John A Belperio

University of California, Los Angeles, Los Angeles, California, United States

Are you John A Belperio?

Claim your profile

Publications (165)819.82 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and abnormal vascularity. IL-13, a profibrotic cytokine that plays a role in IPF, functions through the Jak/STAT pathway after binding to the IL-13 receptor alpha 1 (IL-13Rα1)/IL-4Rα complex. IL-13 also binds to IL-13Rα2, which has been thought to function as a non-signaling decoy receptor, although possible signaling roles of this receptor have been proposed. CXCR3 and its IFN-inducible ligands-CXCL9, CXCL10, and CXCL11-have been implicated in vascular remodelling and fibroblast motility during the development of IPF. In this study, CXCR3 expression was demonstrated in cultured pulmonary fibroblasts from wild-type BALB/c mice, and was found to be necessary for the IL-13 mediated gene and protein upregulation of IL-13Rα2. In fibroblasts from CXCR3-deficient mice, STAT6 activation was prolonged. This study is the first to demonstrate the expression of CXCR3 in fibroblasts and its association with the expression of IL-13Rα2. Taken together, the results from this study point strongly to a requirement for CXCR3 for IL-13 mediated IL-13Rα2 gene expression. Understanding the function of CXCR3 in IL-13 mediated lung injury may lead to novel approaches to combat the development of pulmonary fibrosis, whether by limiting the effects of IL-13 or by manipulation of angiostatic pathways. The elucidation of the complex relationship between both of these anti-fibrotic receptors and manipulation of the CXCR3-mediated regulation of IL-13Rα2 may represent a novel therapeutic modality in cases of acute lung injury or chronic inflammation that may progress to fibrosis.
    American Journal of Respiratory Cell and Molecular Biology 12/2014; · 4.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: Primary graft dysfunction (PGD) causes early mortality after lung transplantation and may contribute to late graft failure. No effective treatments exist. The pathogenesis of PGD is unclear, though both neutrophils and activated platelets have been implicated. We hypothesized that neutrophil extracellular traps (NETs) contribute to lung injury in PGD in a platelet-dependent manner. Objectives: To study NETs in experimental models of PGD and in lung transplant patients. Methods: Two experimental murine PGD models were studied: hilar clamp (HC) and orthotopic lung transplantation after prolonged cold ischemia (OLT-PCI). NETs were assessed by immunofluorescence microscopy and ELISA. Platelet activation was inhibited with aspirin, and NETs were disrupted with deoxyribonuclease (DNaseI). NETs were also measured in bronchoalveolar lavage fluid (BALF) and plasma from lung transplant patients with and without PGD. Measurements and Main Results: NETs were increased after either HC or OLT-PCI compared to surgical controls. Activation and intrapulmonary accumulation of platelets were increased in OLT-PCI, and platelet inhibition reduced NETs and lung injury and improved oxygenation. Disruption of NETs by intrabronchial administration of DNaseI also reduced lung injury and improved oxygenation. In BALF from human lung transplant recipients, NETs were more abundant in patients with PGD. Conclusions: NETs accumulate in the lung in both experimental and clinical PGD. In experimental PGD, NET formation is platelet-dependent, and disruption of NETs with DNaseI reduces lung injury. These data are the first description of a pathogenic role for NETs in solid organ transplantation and suggest that NETs are a promising therapeutic target in PGD.
    American Journal of Respiratory and Critical Care Medicine 12/2014; · 11.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) is a significant complication of sarcoidosis, occurring in approximately 6 to > 20% of cases, and markedly increases mortality among these patients. The clinician should exercise a high index of suspicion for sarcoidosis-associated PH (SAPH) given the nonspecific symptomatology and the limitations of echocardiography in this patient population. The pathophysiology of PH in sarcoidosis is complex and multifactorial. Importantly, there are inherent differences in the pathogenesis of SAPH compared with idiopathic pulmonary arterial hypertension, making the optimal management of SAPH controversial. In this article, we review the epidemiology, diagnosis, prognosis, and treatment considerations for SAPH. Lung transplantation (LT) is a viable therapeutic option for sarcoid patients with severe pulmonary fibrocystic sarcoidosis or SAPH refractory to medical therapy. We discuss the role for LT in patients with sarcoidosis, review the global experience with LT in this population, and discuss indications and contraindications to LT.
