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Maphosphamide, a cyclophosphamide analog, increases proinflammatory and permeability responses on endothelial cells in vitro

1Josep Carreras Leukaemia Research Institute, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain., Barcelona, Catalonia, Spain, 2Hematopathology, Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain., Barcelona, Catalonia, Spain, 3HEMATOPATHOLOGY, PATHOLOGY DEPARTMENT, CENTRE DE DIAGNÒSTIC BIOMÈDIC. HOSPITAL CLINIC BARCELONA, BARCELONA, Catalonia, Spain, 4Stem Cell Transplantation Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain., Barcelona, Catalonia, Spain, 5Hospital Clinic, IDIBAPS, University of Barcelona, Spain, Barcelona, Catalonia, Spain

Abstract Number: PB1266

Meeting: ISTH 2022 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Blood Cells and Vessel Wall

Background: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Allo-HCT causes endothelial activation and damage. In addition, endothelial dysfunction plays a key role in the GVHD pathophysiology. The immunosuppressive drugs administered during allo-HCT exhibit a detrimental impact on the endothelium. Administration of post-transplant cyclophosphamide has significantly decreased GVHD incidence.

Aims: To evaluate the effect of maphosphamide (MPH), a cyclosphosphamide analog with direct activity, on endothelial cells in comparison to cyclosporine A (CSA), a standard immunosuppressant with known damaging effect on the endothelium.

Methods: Human microvascular endothelial cells (ECs) in culture were exposed (48h) to MPH (2µg/ml) and CSA (200ng/ml), to explore changes in markers of endothelial damage, such as: i) the adhesion receptor VCAM-1, ii) production of VWF, iii) the cell permeability protein VE-cadherin, and iv) activation of the inflammation-related protein p38 MAPK.

Results: Both MPH and CSA induced statistically significant increments in VCAM-1 expression in comparison to control cells (fold increases: 2.8±0.4 and 2.6±0.3, respectively, p < 0.01). While the production of VWF was enhanced in response to CSA (fold increase: 1.4±0.2, p < 0.05), it was reduced with MPH (0.8±0.1, p < 0.05). VE-cadherin expression decreased significantly in response to MPH (fold increase: 0.7±0.1, p < 0.01), whereas no effect was observed with CSA. Activation of p38 MAPK occurred in response to both compounds but it was higher and faster for CSA.

Conclusion(s): Our results demonstrate that maphosphamide exerted a proinflammatory effect on endothelial cells similar to the observed with cyclosporine A. The decreased expression of VE-cadherin with maphosphamide could indicate an increased endothelial permeability. Therefore, the cyclophosphamide analog is not exempt of an activating action on the endothelium. Further studies are needed to explore the mechanisms of cyclophosphamide in this setting.

To cite this abstract in AMA style:

Martinez-Sanchez J, Pascual-Diaz R, Palomo M, Moreno-Castaño A, Ventosa H, Rovira M, Escolar G, Carreras E, Diaz-Ricart M. Maphosphamide, a cyclophosphamide analog, increases proinflammatory and permeability responses on endothelial cells in vitro [abstract]. https://abstracts.isth.org/abstract/maphosphamide-a-cyclophosphamide-analog-increases-proinflammatory-and-permeability-responses-on-endothelial-cells-in-vitro/. Accessed October 2, 2023.

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