Therapeutic implications of human umbilical cord derived mesenchymal stromal cells in acute lung injury associated with Influenza A/H5N1 infection

2018 ◽  
Author(s):  
Hayley Loy
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Influenza A ◽  
Human Umbilical Cord ◽  
H5n1 Infection ◽  
Therapeutic Implications

scholarly journals Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis

2019 ◽  
Vol 8 (6) ◽  
pp. 847 ◽  
Author(s):  
Mirjana Jerkic ◽  
Claire Masterson ◽  
Lindsay Ormesher ◽  
Stéphane Gagnon ◽  
Sakshi Goyal ◽  
...  
Keyword(s):  
Lung Injury ◽  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Injury Severity ◽  
Therapeutic Potential ◽  
Human Macrophage ◽  
Human Umbilical Cord ◽  
Macrophage Function ◽  
E Coli

Enhancing the immunomodulatory effects of mesenchymal stromal cells (MSCs) may increase their effects in sepsis. We tested the potential for overexpression of Interleukin-10 (IL-10) in human umbilical cord (UC) MSCs to increase MSC efficacy in Escherichia coli (E. coli) pneumosepsis and to enhance human macrophage function. Pneumonia was induced in rats by intratracheal instillation of E. coli ((2.0–3.0) × 109 Colony forming units (CFU)/kg). One hour later, animals were randomized to receive (a) vehicle; (b) naïve UC-MSCs; or (c) IL-10 overexpressing UC-MSCs (1 × 107 cells/kg). Lung injury severity, cellular infiltration, and E. coli colony counts were assessed after 48 h. The effects and mechanisms of action of IL-10 UC-MSCs on macrophage function in septic rodents and in humans were subsequently assessed. Survival increased with IL-10 (9/11 (82%)) and naïve (11/12 (91%)) UC-MSCs compared to vehicle (9/15 (60%, p = 0.03). IL-10 UC-MSCs—but not naïve UC-MSCs—significantly decreased the alveolar arterial gradient (455 ± 93 and 520 ± 81, mmHg, respectively) compared to that of vehicle animals (544 ± 52, p = 0.02). Lung tissue bacterial counts were significantly increased in vehicle- and naïve-UC-MSC-treated animals but were not different from sham animals in those treated with IL-10 overexpressing UC-MSCs. IL-10 (but not naïve) UC-MSCs decreased alveolar neutrophils and increased alveolar macrophage percentages compared to vehicle. IL-10 UC-MSCs decreased structural lung injury compared to naïve UC-MSC or vehicle therapy. Alveolar macrophages from IL-10-UC-MSC-treated rats and from human volunteers demonstrated enhanced phagocytic capacity. This was mediated via increased macrophage hemeoxygenase-1, an effect blocked by prostaglandin E2 and lipoxygenase A4 blockade. IL-10 overexpression in UC-MSCs enhanced their effects in E. coli pneumosepsis and increased macrophage function. IL-10 UC-MSCs similarly enhanced human macrophage function, illustrating their therapeutic potential for infection-induced acute respiratory distress syndrome (ARDS).

scholarly journals Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

2016 ◽  
Vol 113 (13) ◽  
pp. 3621-3626 ◽  
Author(s):  
Michael C. W. Chan ◽  
Denise I. T. Kuok ◽  
Connie Y. H. Leung ◽  
Kenrie P. Y. Hui ◽  
Sophie A. Valkenburg ◽  
...  
Keyword(s):  
Hong Kong ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Influenza A ◽  
Alveolar Fluid Clearance ◽  
Protein Permeability

Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium’s protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.

scholarly journals Therapeutic effect of human umbilical cord-derived multipotent mesenchymal stromal cells in a patient with Crigler–Najjar syndrome type I

2019 ◽  
Vol 64 (4) ◽  
pp. 26-34
Author(s):  
G. T. Sukhikh ◽  
A. V. Degtyareva ◽  
D. N. Silachev ◽  
K. V. Gorunov ◽  
I. V. Dubrovina ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Multipotent Mesenchymal Stromal Cells ◽  
Human Umbilical Cord ◽  
Type I ◽  
Syndrome Type ◽  
Safe Level ◽  
Period 2

