Therapeutic Efficacy of Human Mesenchymal Stromal Cells in the Repair of Established Ventilator-induced Lung Injury in the Rat

2015 ◽  
Vol 122 (2) ◽  
pp. 363-373 ◽  
Author(s):  
Mairead Hayes ◽  
Claire Masterson ◽  
James Devaney ◽  
Frank Barry ◽  
Steve Elliman ◽  
...  
Keyword(s):  
Lung Injury ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Keratinocyte Growth Factor ◽  
Lung Compliance ◽  
Human Mscs ◽  
Lung Repair ◽  
Ventilator Induced Lung Injury ◽  
In Series ◽  
Phosphate Buffered Saline

Abstract Background: Rodent mesenchymal stem/stromal cells (MSCs) enhance repair after ventilator-induced lung injury (VILI). We wished to determine the therapeutic potential of human MSCs (hMSCs) in repairing the rodent lung. Methods: In series 1, anesthetized rats underwent VILI (series 1A, n = 8 to 9 per group) or protective ventilation (series 1B, n = 4 per group). After VILI, they were randomized to intravenous administration of (1) vehicle (phosphate-buffered saline); (2) fibroblasts (1 × 107 cells/kg); or (3) human MSCs (1 × 107 cells/kg) and the effect on restoration of lung function and structure assessed. In series 2, the efficacy of hMSC doses of 1, 2, 5, and 10 million/kg was examined (n = 8 per group). Series 3 compared the efficacy of both intratracheal and intraperitoneal hMSC administration to intravascular delivery (n = 5–10 per group). Series 4 examined the efficacy of delayed hMSC administration (n = 8 per group). Results: Human MSC’s enhanced lung repair, restoring oxygenation (131 ± 19 vs. 103 ± 11 vs. 95 ± 11 mmHg, P = 0.004) compared to vehicle or fibroblast therapy, respectively. hMSCs improved lung compliance, reducing alveolar edema, and restoring lung architecture. hMSCs attenuated lung inflammation, decreasing alveolar cellular infiltration, and decreasing cytokine-induced neutrophil chemoattractant-1 and interleukin-6 while increasing keratinocyte growth factor concentrations. The lowest effective hMSC dose was 2 × 106 hMSC/kg. Intraperitoneal hMSC delivery was less effective than intratracheal or intravenous hMSC. hMSCs enhanced lung repair when administered at later time points after VILI. Conclusions: hMSC therapy demonstrates therapeutic potential in enhancing recovery after VILI.

scholarly journals Effects of Intratracheal Mesenchymal Stromal Cell Therapy during Recovery and Resolution after Ventilator-induced Lung Injury

2013 ◽  
Vol 118 (4) ◽  
pp. 924-932 ◽  
Author(s):  
Gerard F. Curley ◽  
Bilal Ansari ◽  
Mairead Hayes ◽  
James Devaney ◽  
Claire Masterson ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Enhanced Recovery ◽  
Lung Compliance ◽  
Lung Water ◽  
Lung Repair ◽  
Ventilator Induced Lung Injury ◽  
Factor Α ◽  
Phosphate Buffered Saline ◽  
Ventilation Induced Lung Injury

Abstract Background: Mesenchymal stromal cells (MSCs) have been demonstrated to attenuate acute lung injury when delivered by intravenous or intratracheal routes. The authors aimed to determine the efficacy of and mechanism of action of intratracheal MSC therapy and to compare their efficacy in enhancing lung repair after ventilation-induced lung injury with intravenous MSC therapy. Methods: After induction of anesthesia, rats were orotracheally intubated and subjected to ventilation-induced lung injury (respiratory rate 18 min−1, Pinsp 35 cm H2O,) to produce severe lung injury. After recovery, animals were randomized to receive: (1) no therapy, n = 4; (2) intratracheal vehicle (phosphate-buffered saline, 300 µl, n = 8); (3) intratracheal fibroblasts (4 × 106 cells, n = 8); (4) intratracheal MSCs (4 × 106 cells, n = 8); (5) intratracheal conditioned medium (300 µl, n = 8); or (6) intravenous MSCs (4 × 106 cells, n = 4). The extent of recovery after acute lung injury and the inflammatory response was assessed after 48 h. Results: Intratracheal MSC therapy enhanced repair after ventilation-induced lung injury, improving arterial oxygenation (mean ± SD, 146 ± 3.9 vs. 110.8 ± 21.5 mmHg), restoring lung compliance (1.04 ± 0.11 vs. 0.83 ± 0.06 ml·cm H2O−1), reducing total lung water, and decreasing lung inflammation and histologic injury compared with control. Intratracheal MSC therapy attenuated alveolar tumor necrosis factor-α (130 ± 43 vs. 488 ± 211 pg·ml−1) and interleukin-6 concentrations (138 ± 18 vs. 260 ± 82 pg·ml−1). The efficacy of intratracheal MSCs was comparable with intravenous MSC therapy. Intratracheal MSCs seemed to act via a paracine mechanism, with conditioned MSC medium also enhancing lung repair after injury. Conclusions: Intratracheal MSC therapy enhanced recovery after ventilation-induced lung injury via a paracrine mechanism, and was as effective as intravenous MSC therapy.

