VEGF Promotes Malaria-Associated Acute Lung Injury in Mice

The spectrum of the clinical presentation and severity of malaria infections is broad, ranging from uncomplicated febrile illness to severe forms of disease such as cerebral malaria (CM), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pregnancy-associated malaria (PAM) or severe anemia (SA). Rodent models that mimic human CM, PAM and SA syndromes have been established. Here, we show that DBA/2 mice infected with P. berghei ANKA constitute a new model for malaria-associated ALI. Up to 60% of the mice showed dyspnea, airway obstruction and hypoxemia and died between days 7 and 12 post-infection. the most common pathological findings were pleural effusion, pulmonary hemorrhage and edema, consistent with increased lung vessel permeability, while the blood-brain barrier was intact. Malaria-associated ALI correlated with high levels of circulating VEGF, produced de novo in the spleen, and its blockage led to protection of mice from this syndrome. in addition, either splenectomization or administration of the anti-inflammatory molecule carbon monoxide led to a significant reduction in the levels of sera VEGF and to protection from ALI. the similarities between the physiopathological lesions described here and the ones occurring in humans, as well as the demonstration that VEGF is a critical host factor in the onset of malaria-associated ALI in mice, not only offers important mechanistic insights into the processes underlying the pathology related with malaria but may also pave the way for interventional studies.Fundacao para a Ciencia e a Tecnologia (FCT)European Science FoundationGemi FundUniv Lisbon, Unidade Malaria, Inst Mol Med, P-1699 Lisbon, PortugalUniv Tecn Lisboa, Fac Vet Med Lisbon, P-1100 Lisbon, PortugalInst Gulbenkian Ciencias, Oeiras, PortugalFac Med Lisbon, Lisbon, PortugalUniv São Paulo, Dept Parasitol, São Paulo, BrazilCtr Reg Oncol Lisboa, Angiogenesis Lab, Ctr Invest Patobiol Mol, Inst Portugue Oncol Francisco Gentil, Lisbon, PortugalFundacao para a Ciencia e a Tecnologia (FCT): POCTI/SAU-IMI/57946/2004Fundacao para a Ciencia e a Tecnologia (FCT): SFRH/BPD/31598/2006Fundacao para a Ciencia e a Tecnologia (FCT): SFRH/BD/10034/2002European Science Foundation: EURYI 2004Web of Scienc