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An endothelial proinflammatory phenotype precedes the development of the engraftment syndrome after autologous Hct

Bone Marrow Transplantation volume 57, pages 721–728 (2022)Cite this article

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Abstract

Engraftment syndrome (ES) is a common complication after autologous hematopoietic cell transplantation (auto-HCT) whose pathophysiological substrate remains unclear. We investigated whether endothelial damage could contribute to ES. Circulating ECs-damage biomarkers were measured in plasma from patients with (ES; n = 14) or without ES (non-ES; n = 20), collected at different time points: before HCT, 5 (S5) and 10 days (S10) after HCT, and at either the ES onset (SON) or the discharge day (SDIS). Also, cultured endothelial cells (ECs) were exposed to serum samples, obtained at the same points, to evaluate changes in ECs-activation (ICAM-1, VE-Cadherin) biomarkers, the reactivity of ECs towards leukocytes, and activation of intracellular signaling proteins related to inflammation (p38MAPK) and proliferation (Erk1/2). Results showed that circulating VWF, sTNFR1 and sVCAM-1 levels were higher in ES patients at all the points assessed, especially at SON. In vitro results showed an increased ICAM-1 expression on ECs exposed to ES samples vs. non-ES samples, especially to S5, with elevated leukocyte adhesion. Also, a lower VE-Cadherin expression and an increased phosphorylation of p38MAPK and Erk1/2 proteins were observed in ECs exposed to ES vs. non-ES samples. Our results indicate that endothelial activation precedes ES development and could be one of its pathophysiological substrates.

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Fig. 1: Circulating biomarkers of endothelial damage.
Fig. 2: ICAM-1 expression and Leukocyte adhesion.
Fig. 3: VE-cadherin expression.
Fig. 4: Activation (phosphorylation) of p38MAPK (P-p38MAPK) and Erk1/2 (P-Erk1/2) proteins in endothelial cells exposed to S5 pooled serum samples from ES patients (n = 4) and non-ES patients (n = 4).

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Acknowledgements

We would like to thank Estefanía Garcia and Lidia Martin for their technical assistance. This study was supported by Premi Fi de Residencia “Emili Letang”, Hospital Clinic Barcelona and, by German José Carreras Leukaemia Foundation (03R/ 2019) and Instituto de Salud Carlos III (FIS PI19/00888). The results from the present study were partially presented at the EBMT Annual Meeting (Frankfurt, 2019) and at the XXXVII SETH Annual Congress (Pamplona, 2021).

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Authors and Affiliations

  1. Hemostasis and Eritropathology Laboratory, Hematopathology, Pathology Department, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic, Barcelona, Spain

    Ana Belén Moreno-Castaño, Marta Palomo, Patricia Molina, Marc Pino, Pilar Gómez-Ramírez, Laura Bonastre, Ginés Escolar & Maribel Diaz-Ricart

  2. Barcelona Endothelium Team, Barcelona, Spain

    Ana Belén Moreno-Castaño, Marta Palomo, Julia Martinez-Sanchez, Ginés Escolar, Enric Carreras & Maribel Diaz-Ricart

  3. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

    Ana Belén Moreno-Castaño, Sergi Torramadé-Moix, Ginés Escolar, Montserrat Rovira, Luis Gerardo Rodríguez-Lobato, Francesc Fernández-Avilés & Maribel Diaz-Ricart

  4. Josep Carreras Leukaemia Research Institute, Hospital Clínic, University of Barcelona, Barcelona, Spain

    Marta Palomo, Julia Martinez-Sanchez, Alex Ramos & Enric Carreras

  5. Hematology Department, Bone Marrow Transplantation Unit, Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic, Barcelona, Spain

    Maria Teresa Solano, Montserrat Rovira, Luis Gerardo Rodríguez-Lobato, Gonzalo Gutiérrez-García & Francesc Fernández-Avilés

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Contributions

ABMC, MP, GGG, FFA, and MDR designed the study. ABMC and TS contributed to sample collection. ABMC, MP, JMS, STM, AR, PM, MPi, PG, and LB performed the laboratory tests and analysis. ABMC and MP analyzed the clinical data and ABMC performed the statistical analysis. FFA, GE, MR, and EC contributed with interpretation of data and its correlation with the clinical setting. ABMC and MDR wrote the manuscript and all authors contributed in the editing of the final manuscript.

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Correspondence to Ana Belén Moreno-Castaño.

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Competing interests

ABMC has been an advisory board member for Siemens in subjects not related to the submitted work. MDR and EC have been granted by and received honoraria from Jazz Pharmaceuticals. The rest of the authors have not any conflict of interest to declare.

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Moreno-Castaño, A.B., Palomo, M., Torramadé-Moix, S. et al. An endothelial proinflammatory phenotype precedes the development of the engraftment syndrome after autologous Hct. Bone Marrow Transplant 57, 721–728 (2022). https://doi.org/10.1038/s41409-022-01610-z

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