Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased-dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation.

Alfred Hospital Lung Transplant Service Melbourne Australia

Medical University of Vienna Vienna Austria

Pomeranian Medical University of Szczecin Szczecin Poland

Toronto Lung Transplant Program University Health Network Toronto Ontario Canada

University Hospital Motol Prague Czech Republic

University of Alberta Edmonton Alberta Canada

University of Maryland Baltimore Maryland USA

University of Texas San Antonio San Antonio Texas USA

Washington University in St Louis St Louis Missouri USA

Komentář v

Am J Transplant. 2022 Apr;22(4):1012-1013. doi: 10.1111/ajt.16925. PubMed

Zobrazit více v PubMed

Chambers DC, Cherikh WS, Harhay MO, et al. The international thoracic organ transplant registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation report-2019; focus theme: donor and recipient size match. J Heart Lung Transplant. 2019;38(10):1042-1055.

Verleden GM, Glanville AR, Lease ED, et al. Chronic lung allograft dysfunction: definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019;38(5):493-503.

Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrom (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30(7):735-742.

Ofek E, Sato M, Saito T, et al. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol. 2013;26(3):350-356.

Weigt SS, Wang X, Palchevskiy V, et al. Gene expression profiling of bronchoalveolar lavage cells preceding a clinical diagnosis of chronic lung allograft dysfunction. Ann Am Thorac Soc. 2017;14(Suppl_3):S252.

Levy L, Tigert A, Huszti E, et al. Epithelial cell death markers in bronchoalveolar lavage correlate with chronic lung allograft dysfunction subtypes and survival in lung transplant recipients-a single-center retrospective cohort study. Transpl Int. 2019;32(9):965-973.

Vanaudenaerde BM, De Vleeschauwer SI, Vos R, et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant. 2008;8(9):1911-1920.

Iasella CJ, Hoji A, Popescu I, et al. Type-1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction. Am J Transplant. 2021;21(6):2145-2160.

Bharat A, Narayanan K, Street T, et al. Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection. Transplantation. 2007;83(2):150-158.

Jonigk D, Izykowski N, Rische J, et al. Molecular profiling in lung biopsies of human pulmonary allografts to predict chronic lung allograft dysfunction. Am J Pathol. 2015;185(12):3178-3188.

Halloran KM, Parkes MD, Chang J, et al. Molecular assessment of rejection and injury in lung transplant biopsies. J Heart Lung Transplant. 2019;38(5):504-513.

Halloran K, Parkes MD, Timofte I, et al. Molecular T-cell mediated rejection in transbronchial and mucosal lung transplant biopsies is associated with future risk of graft loss. J Heart Lung Transplant. 2020;39(12):1327-1337.

Halloran K, Parkes MD, Timofte IL, et al. Molecular phenotyping of rejection-related changes in mucosal biopsies from lung transplants. Am J Transplant. 2020;20(4):954-966.

Reeve J, Bohmig GA, Eskandary F, et al. Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes. JCI Insight. 2017;2(12):e94197.

Parkes MD, Aliabadi AZ, Cadeiras M, et al. An integrated molecular diagnostic system for rejection and injury in heart transplant biopsies. J Heart Lung Transplant. 2019;38(6):636-646.

Madill-Thomsen K, Abouljoud M, Bhati C, et al. The molecular diagnosis of rejection in liver transplant biopsies: first results of the INTERLIVER study. Am J Transplant. 2020;20(8):2156-2172.

Doncheva NT, Morris JH, Gorodkin J, Jensen LJ. Cytoscape stringapp: network analysis and visualization of proteomics data. J Proteome Res. 2019;18(2):623-632.

Maere S, Heymans K, Kuiper M. BiNGO: a cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 2005;21(16):3448-3449.

Reeve J, Bohmig GA, Eskandary F, et al. Generating automated kidney transplant biopsy reports combining molecular measurements with ensembles of machine learning classifiers. Am J Transplant. 2019;19(10):2719-2731.

Gene lists. https://www.ualberta.ca/medicine/institutes-centres-groups/atagc/research/gene-lists.html. Accessed July 2, 2021.

Land WG, Agostinis P, Gasser S, Garg AD, Linkermann A. Transplantation and damage-associated molecular patterns (DAMPs). Am J Transplant. 2016;16(12):3338-3361.

Famulski KS, Broderick G, Einecke G, et al. Transcriptome analysis reveals heterogeneity in the injury response of kidney transplants. Am J Transplant. 2007;7(11):2483-2495.

Famulski KS, Reeve J, de Freitas DG, Kreepala C, Chang J, Halloran PF. Kidney transplants with progressing chronic diseases express high levels of acute kidney injury transcripts. Am J Transplant. 2013;13(3):634-644.

Einecke G, Reeve J, Mengel M, et al. Expression of B cell and immunoglobulin transcripts is a feature of inflammation in late allografts. Am J Transplant. 2008;8(7):1434-1443.

Famulski KS, Sis B, Billesberger L, Halloran PF. Interferon-gamma and donor MHC class I control alternative macrophage activation and activin expression in rejecting kidney allografts: a shift in the Th1-Th2 paradigm. Am J Transplant. 2008;8(3):547-556.

