(+) cells also produce IL-10 and IFN-γ, a characteristic profile of type 1 regulatory T cells (Tr1). The data suggest that a group of Tr1 cells have addition roles in immune homeostasis by producing IL-2 along with other cytokines and help maintaining Tregs.
Subject(s)
Health , Interleukin-2/biosynthesis , T-Lymphocytes, Regulatory/cytology , Aging/immunology , Animals , Antigens, Surface/metabolism , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation , Gene Knock-In Techniques , Green Fluorescent Proteins/metabolism , Homologous Recombination/genetics , Integrases/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes, Regulatory/metabolism , Th1 Cells/cytology , Th2 Cells/cytologyABSTRACT
The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphoid organs called milky spots. The omentum has been used for its healing potential for over 100 years by transposing the omental pedicle to injured organs (omental transposition), but the mechanism by which omentum helps the healing process of damaged tissues is not well understood. Omental transposition promotes expansion of pancreatic islets, hepatocytes, embryonic kidney, and neurons. Omental cells (OCs) can be activated by foreign bodies in vivo. Once activated, they become a rich source for growth factors and express pluripotent stem cell markers. Moreover, OCs become engrafted in injured tissues suggesting that they might function as stem cells.Omentum consists of a variety of phenotypically and functionally distinctive cells. To understand the mechanism of tissue repair support by the omentum in more detail, we analyzed the cell subsets derived from the omentum on immune and inflammatory responses. Our data demonstrate that the omentum contains at least two groups of cells that support tissue repair, immunomodulatory myeloid derived suppressor cells and omnipotent stem cells that are indistinguishable from mesenchymal stem cells. Based on these data, we propose that the omentum is a designated organ for tissue repair and healing in response to foreign invasion and tissue damage.
Subject(s)
Lung Injury/therapy , Omentum/physiology , Regeneration/physiology , Tissue Engineering/methods , Tissue Transplantation/methods , Totipotent Stem Cells/transplantation , Analysis of Variance , Animals , Bleomycin/toxicity , Blotting, Western , Bronchoalveolar Lavage , Cell Proliferation , DNA Primers/genetics , Flow Cytometry , Fluorescent Antibody Technique , Lung Injury/chemically induced , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Omentum/cytology , Omentum/transplantation , Osteopontin/metabolism , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/physiology , Tissue Transplantation/physiology , Totipotent Stem Cells/physiologyABSTRACT
Interstitial pulmonary fibrosis is caused by the excess production of extracellular matrix (ECM) by Fb in response to TGF-ß1. Here, we show that the peptidyl-prolyl isomerase Pin1 modulates the production of many pro- and antifibrogenic cytokines and ECM. After acute, bleomycin injury, Pin1(-/-) mice showed reduced, pulmonary expression of collagens, tissue inhibitors of metalloproteinases, and fibrogenic cytokines but increased matrix metalloproteinases, compared with WT mice, despite similar levels of inflammation. In primary fibroblasts, Pin1 was required for TGF-ß-induced phosphorylation, nuclear translocation, and transcriptional activity of Smad3. In Pin1(-/-) cells, inhibitory Smad6 was found in the cytoplasm rather than nucleus. Smad6 knockdown in Pin1(-/-) fibroblasts restored TGF-ß-induced Smad3 activation, translocation, and target gene expression. Therefore, Pin1 is essential for normal Smad6 function and ECM production in response to injury or TGF-ß and thus may be an attractive therapeutic target to prevent excess scarring in diverse lung diseases.