    Seminars in Respiratory and Critical Care Medicine 06/2014; 35(3):362-371. · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatopulmonary syndrome (HPS) is characterized by impaired oxygenation due to pulmonary vascular dilatation in patients with end-stage liver disease. At our center, we identified 29 patients who were listed for liver transplantation (LT) with a model for end-stage liver disease exception for HPS between 2001 and 2012. Five of these patients were found to have concurrent interstitial lung disease (ILD). The chest high-resolution computed-tomography demonstrated ground-glass opacities and subpleural reticulation, most consistent with nonspecific interstitial pneumonia (NSIP). All four of our patients who underwent LT experienced prolonged hypoxemia postoperatively, with one surgery-related death. However, the three surviving patients had eventual resolution of their hypoxemia with no evidence of ILD progression. In conclusion, we report a high prevalence of ILD, most consistent with NSIP, among patients with HPS. Although there may be increased perioperative risks, the finding of ILD in patients with HPS should not be considered an absolute contraindication to LT.
    Beiträge zur Klinik der Tuberkulose 03/2014; · 2.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH)-targeted therapy in the setting of pulmonary fibrosis (PF) is controversial; the main clinical concern is worsening of systemic hypoxaemia. We sought to determine the effects of gentle initiation and chronic administration of parenteral treprostinil on right heart function in patients with PF associated with an advanced PH phenotype. Open-label, prospective analysis of patients with PF-PH referred for lung transplantation (LT). Advanced PH was defined as mean pulmonary artery pressure (mPAP) ≥35 mm Hg. We compared haemodynamics, Doppler echocardiography (DE), oxygenation, dyspnoea and quality of life indices, and 6 min walk distance (6MWD) before and 12 weeks after parenteral treprostinil. 15 patients were recruited in the study. After therapy, there were significant improvements in right heart haemodynamics (right atrial pressure (9.5 ± 3.4 vs 6.0 ± 3.7); mPAP (47 ± 8 vs 38.9 ± 13.4); CI (2.3 ± 0.5 vs 2.7 ± 0.6); pulmonary vascular resistance (698 ± 278 vs 496 ± 229); transpulmonary gradient (34.7 ± 8.7 vs 28.5 ± 10.3); mvO2 (65 ± 7.2 vs 70.9 ± 7.4); and stroke volume index (29.2 ± 6.7 vs 33 ± 7.3)) and DE parameters reflecting right heart function (right ventricular (RV) end diastolic area (36.4 ± 5.2 vs 30.9 ± 8.2 cm(2)), left ventricular eccentricity index (1.7 ± 0.6 vs 1.3 ± 0.5), tricuspid annular planar systolic excursion (1.6 ± 0.5 vs 1.9 ± 0.2 cm)). These changes occurred without significant alteration in systemic oxygenation, heart rate, or mean systemic arterial pressure. In addition, improvements were seen in 6MWD (171 ± 93 vs 230 ± 114), 36-Item Short Form Health Survey Mental Component Summary aggregate (38 ± 11 vs 44.2 ± 10.7), University of California, San Diego Shortness of Breath Questionnaire (87 ± 17.1 vs 73.1 ± 21), and brain natriuretic peptide (558 ± 859 vs 228 ± 340). PH-targeted therapy may improve right heart haemodynamics and echocardiographic function without affecting systemic oxygen saturation in an advanced PH phenotype associated with RV dysfunction in the setting of PF.
    Thorax 02/2014; 69(2):123-9. · 8.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) may complicate connective tissue disease (CTD), particularly systemic sclerosis (SSc, scleroderma), and markedly increases mortality. More than 70% of cases of PH complicating CTD occur in SSc, which is the major focus of this article. Pulmonary complications (i.e., interstitial lung disease [ILD] and PH) are the leading causes of scleroderma-related deaths. "Isolated" PH (i.e., without ILD) complicates SSc in 7.5 to 20% of cases; secondary PH may also occur in patients with SSc-associated ILD. Several clinical markers and specific autoantibody profiles have been associated with PH in SSc. The role of PH-specific therapy is controversial, as prognosis and responsiveness to therapy are worse in SSc-associated PH compared with idiopathic pulmonary arterial hypertension. We discuss medical therapies for CTD-associated PH and the role of lung transplantation for patients failing medical therapy.
    Seminars in Respiratory and Critical Care Medicine 10/2013; 34(5):581-99. · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) may complicate parenchymal lung disease, specifically interstitial lung diseases and chronic obstructive pulmonary disease, and uniformly increases the mortality risk. The epidemiology and degree of PH is variable and unique to the underlying lung disease. The clinician should exercise a high index of suspicion for PH complicating parenchymal lung disease especially given the nonspecific symptomatology and the limitations of echocardiography in this patient population. In general, PH-specific therapies in this setting have been poorly studied, with concern for increased shunting and/or ventilation/perfusion (V/Q) mismatch and resultant hypoxemia. A better understanding of the mechanisms underlying PH related to parenchymal lung disease may lead to novel pharmacological targets to prevent or treat this serious complication.
