Zehong Guan

University of Toronto, Toronto, Ontario, Canada

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Publications (15)81.97 Total impact

  • Y Matsuda · X Wang · H Oishi · Z Guan · M Saito · M Liu · S Keshavjee · C-W Chow ·
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    ABSTRACT: Chronic lung allograft dysfunction, the major cause of death following lung transplantation, usually manifests as irreversible airflow obstruction associated with obliterative bronchiolitis (OB), a lesion characterized by chronic inflammation, lymphoid neogenesis, fibroproliferation and small airway obliteration. Spleen tyrosine kinase (Syk), a tyrosine kinase that regulates B cell function and innate immunity, has been implicated in the pathogenesis of chronic inflammation and tissue repair. This study evaluated the role of Syk in development of OB, using an intrapulmonary tracheal transplant model of OB with the conditional Syk-knockout Syk(flox/flox) //rosa26-CreER(T2) mice and a Syk-selective inhibitor, GSK2230413. BALB/c trachea allografts were transplanted into Syk-knockout (Syk(del/del) ) mice or wild-type C57BL/6 recipients treated with GSK2230413. At day 28, histological analysis revealed that in the Syk(del/del) and GSK2230413-treated C57BL/6 recipients, the graft lumen remained open compared with allografts transplanted into Syk-expressing (Syk(flox/flox) ) and placebo control-treated C57BL/6 recipients. Immunofluorescence showed lymphoid neogenesis with distinct B and T cell zones in control mice. In contrast, lymphoid neogenesis was absent and few B or T cells were found in Syk(del/del) and GSK2230413-treated mice. These observations suggest that inhibition of Syk may be a potential therapeutic strategy for the management of OB following lung transplantation. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
    American Journal of Transplantation 08/2015; DOI:10.1111/ajt.13442 · 5.68 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S91-S92. DOI:10.1016/j.healun.2015.01.244 · 6.65 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S52-S53. DOI:10.1016/j.healun.2015.01.131 · 6.65 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S93. DOI:10.1016/j.healun.2015.01.247 · 6.65 Impact Factor
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    ABSTRACT: Objectives: To study the impact of ex vivo lung perfusion (EVLP) on cytokines, chemokines, and growth factors and their correlation with graft performance either during perfusion or after transplantation. Background: EVLP is a modern technique that preserves lungs on normothermia in a metabolically active state. The identification of biomarkers during clinical EVLP can contribute to the safe expansion of the donor pool. Methods: High-risk brain death donors and donors after cardiac death underwent 4 to 6 hours EVLP. Using a multiplex magnetic bead array assay, we evaluated analytes in perfusate samples collected at 1 hour and 4 hours of EVLP. Donor lungs were divided into 3 groups: (I) Control: bilateral transplantation with good early outcome [absence of primary graft dysfunction- (PGD) grade 3]; (II) PGD3: bilateral transplantation with PGD grade 3 anytime within 72 hours; (III) Declined: lungs unsuitable for transplantation after EVLP. Results: Of 50 cases included in this study, 27 were in Control group, 7 in PGD3, and 16 in Declined. From a total of 51 analytes, 34 were measurable in perfusates. The best marker to differentiate declined lungs from control lungs was stem cell growth factor -β [P < 0.001, AUC (area under the curve) = 0.86] at 1 hour. The best markers to differentiate PGD3 cases from controls were interleukin-8 (P < 0.001, AUC = 0.93) and growth-regulated oncogene-α (P = 0.001, AUC = 0.89) at 4 hours of EVLP. Conclusions: Perfusate protein expression during EVLP can differentiate lungs with good outcome from lungs PGD3 after transplantation. These perfusate biomarkers can be potentially used for more precise donor lung selection improving the outcomes of transplantation.
    The Journal of Heart and Lung Transplantation 11/2014; 32(4). DOI:10.1097/SLA.0000000000000974 · 6.65 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S98. DOI:10.1016/j.healun.2014.01.296 · 6.65 Impact Factor
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    ABSTRACT: The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 ± 0.6 vs. 2.0 ± 0.6 (mean ± SD); p = 0.025; n = 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-γt without affecting levels of IL-12 and interferon-γ (IFN-γ). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation.
