Abstract
BackgroundThe highly pathogenic avian influenza A/H5N1 virus is one of the causative agents of acute lung injury (ALI) with high mortality rate. Studies on therapeutic administration of bone marrow-derived mesenchymal stem cells (MSCs) in ALI caused by the viral infection have been limited in number and have shown conflicting results. The aim of the present investigation is to evaluate the therapeutic potential of MSC administration in A/H5N1-caused ALI, using a mouse model.MethodsMSCs were prepared from the bone marrow of 9 to 12 week-old BALB/c mice. An H5N1 virus of A/turkey/East Java/Av154/2013 was intranasally inoculated into BALB/c mice. On days 2, 4, and 6 after virus inoculation, MSCs were intravenously administered into the mice. To evaluate effects of the treatment, we examined for lung alveolar protein as an indicator for lung injury, PaO2/FiO2 ratio for lung functioning, and lung histopathology. Expressions of NF-κB, RAGE (transmembrane receptor for damage associated molecular patterns), TNFα, IL-1β, Sftpc (alveolar cell type II marker), and Aqp5+ (alveolar cell type I marker) were examined by immunohistochemistry. In addition, body weight, virus growth in lung and brain, and duration of survival were measured.ResultsThe administration of MSCs lowered the level of lung damage in the virus-infected mice, as shown by measuring lung alveolar protein, PaO2/FiO2 ratio, and histopathological score. In the MSC-treated group, the expressions of NF-κB, RAGE, TNFα, and IL-1β were significantly suppressed in comparison with a mock-treated group, while those of Sftpc and Aqp5+ were enhanced. Body weight, virus growth, and survival period were not significantly different between the groups.ConclusionThe administration of MSCs prevented further lung injury and inflammation, and enhanced alveolar cell type II and I regeneration, while it did not significantly affect viral proliferation and mouse morbidity and mortality. The results suggested that MSC administration was a promissing strategy for treatment of acute lung injuries caused by the highly pathogenic avian influenza A/H5N1 virus, although further optimization and combination use of anti-viral drugs will be obviously required to achieve the goal of reducing mortality.
Highlights
The highly pathogenic avian influenza A/H5N1 virus is one of the causative agents of acute lung injury (ALI) with high mortality rate
The results suggested that mesenchymal stem cells (MSCs) administration was a promissing strategy for treatment of acute lung injuries caused by the highly pathogenic avian influenza A/H5N1 virus, further optimization and combination use of anti-viral drugs will be obviously required to achieve the goal of reducing mortality
MSCs attenuated pro-inflammatory signaling and cytokines in the lungs of mice with the a/H5N1 lethal infection We measured the protein levels of NF-kB, receptor for advanced glycation end products (RAGE), tumor necrosis factor-α (TNFα), and IL-1β in lung tissue and we found that positive expression levels were induced by the A/H5N1 lethal infection (Fig. 6a, mock-treated groups)
Summary
The highly pathogenic avian influenza A/H5N1 virus is one of the causative agents of acute lung injury (ALI) with high mortality rate. Studies on therapeutic administration of bone marrow-derived mesenchymal stem cells (MSCs) in ALI caused by the viral infection have been limited in number and have shown conflicting results. The aim of the present investigation is to evaluate the therapeutic potential of MSC administration in A/ H5N1-caused ALI, using a mouse model. Acute lung injury (ALI) can cause acute respiratory failure, namely acute respiratory distress syndrome (ARDS) [1, 2]. Infection with the highly pathogenic avian influenza A/H5N1 virus is one of the causes for ARDS [4, 5]. Since antiviral medicines cannot repair tissue injury caused by influenza viruses [6], cell-based therapy is a potential new therapeutic approach. Studies of the role of MSCs in ALI induced by influenza A viruses have yielded conflicting results to date [8,9,10,11,12]
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