    Seminars in Respiratory and Critical Care Medicine 10/2013; 34(5):600-19. · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: acute rejection, lymphocytic bronchiolitis, organizing pneumonia, and diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a Type I immune response would mediate this process. Objectives: Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology. Methods: Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time-dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates. Results: There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (HR 3.0 95% CI 1.9-4.7) and death (HR 2.3 95% CI 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BALF measurements predicted the development of CLAD. Conclusions: DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant Type I immune response involving CXCR3/ligands.
    American Journal of Respiratory and Critical Care Medicine 09/2013; · 11.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, chronic lung allograft dysfunction (CLAD), most commonly manifest as bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. The pathogenesis of BOS is complex and involves alloimmune and nonalloimmune pathways. Clinically, BOS manifests as airway obstruction and dyspnea that are classically progressive and ultimately fatal; however, the course is highly variable, and distinguishable phenotypes may exist. There are few controlled studies assessing treatment efficacy, but only a minority of patients respond to current treatment modalities. Ultimately, preventive strategies may prove more effective at prolonging survival after lung transplantation, but their remains considerable debate and little data regarding the best strategies to prevent BOS. A better understanding of the risk factors and their relationship to the pathological mechanisms of chronic lung allograft rejection should lead to better pharmacological targets to prevent or treat this syndrome.
    Seminars in Respiratory and Critical Care Medicine 06/2013; 34(3):336-351. · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: DNA viruses with potential to cause complications after lung transplantation include the human Herpesviridae family consisting of cytomegalovirus (CMV), herpes simplex virus 1 and 2 (HSV-1, -2), varicella-zoster virus (VZV), human herpesvirus 6, 7, and 8 (HHV-6, -7, -8), and Epstein-Barr virus (EBV); the Polyomaviridae family consisting of BK virus and JC virus; and the Adenoviridae family consisting of more than 50 adenovirus subtypes. This is a diverse group of viruses with equally diverse immediate and long-term impacts on allograft function and clinical outcomes following lung transplantation. This article discusses the individual pathogens, their epidemiology and clinical manifestations, as well as treatment and preventive strategies in this era of antiviral treatment regimens.
    Seminars in Respiratory and Critical Care Medicine 06/2013; 34(3):380-404. · 2.75 Impact Factor
  • John A Belperio, Jason D Christie
    Seminars in Respiratory and Critical Care Medicine 06/2013; 34(3):273-274. · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aspergillus colonization after lung transplantation may increase the risk for bronchiolitis obliterans syndrome (BOS), a disease of small airways. We hypothesized that colonization with small conidia Aspergillus species would be associated with a greater risk of BOS, based upon an increased likelihood of deposition in small airways. We studied adult primary lung recipients from two large centers; 298 recipients at University of California, Los Angeles and 482 recipients at Duke University Medical Center. We grouped Aspergillus species by conidia diameter ≤3.5 μm. We assessed the relationship of colonization with outcomes in Cox models. Pre-BOS colonization with small conidia Aspergillus species, but not large, was a risk factor for BOS (p = 0.002, HR 1.44, 95% CI 1.14-1.82), along with acute rejection, single lung and Pseudomonas. Colonization with small conidia species also associated with risk of death (p = 0.03, HR 1.30, 95% CI 1.03-1.64). Although other virulence traits besides conidia size may be important, we have demonstrated in two large independent cohorts that colonization with small conidia Aspergillus species increases the risk of BOS and death. Prospective evaluation of strategies to prevent Aspergillus colonization of small airways is warranted, with the goal of preserving lung allograft function as long as possible.
    American Journal of Transplantation 02/2013; · 6.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rationale Pseudomonas aeruginosa is the most commonly isolated gram negative bacterium after lung transplantation and has been shown to upregulate ELR+ CXC chemokines associated with bronchiolitis obliterans syndrome (BOS), but the effect of pseudomonas on BOS and death has not been well defined. Objectives Determine if the influence of pseudomonas isolation and ELR+ CXC chemokines on the subsequent development of BOS and the occurrence of death is time dependent. Methods A three state model was developed to assess the likelihood of transitioning from lung transplant (State 1) to BOS (State 2), from transplant (State 1) to death (State 3), and from BOS (State 2) to death (State 3). This Cox Semi-Markovian approach determines State survival rates and cause-specific hazards for movement from one State to another. Measurements and Main Results The likelihood of transition from transplant to BOS was increased by acute rejection, CXCL5 and the interaction between pseudomonas and CXCL1. Importantly, the pseudomonas effect in this transition was due entirely to infection rather than colonization. Movement from transplant to death was facilitated by pseudomonas infection and single lung transplant. Transition from BOS to death was effected by the length of time in State 1 and the interactions between any pseudomonas isolation and CXCL5 and aspergillus, either independently or in combination. Conclusions Our model demonstrates that common post-transplantation events drive movement from one post-transplantation State to another and influence outcomes differently dependent upon when after transplantation they occur. Furthermore, pseudomonas and the ELR+ CXC chemokines may interact to negatively influence lung transplant outcomes.
