Pathogenic CD8+ T Cells Cause Increased Levels of VEGF-A in Experimental Malaria-Associated Acute Respiratory Distress Syndrome, but Therapeutic VEGFR Inhibition Is Not Effective.

Thao-Thy Pham,Louis Boon,Chris J Janse,Sofie Knoops,Ghislain Opdenakker,Kathleen Van Den Eynde,Melissa Verheijen,Philippe E Van Den Steen,Leen Vandermosten,Katrien Deroost

doi:10.3389/fcimb.2017.00416

Abstract

Malaria is a severe disease and kills over 400,000 people each year. Malarial complications are the main cause of death and include cerebral malaria and malaria-associated acute respiratory distress syndrome (MA-ARDS). Despite antimalarial treatment, lethality rates of MA-ARDS are still between 20 and 80%. Patients develop pulmonary edema with hemorrhages and leukocyte extravasation in the lungs. The vascular endothelial growth factor-A (VEGF-A) and the placental growth factor (PlGF) are vascular permeability factors and may be involved in the disruption of the alveolar-capillary membrane, leading to alveolar edema. We demonstrated increased pulmonary VEGF-A and PlGF levels in lungs of mice with experimental MA-ARDS. Depletion of pathogenic CD8+ T cells blocked pulmonary edema and abolished the increase of VEGF-A and PlGF. However, neutralization of VEGF receptor-2 (VEGFR-2) with the monoclonal antibody clone DC101 did not decrease pulmonary pathology. The broader spectrum receptor tyrosine kinase inhibitor sunitinib even increased lung pathology. These data suggest that the increase in alveolar VEGF-A and PlGF is not a cause but rather a consequence of the pulmonary pathology in experimental MA-ARDS and that therapeutic inhibition of VEGF receptors is not effective and even contra-indicated.

Highlights

Malaria is a severe disease which affects 200 million people and causes more than 400,000 deaths each year
We investigated the expression of vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) in our experimental malariaassociated acute respiratory distress syndrome (MA-ARDS) model with C57BL/6 mice infected with P. berghei NK65 (PbNK65)
With PbNK65 2168cl2, the lung pathology was accompanied by a trend toward increased PlGF protein levels in bronchoalveolar lavage fluid (BALF) and a significant increase of pulmonary PlGF mRNA expression (Figures 2A,B)

Summary

Introduction

Malaria is a severe disease which affects 200 million people and causes more than 400,000 deaths each year. Despite the availability of efficient antimalarial treatments and preventive measures, transmission and severe or complicated disease are still reported in 91 countries. There is an increased incidence of MA-ARDS cases due to P. vivax in Southeast Asia and South America (Gupta et al, 2015) This malarial lung pathology is one of the main complications of malaria caused by P. knowlesi, a zoonotic parasite in Southeast Asia (Cox-Singh et al, 2010; William et al, 2011; Van den Steen et al, 2013). MA-ARDS mainly occurs in adults without pre-existing semi-immunity (e.g., travelers and adults in low-transmission areas), has a poor prognosis and leads to a lethality rate of 20–80%, despite antimalarial treatment (Taylor et al, 2012; Van den Steen et al, 2013). The only available therapy is mechanical ventilation (Taylor et al, 2012; Van den Steen et al, 2013)

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