    American Journal of Transplantation 04/2013; 13(6). DOI:10.1111/ajt.12230 · 5.68 Impact Factor
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    ABSTRACT: Normothermic ex vivo lung perfusion (EVLP) is a preservation technique that allows reassessment and improvement of donor lungs prior to transplantation. We hypothesized that the endothelin-1 (ET-1) axis is associated with donor lung performance during EVLP and recipient outcomes after transplantation.Methods and MaterialsWe assessed levels of ET-1, big ET-1 and endothelin converting enzyme 1 (ECE-1) in the perfusates of donor lungs enrolled in a clinical trial EVLP. The trial included lungs from high-risk brain death donors (BDD) and lungs from donation after cardiac death (DCD). They were divided into three groups: I. Control: bilateral transplantation with good early outcomes (absence of PGD grade 3); II. PGD3: bilateral lung transplantation with PGD grade 3 whithin 72 hours; III. Declined: lungs rejected following EVLP. Single-lung transplants and patients bridged with extracorporeal life support were excluded.ResultsThere were 25 cases in group I, 7 in group II and 16 in group III. At 1 hour of EVLP, perfusates of declined lungs had significantly higher levels of ET-1 (3.1±2.1 vs 1.8±2.3 pg/ml, p=0.01) and big ET-1 (15.8±14.2 vs 7.0±6.5, p=0.001) compared to control lungs. At the 4 hours of EVLP, declined lungs also had higher levels of ET-1 (2.7±2.2 vs 1.3±1.1 pg/ml, p=0.007) and big ET-1 (31.7±17.4 vs 19.4±9.5 pg/ml, p=0.007) compared to controls. In BDD lungs the ET-1 axis did not show significant differences between groups. However for DCD cases, groups II and III had higher ET-1 and big ET-1 levels at 4 hr perfusion when compared to group I (group II vs I: ET-1 p=0.03, big ET-1 p=0.01; group III vs I: ET-1 p=0.007, big ET-1 p=0.003). There were no differences in ECE-1 levels between groups.Conclusions In DCD lungs ET-1 and big ET-1 in perfusate predicted outcomes after lung transplantation. They were also associated with non-utilization of lungs after EVLP and thus could represent useful biomarkers to improve the accuracy of selection of donor lungs.
    The Journal of Heart and Lung Transplantation 04/2013; 32(4):S67. DOI:10.1016/j.healun.2013.01.981 · 6.65 Impact Factor
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    ABSTRACT: Obliterative bronchiolitis after lung transplantation is associated with intrapulmonary lymphoid neogenesis. The purpose of this study was to examine the role of lymphoid neogenesis, especially its relationship with secondary lymphoid organs (SLOs) in allograft airway rejection. A murine intrapulmonary tracheal transplant model and a conventional subcutaneous tracheal transplant model were tested using wild-type control mice and splenectomized lymphotoxin α knockout (LT) mice deficient in SLOs as recipients. In both subcutaneous and intrapulmonary tracheal transplant models using wild-type animals, tracheal isografts remained open without rejection, whereas allografts showed progressive luminal obliteration after transplantation. Lymphoid neogenesis containing alloreactive T cells was observed in the lungs, which received an intrapulmonary tracheal allograft. Despite a lack of SLOs, intrapulmonary allografts in splenectomized LT mice were rejected and obliterated by day 28, but the rejection of subcutaneous allografts was significantly delayed. Extensive lymphoid neogenesis was observed in the lungs of both intrapulmonary and subcutaneous allograft LT recipients. Increased proliferation of CD4 T cells and B220 B cells was observed in the lungs but not in the thymus or bone marrow. Intrapulmonary lymphoid neogenesis is capable of mounting alloimmune responses without SLOs. Tracheal allograft rejection occurs as efficiently as in wild-type animals when it is placed in the lungs. Tracheal allograft rejection in the subcutaneous tissue occurs in a delayed manner without SLO in association with intrapulmonary lymphoid neogenesis.
    Transplantation 06/2012; 93(12):1212-20. DOI:10.1097/TP.0b013e318250fbf5 · 3.83 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2012; 31(4):S141. DOI:10.1016/j.healun.2012.01.407 · 6.65 Impact Factor
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    ABSTRACT: Pulmonary ischemia-reperfusion is a pathological process seen in several clinical conditions, including lung transplantation, cardiopulmonary bypass, resuscitation for circulatory arrest, atherosclerosis, and pulmonary embolism. A better understanding of its molecular mechanisms is very important. Rat left lung underwent in situ ischemia for 60 min, followed by 2 h of reperfusion. The gene expression profiles and Src protein tyrosine kinase (PTK) phosphorylation were studied over time, and PP2, an Src PTK inhibitor, was intravenously administered 10 min before lung ischemia to determine the role of Src PTK in lung injury. Reperfusion following ischemia significantly changed the expression of 169 genes, with Mmp8, Mmp9, S100a9, and S100a8 being the most upregulated genes. Ischemia alone only affected expression of 9 genes in the lung. However, Src PTK phosphorylation (activation) was increased in the ischemic lung, mainly on the alveolar wall. Src PTK inhibitor pretreatment decreased phosphorylation of Src PTKs, total protein tyrosine phosphorylation, and STAT3 phosphorylation. It increased phosphorylation of the p85α subunit of PI3 kinase, a signal pathway that can inhibit coagulation and inflammation. PP2 reduced leukocyte infiltration in the lung, apoptotic cell death, fibrin deposition, and severity of acute lung injury after reperfusion. Src inhibition also significantly reduced CXCL1 (GRO/KI) and CCL2 (MCP-1) chemokine levels in the serum. During pulmonary ischemia, Src PTK activation, rather than alteration in gene expression, may play a critical role in reperfusion-induced lung injury. Src PTK inhibition presents a new prophylactic treatment for pulmonary ischemia-reperfusion-induced acute lung injury.