Subject(s)
Peptidylprolyl Isomerase/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction , Smad3 Protein/metabolism , Smad6 Protein/metabolism , Active Transport, Cell Nucleus/drug effects , Animals , Bleomycin , Cell Nucleus/metabolism , Cells, Cultured , Cytoplasm/metabolism , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Immunoblotting , Immunoprecipitation , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , Mutation , NIMA-Interacting Peptidylprolyl Isomerase , Peptidylprolyl Isomerase/genetics , Phosphorylation/drug effects , Protein Binding/drug effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , RNA Interference , Smad3 Protein/genetics , Smad6 Protein/genetics , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta1/pharmacologyABSTRACT
BACKGROUND: The biologic mechanisms by which laparoscopic antireflux surgery (LARS) might influence the inflammatory process leading to bronchiolitis obliterans syndrome are unknown. We hypothesized that LARS alters the pulmonary immune profile in lung transplant patients with gastroesophageal reflux disease. METHODS: In 8 lung transplant patients with gastroesophageal reflux disease, we quantified and compared the pulmonary leukocyte differential and the concentration of inflammatory mediators in the bronchoalveolar lavage fluid (BALF) 4 weeks before LARS, 4 weeks after LARS, and 12 months after lung transplantation. Freedom from bronchiolitis obliterans syndrome (graded 1-3 according to the International Society of Heart and Lung Transplantation guidelines), forced expiratory volume in 1 second trends, and survival were also examined. RESULTS: At 4 weeks after LARS, the percentages of neutrophils and lymphocytes in the BALF were reduced (from 6.6% to 2.8%, P = 0.049, and from 10.4% to 2.4%, P = 0.163, respectively). The percentage of macrophages increased (from 74.8% to 94.6%, P = 0.077). Finally, the BALF concentration of myeloperoxide and interleukin-1ß tended to decrease (from 2109 to 1033 U/mg, P = 0.063, and from 4.1 to 0 pg/mg protein, P = 0.031, respectively), and the concentrations of interleukin-13 and interferon-γ tended to increase (from 7.6 to 30.4 pg/mg protein, P = 0.078 and from 0 to 159.5 pg/mg protein, P = 0.031, respectively). These trends were typically similar at 12 months after transplantation. At a mean follow-up of 19.7 months, the survival rate was 75% and the freedom from bronchiolitis obliterans syndrome was 75%. Overall, the forced expiratory volume in 1 second remained stable during the first year after transplantation. CONCLUSIONS: Our preliminary study has demonstrated that LARS can restore the physiologic balance of pulmonary leukocyte populations and that the BALF concentration of pro-inflammatory mediators is altered early after LARS. These results suggest that LARS could modulate the pulmonary inflammatory milieu in lung transplant patients with gastroesophageal reflux disease.
Subject(s)
Bronchiolitis Obliterans/prevention & control , Fundoplication , Gastroesophageal Reflux/surgery , Lung Transplantation/immunology , Postoperative Complications/prevention & control , Adult , Bronchiolitis Obliterans/etiology , Bronchoalveolar Lavage Fluid/immunology , Female , Gastroesophageal Reflux/complications , Gastroesophageal Reflux/immunology , Graft Rejection/prevention & control , Humans , Laparoscopy , Male , Middle Aged , Postoperative Complications/etiologyABSTRACT
BACKGROUND: The prevalence of vitamin D deficiency in lung disease is greater than in the general population. Vitamin D deficiency may negatively affect immune and lung function. Accordingly, we hypothesized that lung transplant recipients with vitamin D deficiency are more susceptible to rejection and infections after transplantation. METHODS: Transplant outcomes were reviewed in a retrospective cohort of 102 lung transplant recipients who had 25-hydroxyvitamin D [25(OH)D] levels drawn during the near-transplant period (100 days pre- or post-transplant). RESULTS: In the near-transplant period, 80% of recipients were 25(OH)D-deficient and 20% were not 25(OH)D-deficient. Episodes of acute cellular rejection in the deficient group were more frequent than in the non-deficient group [mean 1.27 (0.99 to 1.55) vs 0.52 (0.12 to 0.93), p = 0.006]. The rejection rate in the deficient group was more than double that of the the non-deficient group [IRR 2.43 (1.30 to 4.52), p = 0.005]. Infectious episodes were also more frequent in the deficient group than in the non-deficient group [mean 4.01 (3.24 to 4.79) vs 2.71 (1.47 to 3.96), p = 0.04]. The mortality rate of recipients who remained 25(OH)D-deficient 1 year after transplant was almost 5-fold higher than in recipients who were not 25(OH)D-deficient [IRR 4.79 (1.06 to 21.63), p = 0.04]. CONCLUSIONS: Low serum 25(OH)D levels in lung transplant recipients were associated with increased incidence of acute rejection and infection. The mortality of recipients who remained deficient 1 year post-transplant was higher than that of recipients who maintained normal vitamin D levels at 1 year post-transplant.
