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

Souza MC, Silva JD, Pádua TA, Torres ND, Antunes MA, Xisto DG, Abreu TP, Capelozzi VL, Morales MM, Sá Pinheiro AA, Caruso-Neves C, Henriques MG, Rocco PR - Stem Cell Res Ther (2015)

Bottom Line: In 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Av Brasil, 4365, Manguinhos, CEP-21040-900, Rio de Janeiro, RJ, Brazil. marianasouza@fiocruz.br.

ABSTRACT

Introduction: Malaria 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.

Methods: Forty C57BL/6 mice were injected intraperitoneally with 5 × 10(6) Plasmodium berghei-infected erythrocytes or saline. After 24 h, mice received saline or bone marrow (BM)-derived MSC (1x10(5)) 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.

Results: In 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.

Conclusions: BM-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.

No MeSH data available.


Related in: MedlinePlus

Survival rate and parasitemia of P. berghei-infected mice. Mice were infected with 5 × 106 parasitized RBCs or mock-infected with saline and, 24 hours after infection, were treated with BM-MSCs. a Survival of mice infected with P. berghei. b Parasitemia was analyzed 5 days after infection using light microscopy. Values are expressed as means ± SD of six animals per group out of three experiments. BM-MSC bone marrow-derived mesenchymal stromal cell, Sal saline
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Fig1: Survival rate and parasitemia of P. berghei-infected mice. Mice were infected with 5 × 106 parasitized RBCs or mock-infected with saline and, 24 hours after infection, were treated with BM-MSCs. a Survival of mice infected with P. berghei. b Parasitemia was analyzed 5 days after infection using light microscopy. Values are expressed as means ± SD of six animals per group out of three experiments. BM-MSC bone marrow-derived mesenchymal stromal cell, Sal saline

Mentions: All untreated P. berghei-infected mice succumb to infection within 12 days. Even though BM-MSC therapy appeared to increase the mortality rate at early time points, evaluation of the full time course allows for the conclusion that BM-MSC therapy increased survival as compared with nontreatment of P. berghei-infected mice (Fig. 1a). At day 5 after infection, parasitemia was analyzed, and treatment with BM-MSCs was found to have decreased parasitemia levels (Fig. 1b).Fig. 1


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

Souza MC, Silva JD, Pádua TA, Torres ND, Antunes MA, Xisto DG, Abreu TP, Capelozzi VL, Morales MM, Sá Pinheiro AA, Caruso-Neves C, Henriques MG, Rocco PR - Stem Cell Res Ther (2015)

Survival rate and parasitemia of P. berghei-infected mice. Mice were infected with 5 × 106 parasitized RBCs or mock-infected with saline and, 24 hours after infection, were treated with BM-MSCs. a Survival of mice infected with P. berghei. b Parasitemia was analyzed 5 days after infection using light microscopy. Values are expressed as means ± SD of six animals per group out of three experiments. BM-MSC bone marrow-derived mesenchymal stromal cell, Sal saline
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4462088&req=5

Fig1: Survival rate and parasitemia of P. berghei-infected mice. Mice were infected with 5 × 106 parasitized RBCs or mock-infected with saline and, 24 hours after infection, were treated with BM-MSCs. a Survival of mice infected with P. berghei. b Parasitemia was analyzed 5 days after infection using light microscopy. Values are expressed as means ± SD of six animals per group out of three experiments. BM-MSC bone marrow-derived mesenchymal stromal cell, Sal saline
Mentions: All untreated P. berghei-infected mice succumb to infection within 12 days. Even though BM-MSC therapy appeared to increase the mortality rate at early time points, evaluation of the full time course allows for the conclusion that BM-MSC therapy increased survival as compared with nontreatment of P. berghei-infected mice (Fig. 1a). At day 5 after infection, parasitemia was analyzed, and treatment with BM-MSCs was found to have decreased parasitemia levels (Fig. 1b).Fig. 1

Bottom Line: In 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Av Brasil, 4365, Manguinhos, CEP-21040-900, Rio de Janeiro, RJ, Brazil. marianasouza@fiocruz.br.

ABSTRACT

Introduction: Malaria 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.

Methods: Forty C57BL/6 mice were injected intraperitoneally with 5 × 10(6) Plasmodium berghei-infected erythrocytes or saline. After 24 h, mice received saline or bone marrow (BM)-derived MSC (1x10(5)) 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.

Results: In 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.

Conclusions: BM-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.

No MeSH data available.


Related in: MedlinePlus