    American Journal of Respiratory and Critical Care Medicine 01/2013; · 11.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Despite data indicating a positive correlation between donor-specific anti-HLA antibodies (DSAs) and early development of bronchiolitis obliterans syndrome (BOS) in lung allografts, the role of an antibody-mediated process in acute and chronic lung allograft rejection has not been elucidated. In this study we evaluated pathologic features of transplant lung biopsies in patients with and without DSAs. METHODS: Forty-one lung transplant biopsies from 41 patients at our institution were included in our study. The biopsy H&E slides were reviewed in a blinded fashion, and scored for presence of microvascular inflammation, acute rejection, bronchiolar inflammation and acute lung injury, as well as diffuse alveolar damage (DAD). Microvascular inflammation was graded by the presence of capillary neutrophils on a scale of 0 to 4(+). For immunohistochemical analysis, the pattern and intensity of staining for C4d and C3d deposition were evaluated in airways and alveolar capillaries. RESULTS: Histopathology suspicious for antibody-mediated rejection (AMR)-defined as≥2(+) neutrophilic infiltration and/or DAD-were more common in DSA-positive cases than controls (11 of 16 vs 6 of 25, p<0.01). Evidence of allograft dysfunction was significantly more common among patients with both DSA and suspicious histopathology compared with controls (5 of 10 vs 3 of 25, p = 0.03). The combination of DSAs and histopathology suspicious for AMR was associated with both BOS (p = 0.002) and mortality (p = 0.03). Immunohistochemistry for C3d and C4d showed no correlation with each other, DSAs or histopathology. CONCLUSIONS: Grade 2(+) neutrophilic infiltration is the histopathologic finding most closely related to DSAs with graft dysfunction and development of BOS in lung transplant recipients and may be a marker for AMR.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 01/2013; · 5.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background. Orthotopic lung transplantation is now widely performed in patients with advanced lung disease. Patients with moderate or severe ventricular systolic dysfunction are typically excluded from lung transplantation; however, there is a paucity of data regarding the prognostic significance of abnormal left ventricular diastolic function and elevated pretransplant pulmonary pressures. Methods. We reviewed the characteristics of 111 patients who underwent bilateral and unilateral lung transplants from 200 to 2009 in order to evaluate the prognostic significance of preoperative markers of diastolic function, including invasively measured pulmonary capillary wedge pressure (PCWP) and echocardiographic variables of diastolic dysfunction including mitral A > E and A' > E'. Results. Out of 111 patients, 62 were male (56%) and average age was 54.0 ± 10.5 years. Traditional echocardiographic Doppler variables of abnormal diastolic function, including A' > E' and A > E, did not predict adverse events (P = 0.49). Mildly elevated pretransplant PCWP (16-20 mmHg) and moderately/severely elevated PCWP (>20 mmHg) were not associated with adverse clinical events after transplant (P = 0.30). Additionally, all clinical endpoints did not show any statistical significance between the two groups. Conclusions. Pre-lung transplant invasive and echocardiographic findings of elevated pulmonary pressures and abnormal left ventricular diastolic function are not predictive of adverse posttransplant clinical events.
    Journal of Transplantation 01/2013; 2013:391620.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Sepsis is a devastating condition with considerable mortality. The causes of long-term mortality are poorly understood. To test the hypothesis that patients with sepsis are more susceptible to recurrent infections and death due to infectious complications, we investigated the outcomes of patients who survived sepsis, with regard to the incidence of recurrent infections and mortality. Materials and Methods: A retrospective study of the patients admitted to the intensive care unit (ICU) for sepsis from 2001 to 2002 who achieved 30-day survival (sepsis survivors [SSs], N = 78) and a control group of patients admitted to the ICU for noninfectious conditions with a similar severity of illness (N = 50) was performed. The primary end point was the number of recurrent infections in the first year posthospitalization. Results: The SSs group had higher rates of infections following hospital discharge compared to controls. Using a multivariable model, having survived sepsis was the strongest predictor of the development of subsequent infections (rate ratio [RR]: 2.83, P= .0006), the need for rehospitalization for infection in the year after the initial hospitalization (RR: 3.78, P = .0009), and postdischarge mortality (hazard ratio = 3.61, P = .003). Conclusions: Critically ill patients who survive sepsis have an increased risk of recurrent infections in the year following their septic episode that is associated with increased mortality.
