Blockade of caspase cascade overcomes malaria-associated acute respiratory distress syndrome in mice

Sercundes, Michelle Klein; Ortolan, Luana dos Santos; Julio, Viviane da Silva; Bella, Leonardo Mendes; Quirino, Thatyane de Castro; Debone, Daniela; Carneiro‐Ramos, Marcela Sorelli; Christoffolete, Marcelo A.; Martins, Joilson O.; Lima, Maria Regina D’Império; Álvarez, José María; Amarante-Mendes, Gustavo P.; Gonçalves, Lígia Antunes; Marinho, Cláudio Romero Farias; Epiphânio, Sabrina

doi:10.1038/s41419-022-04582-6

Cited by 8 publications

(11 citation statements)

References 54 publications

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“…The results depended on the type of endothelial cell, culture conditions and Plasmodium parasites (N'Dilimabaka et al 2014). Other studies showed that iRBCs induce lung endothelial cell apoptosis through caspase 3, 8 and 9 activation with increasing cellular permeability (Pino et al 2003;Sercundes et al 2022). Interestingly, apoptotic brain endothelial cells were not associated with loss of BBB integrity in mice with cerebral malaria (Shaw et al 2015).…”

Section: Discussionmentioning

confidence: 98%

In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors

Pais¹,

Penha‐Gonçalves²

2023

Preprint

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Cerebral malaria (CM) is a severe neurological condition caused by Plasmodium falciparum. Disruption of the brain-blood barrier (BBB) is a key pathological event leading to brain edema and vascular leakage in both humans and in the mouse model of CM. Interactions of brain endothelial cells with infected red blood cells (iRBCs), and with circulating inflammatory mediators and immune cells contribute to BBB dysfunction in CM. Adjunctive therapies for CM aim at preserving the BBB to prevent neurologic deficits. Experimental animal and cellular models are essential to develop new therapeutic strategies. However, in mice, the disease develops rapidly, which offers a very narrow time window for testing the therapeutic potential of drugs acting in the BBB. Here, we establish a brain endothelial cell barrier whose disturbance can be monitored by several parameters. Using this system, we found that incubation with iRBCs and with extracellular particles (EPs) released by iRBCs changes endothelial cell morphology, decreases the tight junction protein zonula occludens-1 (ZO-1), increases the gene expression of the intercellular adhesion molecule 1 (ICAM-1) and induces a significant reduction in transendothelial electrical resistance (TEER) with increased permeability. We propose this in vitro experimental setup as a straightforward tool to investigate molecular interactions and pathways causing endothelial barrier dysfunction and to test compounds that may target BBB and be effective against CM. A pre-selection of the effective compounds that strengthen the resistance of the brain endothelial cell barrier to Plasmodium-induced blood factors in vitro may increase the likelihood of their efficacy in preclinical disease mouse models of CM and in subsequent clinical trials with patients.

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Section: Discussionmentioning

confidence: 98%

In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors

Pais¹,

Penha‐Gonçalves²

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The results depended on the type of endothelial cell, culture conditions, and Plasmodium parasites (N’Dilimabaka et al 2014 ). Other studies showed that iRBCs induce lung endothelial cell apoptosis through caspase 3, 8, and 9 activation with increasing cellular permeability (Pino et al 2003 ; Sercundes et al 2022 ). Interestingly, apoptotic brain endothelial cells were not associated with loss of BBB integrity in mice with cerebral malaria (Shaw et al 2015 ).…”

Section: Discussionmentioning

confidence: 98%

In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors

Pais

Penha‐Gonçalves

2023

Parasitol Res

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Cerebral malaria (CM) is a severe neurological condition caused by Plasmodium falciparum. Disruption of the brain-blood barrier (BBB) is a key pathological event leading to brain edema and vascular leakage in both humans and in the mouse model of CM. Interactions of brain endothelial cells with infected red blood cells (iRBCs) and with circulating inflammatory mediators and immune cells contribute to BBB dysfunction in CM. Adjunctive therapies for CM aim at preserving the BBB to prevent neurologic deficits. Experimental animal and cellular models are essential to develop new therapeutic strategies. However, in mice, the disease develops rapidly, which offers a very narrow time window for testing the therapeutic potential of drugs acting in the BBB. Here, we establish a brain endothelial cell barrier whose disturbance can be monitored by several parameters. Using this system, we found that incubation with iRBCs and with extracellular particles (EPs) released by iRBCs changes endothelial cell morphology, decreases the tight junction protein zonula occludens-1 (ZO-1), increases the gene expression of the intercellular adhesion molecule 1 (ICAM-1), and induces a significant reduction in transendothelial electrical resistance (TEER) with increased permeability. We propose this in vitro experimental setup as a straightforward tool to investigate molecular interactions and pathways causing endothelial barrier dysfunction and to test compounds that may target BBB and be effective against CM. A pre-selection of the effective compounds that strengthen the resistance of the brain endothelial cell barrier to Plasmodium-induced blood factors in vitro may increase the likelihood of their efficacy in preclinical disease mouse models of CM and in subsequent clinical trials with patients.