Subject(s)
Graft Rejection/epidemiology , Lung Transplantation , Respiratory Tract Infections/epidemiology , Vitamin D Deficiency/complications , Vitamin D/blood , Adult , Aged , Cohort Studies , Cystic Fibrosis/surgery , Female , Humans , Incidence , Kaplan-Meier Estimate , Lung Transplantation/mortality , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/surgery , Retrospective Studies , Risk Factors , Survival Rate , Vitamin D Deficiency/bloodABSTRACT
Naturally arising CD4(+)CD25(+)FoxP3(+) regulatory T cells (nTregs) have an essential role in maintenance of immune homeostasis and peripheral tolerance. Previously, we reported that conventional CD4(+) and CD8(+) T cells undergo p53-induced CD28-dependent apoptosis (PICA) when stimulated with a combination of immobilized anti-CD3 and anti-CD28 Abs, whereas nTregs expand robustly under the same conditions, suggesting that there is a differential survival mechanism against PICA between conventional T cells and nTregs. In this study, we demonstrate that TGF-ß signaling is required for nTregs to survive PICA. Conversely, when an active form of exogenous TGF-ß is present, conventional T cells become resistant to PICA and undergo robust expansion instead of apoptosis, with reduction of the proapoptotic protein Bim and FoxO3a. A substantial fraction of PICA-resistant T cells expressed IL-9 (T(H)9 cells). Moreover, the presence of IL-6 along with TGF-ß led to the generation of T(H)17 cells from conventional T cells. Together, the data demonstrate a novel role for TGF-ß in the homeostasis of regulatory T cells and effector T cell differentiation and expansion.
Subject(s)
Apoptosis/immunology , Cell Differentiation/immunology , Signal Transduction/immunology , T-Lymphocytes, Helper-Inducer/immunology , Transforming Growth Factor beta/immunology , Animals , Apoptosis/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/immunology , Bcl-2-Like Protein 11 , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/genetics , Cell Survival/genetics , Cell Survival/immunology , Forkhead Box Protein O3 , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Interleukin-9/genetics , Interleukin-9/immunology , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Mice, Transgenic , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/immunology , Signal Transduction/genetics , Transforming Growth Factor beta/geneticsABSTRACT
BACKGROUND: Evidence is increasingly convincing that lung transplantation is a risk factor of gastroesophageal reflux disease (GERD). However, it is still not known if the type of lung transplant (unilateral, bilateral, or retransplant) plays a role in the pathogenesis of GERD. STUDY DESIGN: The records of 61 lung transplant patients who underwent esophageal function tests between September 2008 and May 2010, were retrospectively reviewed. These patients were divided into 3 groups based on the type of lung transplant they received: unilateral (n=25); bilateral (n=30), and retransplant (n=6). Among these groups we compared: (1) the demographic characteristics (eg, sex, age, race, and body mass index); (2) the presence of Barrett esophagus, delayed gastric emptying, and hiatal hernia; and (3) the esophageal manometric and pH-metric profile. RESULTS: Distal and proximal reflux were more prevalent in patients with bilateral transplant or retransplant and less prevalent in patients after unilateral transplant, regardless of the cause of their lung disease. The prevalence of hiatal hernia, Barrett esophagus, and the manometric profile were similar in all groups of patients. CONCLUSIONS: Although our data show a discrepancy in prevalence of GERD in patients with different types of lung transplantation, we cannot determine the exact cause for these findings from this study. We speculate that the extent of dissection during the transplant places the patients at risk for GERD. On the basis of the results of this study, a higher level of suspicion of GERD should be held in patients after bilateral or retransplantation.