    Intensive Care Medicine 02/2012; 38(5):894-905. DOI:10.1007/s00134-012-2498-z · 7.21 Impact Factor

  • American Journal Of Pathology 09/2011; 179(3):1287-1300. DOI:10.1016/j.ajpath.2011.05.032 · 4.59 Impact Factor
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    ABSTRACT: Obliterative bronchiolitis after lung transplantation is a chronic inflammatory and fibrotic condition of small airways. The fibrosis associated with obliterative bronchiolitis might be reversible. Matrix metalloproteinases (MMPs) participate in inflammation and tissue remodeling. MMP-2 localized to myofibroblasts in post-transplant human obliterative bronchiolitis lesions and to allograft fibrosis in a rat intrapulmonary tracheal transplant model. Small numbers of infiltrating T cells were also observed within the fibrosis. To modulate inflammation and tissue remodeling, the broad-spectrum MMP inhibitor SC080 was administered after the allograft was obliterated, starting at post-transplant day 21. The allograft lumen remained obliterated after treatment. Only low-dose (2.5 mg/kg per day) SC080 significantly reduced collagen deposition, reduced the number of myofibroblasts and the infiltration of T cells in association with increased collagenolytic activity, increased MMP-2 gene expression, and decreased MMP-8, MMP-9, and MMP-13 gene expression. In in vitro experiments using cultured myofibroblasts, a relatively low concentration of SC080 increased MMP-2 activity and degradation of type I collagen. Moreover, coculture with T cells facilitated persistence of myofibroblasts, suggesting a role for T-cell infiltration in myofibroblast persistence in fibrosis. By combining low-dose SC080 with cyclosporine in vivo at post-transplant day 28, partial reversal of obliterative fibrosis was observed at day 42. Thus, modulating MMP activity might reverse established allograft airway fibrosis by regulating inflammation and tissue remodeling.
    American Journal Of Pathology 09/2011; 179(3):1287-300. · 4.59 Impact Factor
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    ABSTRACT: Lymphoid neogenesis is associated with the development of chronic lung allograft dysfunction (CLAD). Activation of stromal resident cells may be an important mechanism of lymphoid neogenesis. Twenty CLAD lungs explanted for retransplantation were immunohistochemically examined for lymphoid neogenesis, ectopic lymphoid chemokines, and dendritic cells (DCs). Formation of peripheral lymph node addressin (PNAd)+ high endothelial venule (HEV)-like vessels was examined in 134 transbronchial biopsies taken over 2 years posttransplant from 20 consecutive lung transplant recipients. CLAD lungs were characterized by higher grades of CXCL12 in alveolar (P=0.002) and airway epithelial cells (P=0.001), CCL21+ lymph vessels (P=0.01), and infiltration of DC-specific intercellular adhesion molecule-grabbing nonintegrin+ immature DCs (P=0.056) than normal control lungs. Activation of stromal resident cells in CLAD lungs was highlighted by formation of lymphoid-like stroma including expression of CCL21 and CXCL13, fibroblastic reticular-like cells and DC-specific lysosome-associated membrane protein+ mature DCs in association with a significantly larger number of lymphoid aggregates (P<0.001) with lymphangitc distribution compared with normal lungs. A larger number of PNAd+ HEV-like vessels were also observed outside of lymphoid aggregates with a lymphangitic distribution (P<0.001). HEV-like vessels in transbronchial biopsies were more graded in lungs that eventually developed CLAD (n=7) than those that did not (n=13) by 3 years after transplantation (P=0.001). Lymphoid neogenesis associated with CLAD accompanies activation of stromal resident cells and formation of lymphoid-like stroma. Induction of PNAd+ HEV-like vessels occurs before the manifestation of CLAD.
    Transplantation 06/2011; 91(12):1398-405. DOI:10.1097/TP.0b013e31821b2f7a · 3.83 Impact Factor