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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

a Photomicrographs of spleen tissue stained with hematoxylin and eosin. Original magnification × 1000; bars = 100 μm. Mice were inoculated with 5 × 106 parasitized RBCs or saline and treated with BM-MSCs. Spleens were excised 5 days after infection. Normal spleen architecture with white pulp (double black arrows). Uninfected mice treated with BM-MSCs also displayed normal spleen architecture (double black arrows). In P. berghei-infected mice, spleen damage was observed with activation of lymphocytes in white pulp, increased deposition of malaria pigment in red pulp (single white arrows), and increased number of lymphoblasts and lymphocytes in white pulp (red double arrows). b A semiquantitative, severity-based score was used to measure malaria pigment deposition, inflammation, fibrosis, and histoarchitectural damage in spleens of mice infected with P. berghei or mock-infected with saline and, 24 hours after infection, treated with BM-MSCs. Values are expressed as median (interquartile range) of six animals in each group. *Significantly different from uninfected group (p <0.05). +Significantly different from P. berghei-infected group (p <0.05). c Representative dot-plots demonstrating CD11b+ fluorescence in splenocytes. BM-MSC bone marrow-derived mesenchymal stromal cell, FSC forward scatter, Sal saline
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Fig3: a Photomicrographs of spleen tissue stained with hematoxylin and eosin. Original magnification × 1000; bars = 100 μm. Mice were inoculated with 5 × 106 parasitized RBCs or saline and treated with BM-MSCs. Spleens were excised 5 days after infection. Normal spleen architecture with white pulp (double black arrows). Uninfected mice treated with BM-MSCs also displayed normal spleen architecture (double black arrows). In P. berghei-infected mice, spleen damage was observed with activation of lymphocytes in white pulp, increased deposition of malaria pigment in red pulp (single white arrows), and increased number of lymphoblasts and lymphocytes in white pulp (red double arrows). b A semiquantitative, severity-based score was used to measure malaria pigment deposition, inflammation, fibrosis, and histoarchitectural damage in spleens of mice infected with P. berghei or mock-infected with saline and, 24 hours after infection, treated with BM-MSCs. Values are expressed as median (interquartile range) of six animals in each group. *Significantly different from uninfected group (p <0.05). +Significantly different from P. berghei-infected group (p <0.05). c Representative dot-plots demonstrating CD11b+ fluorescence in splenocytes. BM-MSC bone marrow-derived mesenchymal stromal cell, FSC forward scatter, Sal saline

Mentions: Spleens from P. berghei-infected mice showed evidence of tissue damage, with activation of lymphocytes in white pulp and increased deposition of malaria pigment in red pulp (Fig. 3b). BM-MSC administration did not affect spleen histology in uninfected mice (Fig. 3a, b); however, administration of BM-MSCs reduced levels of malaria pigment and increased the CD11b+ cell count in spleens of P. berghei-infected mice (Fig. 3c).Fig. 3


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)

a Photomicrographs of spleen tissue stained with hematoxylin and eosin. Original magnification × 1000; bars = 100 μm. Mice were inoculated with 5 × 106 parasitized RBCs or saline and treated with BM-MSCs. Spleens were excised 5 days after infection. Normal spleen architecture with white pulp (double black arrows). Uninfected mice treated with BM-MSCs also displayed normal spleen architecture (double black arrows). In P. berghei-infected mice, spleen damage was observed with activation of lymphocytes in white pulp, increased deposition of malaria pigment in red pulp (single white arrows), and increased number of lymphoblasts and lymphocytes in white pulp (red double arrows). b A semiquantitative, severity-based score was used to measure malaria pigment deposition, inflammation, fibrosis, and histoarchitectural damage in spleens of mice infected with P. berghei or mock-infected with saline and, 24 hours after infection, treated with BM-MSCs. Values are expressed as median (interquartile range) of six animals in each group. *Significantly different from uninfected group (p <0.05). +Significantly different from P. berghei-infected group (p <0.05). c Representative dot-plots demonstrating CD11b+ fluorescence in splenocytes. BM-MSC bone marrow-derived mesenchymal stromal cell, FSC forward scatter, Sal saline
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: a Photomicrographs of spleen tissue stained with hematoxylin and eosin. Original magnification × 1000; bars = 100 μm. Mice were inoculated with 5 × 106 parasitized RBCs or saline and treated with BM-MSCs. Spleens were excised 5 days after infection. Normal spleen architecture with white pulp (double black arrows). Uninfected mice treated with BM-MSCs also displayed normal spleen architecture (double black arrows). In P. berghei-infected mice, spleen damage was observed with activation of lymphocytes in white pulp, increased deposition of malaria pigment in red pulp (single white arrows), and increased number of lymphoblasts and lymphocytes in white pulp (red double arrows). b A semiquantitative, severity-based score was used to measure malaria pigment deposition, inflammation, fibrosis, and histoarchitectural damage in spleens of mice infected with P. berghei or mock-infected with saline and, 24 hours after infection, treated with BM-MSCs. Values are expressed as median (interquartile range) of six animals in each group. *Significantly different from uninfected group (p <0.05). +Significantly different from P. berghei-infected group (p <0.05). c Representative dot-plots demonstrating CD11b+ fluorescence in splenocytes. BM-MSC bone marrow-derived mesenchymal stromal cell, FSC forward scatter, Sal saline
Mentions: Spleens from P. berghei-infected mice showed evidence of tissue damage, with activation of lymphocytes in white pulp and increased deposition of malaria pigment in red pulp (Fig. 3b). BM-MSC administration did not affect spleen histology in uninfected mice (Fig. 3a, b); however, administration of BM-MSCs reduced levels of malaria pigment and increased the CD11b+ cell count in spleens of P. berghei-infected mice (Fig. 3c).Fig. 3

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