Mesenchymal stromal cell therapy attenuated lung and kidney injury but not brain damage in experimental cerebral malaria.

Thiago P Abreu,Ana A Sá Pinheiro,Mariana A Antunes,Natália D Torres,Tatiana A Pádua,Marcelo M Morales,Maria G Henriques,Vera L Capelozzi,Debora G Xisto,Patricia Rm Rocco,Johnatas D Silva,Mariana C Souza,Celso Caruso-Neves

doi:10.1186/s13287-015-0093-2

Thiago P Abreu, Ana A Sá Pinheiro + Show 11 more

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https://doi.org/10.1186/s13287-015-0093-2

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Abstract

IntroductionMalaria is the most relevant parasitic disease worldwide, and still accounts for 1 million deaths each year. Since current antimalarial drugs are unable to prevent death in severe cases, new therapeutic strategies have been developed. Mesenchymal stromal cells (MSC) confer host resistance against malaria; however, thus far, no study has evaluated the therapeutic effects of MSC therapy on brain and distal organ damage in experimental cerebral malaria.MethodsForty C57BL/6 mice were injected intraperitoneally with 5 × 106Plasmodium berghei-infected erythrocytes or saline. After 24 h, mice received saline or bone marrow (BM)-derived MSC (1x105) intravenously and were housed individually in metabolic cages. After 4 days, lung and kidney morphofunction; cerebrum, spleen, and liver histology; and markers associated with inflammation, fibrogenesis, and epithelial and endothelial cell damage in lung tissue were analyzed.ResultsIn P. berghei-infected mice, BM-MSCs: 1) reduced parasitemia and mortality; 2) increased phagocytic neutrophil content in brain, even though BM-MSCs did not affect the inflammatory process; 3) decreased malaria pigment detection in spleen, liver, and kidney; 4) reduced hepatocyte derangement, with an increased number of Kupffer cells; 5) decreased kidney damage, without effecting significant changes in serum creatinine levels or urinary flow; and 6) reduced neutrophil infiltration, interstitial edema, number of myofibroblasts within interstitial tissue, and collagen deposition in lungs, resulting in decreased lung static elastance. These morphological and functional changes were not associated with changes in levels of tumor necrosis factor-α, keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8), or interferon-γ, which remained increased and similar to those of P. berghei animals treated with saline. BM-MSCs increased hepatocyte growth factor but decreased VEGF in the P. berghei group.ConclusionsBM-MSC treatment increased survival and reduced parasitemia and malaria pigment accumulation in spleen, liver, kidney, and lung, but not in brain. The two main organs associated with worse prognosis in malaria, lung and kidney, sustained less histological damage after BM-MSC therapy, with a more pronounced improvement in lung function.

Highlights

Malaria is the most relevant parasitic disease worldwide, and still accounts for 1 million deaths each year
In P. berghei-infected mice, Bone marrow mesenchymal stromal cell (BM-Mesenchymal stromal cells (MSC)): 1) reduced parasitemia and mortality; 2) increased phagocytic neutrophil content in brain, even though bone marrow (BM)-MSCs did not affect the inflammatory process; 3) decreased malaria pigment detection in spleen, liver, and kidney; 4) reduced hepatocyte derangement, with an increased number of Kupffer cells; 5) decreased kidney damage, without effecting significant changes in serum creatinine levels or urinary flow; and 6) reduced neutrophil infiltration, interstitial edema, number of myofibroblasts within interstitial tissue, and collagen deposition in lungs, resulting in decreased lung static elastance. These morphological and functional changes were not associated with changes in levels of tumor necrosis factor-α, keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8), or interferon-γ, which remained increased and similar to those of P. berghei animals treated with saline
The two main organs associated with worse prognosis in malaria, lung and kidney, sustained less histological damage after BM-MSC therapy, with a more pronounced improvement in lung function

Summary

Introduction

Malaria is the most relevant parasitic disease worldwide, and still accounts for 1 million deaths each year. Mesenchymal stromal cells (MSC) confer host resistance against malaria; far, no study has evaluated the therapeutic effects of MSC therapy on brain and distal organ damage in experimental cerebral malaria. Cerebral malaria is characterized by multiple organ dysfunction triggered by circulating parasitized red blood cells (RBCs). Disruption of the blood–brain barrier (BBB), sequestration of parasitized RBCs in the brain, lung, and kidneys, and a systemic inflammatory response, including production of cytokines and activation of inflammatory cells, have been consistently observed in both human and nonprimate models of cerebral malaria [4]. Recent studies report that current antimalarial drugs are insufficient to prevent death in severe cases of malaria; adjunctive therapies aiming to modulate the systemic inflammatory response triggered by malaria have been proposed [5]

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