Famulski KS, Einecke G, Sis B, et al. Defining the canonical form of T-cell-mediated rejection in human kidney transplants. Am J Transplant. 2010;10(4):810-820.

Halloran PF, Venner JM, Famulski KS. Comprehensive analysis of transcript changes associated with allograft rejection: combining universal and selective features. Am J Transplant. 2017;17(7):1754-1769.

Hidalgo LG, Einecke G, Allanach K, et al. The transcriptome of human cytotoxic T cells: measuring the burden of CTL-associated transcripts in human kidney transplants. Am J Transplant. 2008;8(3):637-646.

Li L, Li SY, Zhong X, et al. SERPINE2 rs16865421 polymorphism is associated with a lower risk of chronic obstructive pulmonary disease in the Uygur population: a case-control study. J Gene Med. 2019;21(9):e3106.

Ochiai H, Okada S, Saito A, et al. Inhibition of insulin-like growth factor-1 (IGF-1) expression by prolonged transforming growth factor-beta1 (TGF-beta1) administration suppresses osteoblast differentiation. J Biol Chem. 2012;287(27):22654-22661.

Tao Y, Zhou X, Liang C, et al. TGF-beta3 and IGF-1 synergy ameliorates nucleus pulposus mesenchymal stem cell differentiation towards the nucleus pulposus cell type through MAPK/ERK signaling. Growth Factors. 2015;33(5-6):326-336.

Schabort EJ, van der Merwe M, Niesler CU. TGF-beta isoforms inhibit IGF-1-induced migration and regulate terminal differentiation in a cell-specific manner. J Muscle Res Cell Motil. 2011;31(5-6):359-367.

Wang Y, Liu C, Xie Z, Lu H. Knockdown of TRIM47 inhibits breast cancer tumorigenesis and progression through the inactivation of PI3K/Akt pathway. Chem Biol Interact. 2020;317:108960.

Oxvig C. The role of PAPP-A in the IGF system: location, location, location. J Cell Commun Signal. 2015;9(2):177-187.

Annunziata M, Granata R, Ghigo E. The IGF system. Acta Diabetol. 2011;48(1):1-9.

Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 2006;116(10):2571-2579.

Ferdous A, Wang ZV, Luo Y, et al. FoxO1-Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth. Nat Commun. 2020;11(1):2551.

Kress E, Samarut J, Plateroti M. Thyroid hormones and the control of cell proliferation or cell differentiation: paradox or duality? Mol Cell Endocrinol. 2009;313(1-2):36-49.

Bornstein P. Thrombospondins function as regulators of angiogenesis. J Cell Commun Signal. 2009;3(3-4):189-200.

Ferrari G, Cook BD, Terushkin V, Pintucci G, Mignatti P. Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. J Cell Physiol. 2009;219(2):449-458.

Scarlett K, Pattabiraman V, Barnett P, Liu D, Anderson LM. The proangiogenic effect of iroquois homeobox transcription factor Irx3 in human microvascular endothelial cells. J Biol Chem. 2015;290(10):6303-6315.

de Souza Junior DA, Santana AC, da Silva EZ, Oliver C, Jamur MC. The role of mast cell specific chymases and tryptases in tumor angiogenesis. Biomed Res Int. 2015;2015:142359.

Zhang Y, Zhang M, Xie W, et al. Gremlin-1 is a key regulator of endothelial-to-mesenchymal transition in human pulmonary artery endothelial cells. Exp Cell Res. 2020;390(1):111941.

Li D, Yuan D, Shen H, Mao X, Yuan S, Liu Q. Gremlin-1: an endogenous BMP antagonist induces epithelial-mesenchymal transition and interferes with redifferentiation in fetal RPE cells with repeated wounds. Mol Vis. 2019;25:625-635.

Sun H, You Y, Guo M, Wang X, Zhang Y, Ye S. Tfcp2l1 safeguards the maintenance of human embryonic stem cell self-renewal. J Cell Physiol. 2018;233(9):6944-6951.

Jaskiewicz A, Pajak B, Orzechowski A. The many faces of rap1 GTPase. Int J Mol Sci. 2018;19(10):2848.

Halloran PF, Bohmig GA, Bromberg JS, et al. Discovering novel injury features in kidney transplant biopsies associated with TCMR and donor aging. Am J Transplant. 2021;21(5):1725-1739.

Venner JM, Famulski KS, Reeve J, Chang J, Halloran PF. Relationships among injury, fibrosis, and time in human kidney transplants. JCI Insight. 2016;1(1):e85323.

Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 2012;1822(9):1442-1452.

Verleden SE, Kirby M, Everaerts S, et al. Small airway loss in the physiologically ageing lung: a cross-sectional study in unused donor lungs. Lancet Respir Med. 2021;9(2):167-174.

Liu J, Jackson K, Weinkauf J, et al. Baseline lung allograft dysfunction negatively impacts survival following lung transplantation. J Heart Lung Transplant. 2016;35(4):S117.

Molecular monitoring of lung allograft health: is it ready for routine clinical use?