Predictive Criteria to Study the Pathogenesis of Malaria-Associated ALI/ARDS in Mice

Abstract

Malaria-associated acute lung injury/acute respiratory distress syndrome (ALI/ARDS) often results in morbidity and mortality. Murine models to study malaria-associated ALI/ARDS have been described; we still lack a method of distinguishing which mice will develop ALI/ARDS before death. This work aimed to characterize malaria-associated ALI/ARDS in a murine model and to demonstrate the first method to predict whether mice are suffering from ALI/ARDS before death. DBA/2 mice infected with Plasmodium berghei ANKA developing ALI/ARDS or hyperparasitemia (HP) were compared using histopathology, PaO2 measurement, pulmonary X-ray, breathing capacity, lung permeability, and serum vascular endothelial growth factor (VEGF) levels according to either the day of death or the suggested predictive criteria. We proposed a model to predict malaria-associated ALI/ARDS using breathing patterns (enhanced pause and frequency respiration) and parasitemia as predictive criteria from mice whose cause of death was known to retrospectively diagnose the sacrificed mice as likely to die of ALI/ARDS as early as 7 days after infection. Using this method, we showed increased VEGF levels and increased lung permeability in mice predicted to die of ALI/ARDS. This proposed method for accurately identifying mice suffering from ALI/ARDS before death will enable the use of this model to study the pathogenesis of this disease.

Association of Heme Oxygenase 1 with Lung Protection in Malaria-Associated ALI/ARDS

“…Respiratory patterns (respiratory frequency (RF) and enhanced pause (Penh)) were monitored on the 7th DAI by placing the mice in the plethysmography chamber (WBP, Buxco Electronics, Wilmington, North Carolina, USA) for 10 minutes (basal level) as described before [14]. The data were collected using Biosystems XA software and included the RF (breaths/minute) and variables to calculate the Penh, a theoretical variable that correlates with both pulmonary resistance and intrapleural pressure [26].…”

“…Identification of ALI/ARDS in mice before death was done as described before [14]. In short, we used two groups of PbA infected mice (10–12 mice per group): the survival group and the euthanized group in which the mice were euthanized on the 7th DAI.…”

“…In contrast, in mice without pleural effusion that died after 13th DAI with pale lungs and high levels of parasitemia, the cause of death was attributed to hyperparasitemia (HP) and, consequently, anemia. In the euthanized group, mice were classified as having been likely to die of ALI/ARDS or HP, by comparing their respiratory patterns and parasitemia levels with the survival group, in which the causa mortis was known, as previously published [14]. …”

“…In this model, an average of 50% of the mice that die between days 7 and 12 after infection have dyspnea, hypoxemia, and reduced respiratory rate. Postmortem studies revealed that these mice had pleural effusion, containing cells such as neutrophils, lymphocytes, monocytes, and macrophages [10, 14]. Furthermore, the vascular endothelial growth factor (VEGF) has been identified as critical in increased pulmonary vascular permeability, a hallmark of ALI/ARDS [10, 15].…”

Physiopathology of Malaria-Associated Acute Respiratory Distress Syndrome

“…It is known that it takes more time to conclude studies in humans, besides ethical impediments. On the other hand, the murine models help to understand the numerous complications of the pathogenesis, such as pulmonary findings, the immune response, especially neutrophils involvement and degrees of hypoxemia, are similar to those observed in humans [9,14,15].…”