    Journal of Intensive Care Medicine 12/2012;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Exercise-induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum–associated ePH treated with open-label daily ambrisentan. Methods Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6-minute walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics. ResultsOf the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm5; P = 0.003) and mean distance covered during 6-minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (−4.1 mm Hg; P = 0.02), and total pulmonary resistance (−93.0 dynes × seconds/cm5; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks. Conclusion Exercise hemodynamics and exercise capacity in patients with SSc spectrum–associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH.
    Arthritis & Rheumatology 12/2012; 64(12). · 7.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The ImmuKnow (Cylex Inc, Columbia, MD) assay measures the amount of adenosine triphosphate (ATP) produced by helper CD4(+) cells after stimulation with a T-cell mitogen. We hypothesized that this assay can be used to assess the immune function of lung transplant recipients and identify those at risk of developing acute cellular rejection and respiratory infection. Lung transplant recipients at University of California Los Angeles between January 1, 2006 and December 31, 2009 received a bronchoscopy with broncheoalveolar lavage, transbronchial biopsy and ImmuKnow values drawn at regular intervals as well as during episodes of clinical deterioration. The recipient's clinical condition at each time-point was classified as healthy, acute cellular rejection, or respiratory infection. Mixed-effects models were used to compare the ATP levels among these groups, and odds ratios for rejection and infection were calculated. The mean ATP level was 431 ± 189 ng/ml for the rejection group vs 377 ± 187 ng/ml for the healthy group (p = 0.10). A recipient with an ATP level > 525 ng/ml was 2.1 times more likely to have acute cellular rejection (95% confidence interval [CI] 1.1-3.8). Similarly, the mean ATP level was 323 ± 169 ng/ml for the infection group vs 377 ± 187 ng/ml for the healthy group (p = 0.03). A recipient with an ATP level < 225 ng/ml was 1.9 times more likely to have respiratory infection (95% CI, 1.1-3.3). However, the test was associated with poor performance characteristics. It had low sensitivity, specificity with an area under the receiver operating characteristic curve of only 0.61 to diagnose rejection and 0.59 to diagnose infection. The ImmuKnow assay appears to have some ability to assess the overall immune function of lung transplant recipients. However, this study does not support its use as a reliable predictor of episodes of acute cellular rejection or respiratory infection.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 09/2012; 31(9):996-1002. · 5.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis. Objectives: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD. Methods: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis. Measurements and Main Results: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5' region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis. Conclusions: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.
    American Journal of Respiratory and Critical Care Medicine 07/2012; 186(6):546-552. · 11.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research. Biomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals derived from the Lung Transplant Outcomes Group cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in 2 ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality. PGD developed in 86 of 315 individuals (27%). Twenty-patients (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (area under the curve [AUC], 0.71) and PAI-1 (AUC, 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC, 0.75), PAI-1 with ICAM-1 (AUC, 0.75), and PAI-1 with SP-D (AUC, 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC, 0.72) and ICAM-1 with sRAGE (AUC, 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved the prediction of 90-day mortality (p < 0.001 each). Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early death and may provide an alternative outcome useful in future research.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 06/2012; 31(9):942-9. · 5.61 Impact Factor

Publication Stats

6k Citations
819.82 Total Impact Points


  • 2001–2014
    • University of California, Los Angeles
      • • Department of Medicine
      • • Division of Pulmonary and Critical Care
      Los Angeles, California, United States
  • 2011–2013
    • Harbor-UCLA Medical Center
      Torrance, California, United States
    • University College Dublin
      • School of Medicine & Medical Science
      Dublin, L, Ireland
    • CSU Mentor
      Long Beach, California, United States
  • 2012
    • National Heart, Lung, and Blood Institute
      Maryland, United States
    • University of Pennsylvania
      • Division of Pulmonary, Allergy and Critical Care
      Philadelphia, PA, United States
  • 2008
    • Columbia University
      New York City, New York, United States
  • 2007
    • University of Virginia
      • Division of Pulmonary and Critical Care
      Charlottesville, VA, United States
  • 2004–2006
    • Children's Hospital Los Angeles
      • • Division of Hospital Medicine
      • • Division of Critical Care Medicine
      Los Angeles, California, United States
  • 2002
    • Henry Ford Hospital
      • Department of Internal Medicine
      Detroit, MI, United States
  • 1999–2000
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States