Subject(s)
Gastroesophageal Reflux/etiology , Lung Transplantation/adverse effects , Adult , Aged , Barium Sulfate , Barrett Esophagus/etiology , Barrett Esophagus/physiopathology , Contrast Media , Female , Gastric Emptying/physiology , Gastroesophageal Reflux/physiopathology , Hernia, Hiatal/diagnostic imaging , Hernia, Hiatal/etiology , Humans , Hydrogen-Ion Concentration , Lung Transplantation/methods , Male , Manometry , Middle Aged , Monitoring, Ambulatory/methods , Radiography , Radiopharmaceuticals , Reoperation , Retrospective Studies , Technetium Tc 99m Sulfur ColloidABSTRACT
Lymphangioleiomyomatosis (LAM) leads to hyperproliferation of abnormal smooth muscle cells in the lungs, associated with diffuse pulmonary parenchymal cyst formation and progressive dyspnea on exertion. The disease targets women of child-bearing age. Complications include pneumothoraces and chylous pleural effusions. Ten-year survival is estimated at 70%, and lung transplantation remains the only validated treatment. It has been observed that LAM cells express markers associated with melanocytic differentiation, including gp100 and MART-1. Other melanocytic markers have also been observed. The same proteins are targeted by T cells infiltrating melanoma tumors as well as by T cells infiltrating autoimmune vitiligo skin, and these antigens are regarded as relatively immunogenic. Consequently, vaccines have been developed for melanoma targeting these and other immunogenic melanocyte differentiation proteins. Preliminary data showing susceptibility of LAM cells to melanoma derived T cells suggest that vaccines targeting melanosomal antigens can be successful in treating LAM.
Subject(s)
Lung Neoplasms/immunology , Lung Neoplasms/therapy , Lymphangioleiomyomatosis/immunology , Lymphangioleiomyomatosis/therapy , Biomarkers, Tumor/immunology , Humans , Immunotherapy/methods , Lung Neoplasms/complications , Lung Neoplasms/pathology , Lung Transplantation/methods , Lymphangioleiomyomatosis/complications , Lymphangioleiomyomatosis/pathologyABSTRACT
Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 µM), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 µM). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2-7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists.
Subject(s)
Bronchoconstriction/physiology , Bronchodilator Agents , KCNQ Potassium Channels , Myocytes, Smooth Muscle , Signal Transduction/drug effects , Aminopyridines/pharmacology , Animals , Anthracenes/pharmacology , Bronchoconstriction/drug effects , Bronchodilator Agents/metabolism , Bronchodilator Agents/pharmacology , Calcium Channel Blockers/pharmacology , Carbamates/pharmacology , Celecoxib , Guinea Pigs , Histamine/pharmacology , Humans , KCNQ Potassium Channels/drug effects , KCNQ Potassium Channels/genetics , KCNQ Potassium Channels/metabolism , Male , Methacholine Chloride/pharmacology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Patch-Clamp Techniques , Phenylenediamines/pharmacology , Pyrazoles/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Sulfonamides/pharmacology , Verapamil/pharmacologyABSTRACT
BACKGROUND: The goal of this study was to determine, in lung transplant patients, if laparoscopic antireflux surgery (LARS) is an effective means to prevent aspiration as defined by the presence of pepsin in the bronchoalveolar lavage fluid (BALF). METHODS: Between September 2009 and November 2010, we collected BALF from 64 lung transplant patients at multiple routine surveillance assessments for acute cellular rejection, or when clinically indicated for diagnostic purposes. The BALF was tested for pepsin by enzyme-linked immunosorbent assay (ELISA). We then compared pepsin concentrations in the BALF of healthy controls (n = 11) and lung transplant patients with and without gastroesophageal reflux disease (GERD) on pH-monitoring (n = 8 and n = 12, respectively), and after treatment of GERD by LARS (n = 19). Time to the development of bronchiolitis obliterans syndrome was contrasted between groups based on GERD status or the presence of pepsin in the BALF. RESULTS: We found that lung transplant patients with GERD had more pepsin in their BALF than lung transplant patients who underwent LARS (P = .029), and that pepsin was undetectable in the BALF of controls. Moreover, those with more pepsin had quicker progression to BOS and more acute rejection episodes. CONCLUSION: This study compared pepsin in the BALF from lung transplant patients with and without LARS. Our data show that: (1) the detection of pepsin in the BALF proves aspiration because it is not present in healthy volunteers, and (2) LARS appears effective as a measure to prevent the aspiration of gastroesophageal refluxate in the lung transplant population. We believe that these findings provide a mechanism for those studies suggesting that LARS may prevent nonallogenic injury to the transplanted lungs from aspiration of gastroesophageal contents.
