title: Mesenchymal stromal cell therapy attenuated lung and kidney injury but not brain damage in experimental cerebral malaria.
abstract: BACKGROUND
  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.
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Av Brasil, 4365, Manguinhos, CEP-21040-900, Rio de Janeiro, RJ, Brazil. marianasouza@fiocruz.br.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Souza
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 Bloco G, Cidade Universitária, CEP-21941-902, Rio de Janeiro, RJ, Brazil. johnatasdutra@gmail.com.
authors.forename: Johnatas D
authors.initials: JD
authors.lastname: Silva
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Av Brasil, 4365, Manguinhos, CEP-21040-900, Rio de Janeiro, RJ, Brazil. tatiana.ap2@gmail.com.
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Pádua
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Av Brasil, 4365, Manguinhos, CEP-21040-900, Rio de Janeiro, RJ, Brazil. nattorres@globo.com.
authors.forename: Natália D
authors.initials: ND
authors.lastname: Torres
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 Bloco G, Cidade Universitária, CEP-21941-902, Rio de Janeiro, RJ, Brazil. maryantunes@gmail.com.
authors.forename: Mariana A
authors.initials: MA
authors.lastname: Antunes
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 Bloco G, Cidade Universitária, CEP-21941-902, Rio de Janeiro, RJ, Brazil. deboraxisto@gmail.com.
authors.forename: Debora G
authors.initials: DG
authors.lastname: Xisto
authors.affiliation: Laboratory of Biochemistry and Cellular Signaling, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 Bloco G, Cidade Universitária, CEP-21941-902, Rio de Janeiro, RJ, Brazil. thiagoswin@hotmail.com.
authors.forename: Thiago P
authors.initials: TP
authors.lastname: Abreu
authors.affiliation: Department of Pathology, Faculty of Medicine, University of São Paulo, Av. Dr. Arnaldo, 455, Cerqueira César, CEP-01246903, São Paulo, SP, Brazil. vcapelozzi@lim05.fm.usp.br.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Capelozzi
authors.affiliation: Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 Bloco G, Cidade Universitária, CEP-21941-902, Rio de Janeiro, RJ, Brazil. mmorales@biof.ufrj.br.
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Morales
authors.affiliation: Laboratory of Biochemistry and Cellular Signaling, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 Bloco G, Cidade Universitária, CEP-21941-902, Rio de Janeiro, RJ, Brazil. acacia@biof.ufrj.br.
authors.forename: Ana A
authors.initials: AA
authors.lastname: Sá Pinheiro
authors.affiliation: Laboratory of Biochemistry and Cellular Signaling, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 Bloco G, Cidade Universitária, CEP-21941-902, Rio de Janeiro, RJ, Brazil. caruso@biof.ufrj.br.
authors.forename: Celso
authors.initials: C
authors.lastname: Caruso-Neves
authors.affiliation: Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Av Brasil, 4365, Manguinhos, CEP-21040-900, Rio de Janeiro, RJ, Brazil. gracahenriques@fiocruz.br.|National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Av Brasil, 4365, Manguinhos, CEP-21040-900, Rio de Janeiro, RJ, Brazil. gracahenriques@fiocruz.br.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Henriques
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Av Carlos Chagas Filho, 373 Bloco G, Cidade Universitária, CEP-21941-902, Rio de Janeiro, RJ, Brazil. prmrocco@biof.ufrj.br.
authors.forename: Patricia R M
authors.initials: PR
authors.lastname: Rocco
mesh_terms: D058186:Acute Kidney Injury / Q000628:therapy*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007668:Kidney / Q000473:pathology / Q000502:physiology; D007728:Kupffer Cells / Q000166:cytology; D008168:Lung / Q000473:pathology / Q000502:physiology; D055370:Lung Injury / Q000628:therapy*; D016779:Malaria, Cerebral / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000472:pathogenicity; D015996:Survival Rate