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“…Contrarily, dysfunction or dysregulation of cell apoptosis led to pathological conditions in numerous lung diseases [ 34 ]. The accumulated evidence showed that MA-ALI was partly characterized by excessive and uncontrolled inflammation and apoptosis in lung tissue [ 35 , 36 ]. A substantial increase in apoptosis or apoptotic biomarkers (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…A substantial increase in apoptosis or apoptotic biomarkers (e.g. TNF, FAS, Bax, Bad, FAS/FASL and caspases-3/8) was commonly observed in leukocytes, alveolar cells and endothelial cells of lung tissue from severe P. falciparum malaria patients with pulmonary edema and experimental MA-ALI mice [ 35 , 36 ]. An in vitro study also showed that apoptosis was detected in human primary pulmonary endothelial cells co-cultured with P. falciparum field isolates [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Blockage of mechanosensitive Piezo1 channel alleviates the severity of experimental malaria-associated acute lung injury

Zhang,

Wang,

Hou

et al. 2024

Parasites Vectors

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Background Malaria-associated acute lung injury (MA-ALI) is a well-recognized clinical complication of severe, complicated malaria that is partly driven by sequestrations of infected red blood cells (iRBCs) on lung postcapillary induced impaired blood flow. In earlier studies the mechanosensitive Piezo1 channel emerged as a regulator of mechanical stimuli, but the function and underlying mechanism of Piezo1 impacting MA-ALI severity via sensing the impaired pulmonary blood flow are still not fully elucidated. Thus, the present study aimed to explore the role of Piezo1 in the severity of murine MA-ALI. Methods Here, we utilized a widely accepted murine model of MA-ALI using C57BL/6 mice with Plasmodium berghei ANKA infection and then added a Piezo1 inhibitor (GsMTx4) to the model. The iRBC-stimulated Raw264.7 macrophages in vitro were also targeted with GsMTx4 to further explore the potential mechanism. Results Our data showed an elevation in the expression of Piezo1 and number of Piezo1+-CD68+ macrophages in lung tissues of the experimental MA-ALI mice. Compared to the infected control mice, the blockage of Piezo1 with GsMTx4 dramatically improved the survival rate but decreased body weight loss, peripheral blood parasitemia/lung parasite burden, experimental cerebral malaria incidence, total protein concentrations in bronchoalveolar lavage fluid, lung wet/dry weight ratio, vascular leakage, pathological damage, apoptosis and number of CD68+ and CD86+ macrophages in lung tissues. This was accompanied by a dramatic increase in the number of CD206+ macrophages (M2-like subtype), upregulation of anti-inflammatory cytokines (e.g. IL-4 and IL-10) and downregulation of pro-inflammatory cytokines (e.g. TNF-α and IL-1β). In addition, GsMTx4 treatment remarkably decreased pulmonary intracellular iron accumulation, protein level of 4-HNE (an activator of ferroptosis) and the number of CD68+-Piezo1+ and CD68+-4-HNE+ macrophages but significantly increased protein levels of GPX4 (an inhibitor of ferroptosis) in experimental MA-ALI mice. Similarly, in vitro study showed that the administration of GsMTx4 led to a remarkable elevation in the mRNA levels of CD206, IL-4, IL-10 and GPX-4 but to a substantial decline in CD86, TNF-α, IL-1β and 4-HNE in the iRBC-stimulated Raw264.7 cells. Conclusions Our findings indicated that blockage of Piezo1 with GsMTx4 alleviated the severity of experimental MA-ALI in mice partly by triggering pulmonary macrophage M2 polarization and subsequent anti-inflammatory responses but inhibited apoptosis and ferroptosis in lung tissue. Our data suggested that targeting Piezo1 in macrophages could be a promising therapeutic strategy for treating MA-ALI. Graphical Abstract

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Blockade of caspase cascade overcomes malaria-associated acute respiratory distress syndrome in mice

Cited by 8 publications

References 54 publications

In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors

In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors

In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors

Blockage of mechanosensitive Piezo1 channel alleviates the severity of experimental malaria-associated acute lung injury

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