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

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.

Therapeutic effect of Lipoxin A4 in malaria-induced acute lung injury

“…Experimental M‐ALI is characterized by cytokine production, alveolar collapse, neutrophil accumulation in the lung parenchyma, and the impairment of lung mechanics . Indeed, modulation of the lung inflammatory response has been shown to attenuate M‐ALI . LXA 4 has been demonstrated to attenuate the inflammatory response in experimental models of LPS‐induced ALI by preventing neutrophil accumulation and restoring endothelial barrier integrity .…”

“…The following changes have also been observed in M‐ALI models: pulmonary dysfunction early after malaria induction, cytokine production, and the presence of parasitized erythrocytes and inflammatory cells in the lung parenchyma . In this context, the modulation of neutrophil accumulation in lung tissue has been hypothesized to have a beneficial impact on host outcome …”

Stem cell therapy: a novel treatment option for cerebral malaria?

“…Souza and colleagues [ 1 ] evaluate, for the first time, the effects of BM-MSC therapy in multiple organ dysfunction during experimental cerebral malaria, and demonstrate that administration of BM-MSCs results in reduced mortality and parasitemia. Although plenty of challenges lie ahead, the results of this study validate the promise of BM-MSC therapy in the treatment of cerebral malaria.…”

“…Even patients that are given standard antimalarial therapy at an early phase still face a high risk of dying despite clearance of the parasite, while approximately 25 % of survivors may develop neurological complications and cognitive impairment. In a recent issue of Stem Cell Research & Therapy , Souza and colleagues [ 1 ] observed that administration of bone marrow-derived mesenchymal stromal cells (BM-MSCs) increased survival and reduced parasitemia and malaria pigment deposition in the spleen, liver, kidney and lung in an experimental mouse model of cerebral malaria. Their findings may provide a new option for the treatment of cerebral malaria.…”

Multiple Organ Dysfunction During Severe Malaria: The Role of the Inflammatory Response

“…Several approaches aiming the inflammatory response have been studied in patients diagnosed with uncomplicated malaria [114,115]; however, the treatment of severe malaria includes only supportive treatment. On the other hand, the use of experimental models of severe malaria suggested that the induction of cytoprotective pathways in brain as well the administration of anti-inflammatory drugs improve the survival of P. berghei-infected mice, especially when administrated as adjunctive treatment to antimalarial drugs [71,76,116,117]. Indeed, a robust clinical evidence is yet necessary to provide the effectiveness of the treatment with inflammatory modulators as an adjunctive therapy to antimalarial drugs to improve patient outcomes.…”