Abstract
Malaria is an enormous burden on global health that caused 409,000 deaths in 2019. Severe malaria can manifest in the lungs, an illness known as acute respiratory distress syndrome (ARDS). Not much is known about the development of malaria-associated ARDS (MA-ARDS), especially regarding cell death in the lungs. We had previously established a murine model that mimics various human ARDS aspects, such as pulmonary edema, hemorrhages, pleural effusion, and hypoxemia, using DBA/2 mice infected with Plasmodium berghei ANKA. Here, we explored the mechanisms and the involvement of apoptosis in this syndrome. We found that apoptosis contributes to the pathogenesis of MA-ARDS, primarily as facilitators of the alveolar-capillary barrier breakdown. The protection of pulmonary endothelium by inhibiting caspase activation could be a promising therapeutic strategy to prevent the pathogenicity of MA-ARDS. Therefore, intervention in the programmed death cell mechanism could help patients not to develop severe malaria.
Highlights
Plasmodium species affecting humans can culminate in severe disease, which includes lung complications as acute respiratory distress syndrome (ARDS) [1,2,3,4,5]
Development of malaria-associated ARDS (MA-ARDS) is associated with increased apoptosis of lung endothelial cells and leukocytes in mice Apoptosis was evaluated in the lung and bronchoalveolar lavage (BAL) of P. berghei-infected mice (ARDS or hyperparasitemia (HP)developing mice)
The TUNEL stain allowed us to identify that the apoptotic cells were endothelial cells and leukocytes, alveolar macrophages and neutrophils, showing that these cells are involved in developing malariaassociated ARDS (Fig. 1F)
Summary
Plasmodium species affecting humans can culminate in severe disease, which includes lung complications as acute respiratory distress syndrome (ARDS) [1,2,3,4,5]. The most common regulated cell death, can be initiated through the intrinsic pathway, as a consequence of mitochondrial outer membrane permeabilization (MOMP), or via the extrinsic pathway, triggered by death receptors located at the cell surface [13]. Both pathways were shown to be involved in the acute lung injury induced by sepsis, cystic fibrosis, diffuse alveolar damage (DAD), and hyperoxia [14,15,16,17,18]. Members of the Bcl-2 protein family such as BAX, BAK, Bad, Bid are responsible for regulating apoptosis, whereas Xiap is a negative regulator that belongs to the family of apoptosis protein inhibitors, especially at the active site of effector caspase 3 and 7 [19,20,21,22]
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