The article presents the results of intravenous transplantation of allogeneic multipotent mesenchymal stromal cells, derived from a human umbilical cord, to a child with Crigler–Najjarsyndrome type I during the first 2 years of life. The therapy is aimed at reduction of the duration of phototherapy while maintaining a safe level of serum bilirubin.In this study, a five-day-old child with the bilirubin level of 340 µmol/l was treated with phototherapy for 16–18 hours daily in the neonatal period. Then, phototherapy was reduced to 14–16 hours. The level of bilirubin varied from 329 to 407 μmol/l. At the age of 2 months, it was decided to use multipotent mesenchymal stromal cells with a significant decrease in the duration of phototherapy up to 2 hours a day. During the observation period (2 years at the time of writing this article) the child received 6 injections of multipotent mesenchymal stromal cells. A positive effect developed within 4–7 days after administration and persisted for 2–3 months. There were no side effects or complications during and after transplantation.Thus, intravenous transplantation of multipotent mesenchymal stromal cells is an effective treatment of Crigler–Najjar syndrome type I; it reducesthe need for phototherapy,significantly improvesthe quality of life of the patients and prolongstheir life with native liver. 

scholarly journals Ifenprodil and Flavopiridol Identified by Genomewide RNA Interference Screening as Effective Drugs To Ameliorate Murine Acute Lung Injury after Influenza A H5N1 Virus Infection

mSystems ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Cong Zhang ◽  
Yuqing Zhang ◽  
Yuhao Qin ◽  
Qingchao Zhang ◽  
Qiang Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lung Injury ◽  
Rna Interference ◽  
Virus Infection ◽  
Lung Injury ◽  
Cell Viability ◽  
Influenza A ◽  
H5n1 Virus ◽  
H5n1 Infection ◽  
Rnai Screening

ABSTRACT Due to the limitations of effective treatments, avian influenza A H5N1 virus is the most lethal influenza virus strain that causes severe acute lung injury (ALI). To develop effective drugs ameliorating H5N1-induced ALI, we explore an RNA interference (RNAi) screening method to monitor changes in cell death induced by H5N1 infection. We performed RNAi screening on 19,424 genes in A549 lung epithelial cells and examined cell death induced by H5N1 infection. These screens identified 1,137 host genes for which knockdown altered cell viability by over 20%. DrugBank searches of these 1,137 host genes identified 146 validated druggable target genes with 372 drug candidates. We obtained 104 commercially available drugs with 65 validated target genes and examined their improvement of cell viability following H5N1 infection. We identified 28 drugs that could significantly recover cell viability following H5N1 infection and tested 10 in an H5N1-induced-ALI mouse model. The neurological drug ifenprodil and the anticancer drug flavopiridol markedly decreased leukocyte infiltration and lung injury scores in infected mouse lungs, significantly ameliorated edema in infected mouse lung tissues, and significantly improved the survival of H5N1-infected mice. Ifenprodil is an antagonist of the N-methyl-d-aspartate (NMDA) receptor, which is linked to inflammation and lung injury. Flavopiridol is an inhibitor of cyclin-dependent kinase 4 (CDK4), which is linked to leukocyte migration and lung injury. These results suggest that ifenprodil and flavopiridol represent novel remedies against potential H5N1 epidemics in addition to their proven indications. Furthermore, our strategy for identifying repurposable drugs could be a general approach for other diseases. IMPORTANCE Drug repurposing is a quick and economical strategy for developing new therapies with approved drugs. H5N1 is a highly pathogenic avian influenza virus subtype that can cause severe acute lung injury (ALI) and a high mortality rate due to limited treatments. The use of RNA interference (RNAi) is a reliable approach to identify essential genes in diseases. In most genomewide RNAi screenings, virus replication is the readout of interference. Since H5N1 virus infection could induce significant cell death and the percentage of cell death is associated with virus lethality, we designed a genomewide RNAi screening method to identify repurposable drugs against H5N1 virus with cell death as the readout. We discovered that the neurological drug ifenprodil and the anticancer drug flavopiridol could effectively ameliorate murine ALI after influenza A H5N1 virus infection, suggesting that they might be novel remedies for H5N1 virus-induced ALI in addition to the traditional indications.

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