Subject(s)
Gastroesophageal Reflux/surgery , Lung Transplantation/methods , Pepsin A/metabolism , Respiratory Aspiration/prevention & control , Adult , Bronchiolitis Obliterans/etiology , Bronchiolitis Obliterans/prevention & control , Bronchoalveolar Lavage Fluid/chemistry , Endoscopy, Gastrointestinal , Female , Humans , Laparoscopy , Lung Transplantation/adverse effects , Male , Middle Aged , Prospective Studies , Respiratory Aspiration/etiology , Time FactorsABSTRACT
OBJECTIVE: To report the long-term outcomes of 1218 organs transplanted from donation after cardiac death (DCD) donors from January 1980 through December 2008. METHODS: One-thousand two-hundred-eighteen organs were transplanted into 1137 recipients from 577 DCD donors. This includes 1038 kidneys (RTX), 87 livers (LTX), 72 pancreas (PTX), and 21 DCD lungs. The outcomes were compared with 3470 RTX, 1157 LTX, 903 PTX, and 409 lung transplants from donors after brain death (DBD). RESULTS: Both patient and graft survival is comparable between DBD and DCD transplant recipients for kidney, pancreas, and lung after 1, 3, and 10 years. Our findings reveal a significant difference for patient and graft survival of DCD livers at each of these time points. In contrast to the overall kidney transplant experience, the most recent 16-year period (n = 396 DCD and 1,937 DBD) revealed no difference in patient and graft survival, rejection rates, or surgical complications but delayed graft function was higher (44.7% vs 22.0%; P < .001). In DCD LTX, biliary complications (51% vs 33.4%; P < .01) and retransplantation for ischemic cholangiopathy (13.9% vs 0.2%; P < .01) were increased. PTX recipients had no difference in surgical complications, rejection, and hemoglobin A1c levels. Surgical complications were equivalent between DCD and DBD lung recipients. CONCLUSION: This series represents the largest single center experience with more than 1000 DCD transplants and given the critical demand for organs, demonstrates successful kidney, pancreas, liver, and lung allografts from DCD donors.
Subject(s)
Death , Tissue and Organ Procurement , Transplants , Adult , Brain Death , Female , Graft Survival , Humans , Kidney Transplantation , Liver Transplantation , Lung Transplantation , Male , Middle Aged , Pancreas Transplantation , Postoperative Complications/etiology , Reoperation , Retrospective Studies , Survival Analysis , Transplants/adverse effects , Treatment Outcome , WisconsinABSTRACT
PURPOSE OF REVIEW: Lung transplantation is now a well established treatment option for several end-stage respiratory diseases. Survival after lung transplantation has significantly improved over the last decade. The primary limitation to increased utilization of lung transplantation remains donor scarcity. Suitable allografts have been procured from donors after determination of neurologic death and from donors after determination of cardiac death (DDCD or DCD). Historically, the first human lung transplantation performed, utilized an allograft procured after cardiovascular death, also referred to as nonheart-beating donor.The experience at University of Wisconsin in 1993 reintroduced DCD lung transplantation with the first successful clinical case. RECENT FINDINGS: A potential additional lung allograft source, DCD lung transplantation has been established with very acceptable outcomes observed by several centers. We provide the relevant background for the rationale of donor allograft expansion to include DCD lungs from controlled (Maastricht category III donors). SUMMARY: This review considers the available evidence for DCD lung transplantation and compares reported primary graft dysfunction rates and current survival data available.