S100A8/A9 as a prognostic biomarker in lung transplantation

OBJECTIVES S100A8/A9 is a damage-associated molecule that augments systemic inflammation. However, its role in the acute phase after lung transplantation (LTx) remains elusive. This study aimed to determine S100A8/A9 levels after lung transplantation (LTx) and evaluate their impact on overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. METHODS Sixty patients were enrolled in this study, and their plasma S100A8/A9 levels were measured on days 0, 1, 2, and 3 after LTx. The association of S100A8/A9 levels with OS and CLAD-free survival was assessed using univariate and multivariate Cox regression analyses. RESULTS S100A8/A9 levels were elevated in a time-dependent manner until 3 days after LTx. Ischemic time was significantly longer in the high S100A8/9 group than in the low S100A8/A9 group (p = .017). Patients with high S100A8/A9 levels (> 2844 ng/mL) had worse prognosis (p = .031) and shorter CLAD-free survival (p = .045) in the Kaplan-Meier survival analysis than those with low levels. Furthermore, multivariate Cox regression analysis showed that high S100A8/A9 levels were a determinant of poor OS (hazard ratio [HR]: 3.7; 95% confidence interval [CI]: 1.2-12; p = .028) and poor CLAD-free survival (HR: 4.1; 95% CI: 1.1-15; p = .03). In patients with a low primary graft dysfunction grade (0-2), a high level of S100A8/A9 was also a poor prognostic factor. CONCLUSIONS Our study provided novel insights into the role of S100A8/A9 as a prognostic biomarker and a potential therapeutic target for LTx.

[1]  Hiromasa Yamamoto,et al.  Functional Blockage of S100A8/A9 Ameliorates Ischemia–Reperfusion Injury in the Lung , 2022, Bioengineering.

[2]  A. Filby,et al.  Effector immune cells in chronic lung allograft dysfunction: A systematic review , 2022, Immunology.

[3]  G. Verleden,et al.  A Focused Review on Primary Graft Dysfunction after Clinical Lung Transplantation: A Multilevel Syndrome , 2022, Cells.

[4]  T. Kuijpers,et al.  S100A8/A9 Is a Marker for the Release of Neutrophil Extracellular Traps and Induces Neutrophil Activation , 2022, Cells.

[5]  S. Toyooka,et al.  Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice. , 2021, Biochemical and biophysical research communications.

[6]  A. Haverich,et al.  The potential of ex vivo lung perfusion on improving organ quality and ameliorating ischemia reperfusion injury , 2021, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  J. Klapper,et al.  Lung transplantation using allografts with more than 8 hours of ischemic time: A single-institution experience. , 2021, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[8]  P. Geraghty,et al.  The S100 Protein Family as Players and Therapeutic Targets in Pulmonary Diseases , 2021, Pulmonary medicine.

[9]  E. Abdelnour-Berchtold,et al.  Effects of cold or warm ischemia and ex-vivo lung perfusion on the release of damage associated molecular patterns and inflammatory cytokines in experimental lung transplantation. , 2021, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[10]  D. Kreisel,et al.  Sterile inflammation in thoracic transplantation , 2020, Cellular and Molecular Life Sciences.

[11]  K. Nakahira,et al.  Cell-free DNA in human ex vivo lung perfusate as a potential biomarker to predict the risk of primary graft dysfunction in lung transplantation. , 2020, The Journal of thoracic and cardiovascular surgery.

[12]  W. Land Use of DAMPs and SAMPs as Therapeutic Targets or Therapeutics: A Note of Caution , 2020, Molecular Diagnosis & Therapy.

[13]  R. Zhou,et al.  DAMP-sensing receptors in sterile inflammation and inflammatory diseases , 2019, Nature Reviews Immunology.

[14]  D. Kreisel,et al.  Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction , 2019, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[15]  G. Verleden,et al.  Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. , 2019, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[16]  D. Dilling,et al.  The Future of Lung Transplantation. , 2019, Chest.

[17]  T. Mohanakumar,et al.  A novel mechanism for immune regulation after human lung transplantation , 2019, The Journal of Thoracic and Cardiovascular Surgery.

[18]  G. Verleden,et al.  Validation of a post-transplant chronic lung allograft dysfunction classification system. , 2019, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[19]  Giou-Teng Yiang,et al.  Current Mechanistic Concepts in Ischemia and Reperfusion Injury , 2018, Cellular Physiology and Biochemistry.

[20]  Huan Yang,et al.  Extracellular HMGB1 as a therapeutic target in inflammatory diseases , 2018, Expert opinion on therapeutic targets.

[21]  P. Corris,et al.  Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation. , 2017, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[22]  C. Benden,et al.  Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation , 2017, Front. Med..

[23]  H. Mal,et al.  Outcomes after lung transplantation. , 2017, Journal of thoracic disease.

[24]  M. Sato,et al.  Distinct Expression Patterns of Alveolar “Alarmins” in Subtypes of Chronic Lung Allograft Dysfunction , 2014, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  A. Bharat,et al.  Immunological link between primary graft dysfunction and chronic lung allograft rejection. , 2008, The Annals of thoracic surgery.

[26]  D. Kreisel,et al.  Orthotopic mouse lung transplantation as experimental methodology to study transplant and tumor biology , 2008, Nature Protocols.

[27]  D. Kreisel,et al.  A Mouse Model of Orthotopic Vascularized Aerated Lung Transplantation , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[28]  A. Bharat,et al.  Early Posttransplant Inflammation Promotes the Development of Alloimmunity and Chronic Human Lung Allograft Rejection , 2007, Transplantation.

[29]  S. Der,et al.  Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. , 2006, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.