VEGF Promotes Malaria-Associated Acute Lung Injury in Mice

Abstract

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.

IL-12Rβ2 Is Essential for the Development of Experimental Cerebral Malaria

“…In vivo analyses showed no brain sequestration of mononuclear cells, no vascular leak, no hemorrhage, and no inflammation in the absence of IL-12Rb2, which were evident in PbA-infected WT mice. In contrast, the absence of IL-12Rb2 did not affect PbA-induced pulmonary microvascular damage, thus confirming the different pathophysiology of PbA-induced ECM and lung pathology (10,38,39). Thus, we demonstrated that PbA-induced brain microvascular damage and inflammation are mainly IL-12Rb2 dependent, whereas PbAinduced lung microvascular damage, edema, and alveolitis are IL-12Rb2 independent.…”

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

“…Studies by Shiloh et al (45) and Kumar et al (41) revealed that in addition to HO-1, CO can induce the M. tuberculosis dormancy regulon as well. Another study observed that treatment of mice with exogenous CO increases Plasmodium liver load (26), but fully prevents cerebral malaria and malaria-associated acute lung injury incidence in mice (27,77).…”

Selective Antihypertensive Dihydropyridines Lower Aβ Accumulation by Targeting both the Production and the Clearance of Aβ across the Blood-Brain Barrier

“…Control experiments were performed to determine whether the intracranial injection procedure and the administration of nilvadipine could affect the permeability of the BBB. Vascular permeability/ BBB leakage was evaluated by measuring the extravasation of the Evans blue dye in the brain as described previously (25,26). Briefly, B6/SJL F1 mice were intraperitoneally injected with 100 μL of 50% DMSO/PBS (vehicle), with 2 mg/kg of nilvadipine or were injected intracranially as described above with 3 μL of vehicle, with 3 nmol of Aβ or went untreated (control mice).…”

“…permeability (25,26). The cold injury procedure which induces a rapid breakdown of the BBB (31) was used as a positive control and lead to a significant extravasation of the Evans blue dye in the brain (see Figure 7).…”