Evaluation of Potential Application of Wharton’s Jelly-Derived Human Mesenchymal Stromal Cells and its Conditioned Media for Dermal Regeneration using Rat Wound Healing Model

2021 ◽  
pp. 1-14
Author(s):  
Caroline Mathen ◽  
Mrunal Ghag Sawant ◽  
Raghubansh Gupta ◽  
Wilfrid Dsouza ◽  
Shilpa G. Krishna
Keyword(s):  
Wound Healing ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Wound Care ◽  
Free Cell ◽  
Conditioned Media ◽  
Human Umbilical Cord ◽  
Human Mscs ◽  
Wound Model

Mesenchymal stromal cells and the derived conditioned media represent an area of tremendous medical interest and, among other clinical applications, are currently being extensively explored for wound healing. The aim of this study was to comparatively evaluate the wound healing potential of xeno-free human umbilical cord-derived mesenchymal stromal cells (MSCs) and the conditioned media (CM) in a full-thickness excision wound model in rats. The evaluation parameters included rate of wound healing, serum cytokine analyses, collagen content, histopathology, and hyperspectral imaging as an independent qualitative and quantitative tool. Both the cell-based and cell-free approaches scored better in lower inflammation, as evidenced in lower IL-10 and stable IL-6 levels, and improved rate of wound healing (<i>p</i> &#x3c; 0.0001). More importantly, no adverse reaction or rejection was observed although human MSCs and CM were used in a xenogeneic model. The presence of hFGF, hHGF, hGCSF, hIL-1Ra, hVEGF, and hIL-6 in the secretome may elucidate the regenerative potential of the xeno-free cell-based and cell-free approaches which have translational value for advanced wound care. The results revealed the therapeutic potential of both the cell-based and cell-free approaches for wound healing.

scholarly journals Fresh and Cryopreserved Human Umbilical-Cord-Derived Mesenchymal Stromal Cells Attenuate Injury and Enhance Resolution and Repair following Ventilation-Induced Lung Injury

2021 ◽  
Vol 22 (23) ◽  
pp. 12842
Author(s):  
Shahd Horie ◽  
Hector Gonzalez ◽  
Jack Brady ◽  
James Devaney ◽  
Michael Scully ◽  
...  
Keyword(s):  
Cell Death ◽  
Lung Injury ◽  
Umbilical Cord ◽  
Stromal Cells ◽  
Wound Repair ◽  
Mechanical Stretch ◽  
Human Umbilical Cord ◽  
In Series ◽  
Epithelial Inflammation ◽  
The Impact

Background: Ventilator-induced lung injury (VILI) frequently worsens acute respiratory distress syndrome (ARDS) severity. Human mesenchymal stem/stromal cells (MSCs) offer considerable therapeutic promise, but the key impediments of clinical translation stem from limitations due to cell source and availability, and concerns regarding the loss of efficacy following cryopreservation. These experiments compared the efficacy of umbilical-cord-derived MSCs (UC-MSCs), a readily available and homogenous tissue source, to the previously more widely utilised bone-marrow-derived MSCs (BM-MSCs). We assessed their capacity to limit inflammation, resolve injury and enhance repair in relevant lung mechanical stretch models, and the impact of cryopreservation on therapeutic efficacy. Methods: In series 1, confluent alveolar epithelial layers were subjected to cyclic mechanical stretch (22% equibiaxial strain) and wound injury, and the potential of the secretome from BM- and UC-derived MSCs to attenuate epithelial inflammation and cell death, and enhance wound repair was determined. In series 2, anesthetized rats underwent VILI, and later received, in a randomised manner, 1 × 107 MSCs/kg intravenously, that were: (i) fresh BM-MSCs, (ii) fresh UC-MSCs or (iii) cryopreserved UC-MSCs. Control animals received a vehicle (PBS). The extent of the resolution of inflammation and injury, and repair was measured at 24 h. Results: Conditioned medium from BM-MSCs and UC-MSCs comparably decreased stretch-induced pulmonary epithelial inflammation and cell death. BM-MSCs and UC-MSCs comparably enhanced wound resolution. In animals subjected to VILI, both fresh BM-MSCs and UC-MSCs enhanced injury resolution and repair, while cryopreserved UC-MSCs comparably retained their efficacy. Conclusions: Cryopreserved UC-MSCs can reduce stretch-induced inflammation and cell death, enhance wound resolution, and enhance injury resolution and repair following VILI. Cryopreserved UC-MSCs represent a more abundant, cost-efficient, less variable and equally efficacious source of therapeutic MSC product.

scholarly journals mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury

JCI Insight ◽  
2021 ◽  
Author(s):  
Hyunwook Lee ◽  
Qinqin Fei ◽  
Adam Streicher ◽  
Wenjuan Zhang ◽  
Colleen Isabelle ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Compliance ◽  
Ventilator Induced Lung Injury

scholarly journals The Extent of Ventilator-Induced Lung Injury in Mice Partly Depends on Duration of Mechanical Ventilation

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Maria A. Hegeman ◽  
Sabrine N. T. Hemmes ◽  
Maria T. Kuipers ◽  
Lieuwe D. J. Bos ◽  
Geartsje Jongsma ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Capillary Permeability ◽  
Statistical Significance ◽  
Lung Compliance ◽  
Alveolar Cell ◽  
Mechanically Ventilated ◽  
Ventilator Induced Lung Injury ◽  
Cell Counts ◽  
Alveolar Capillary

Background. Mechanical ventilation (MV) has the potential to initiate ventilator-induced lung injury (VILI). The pathogenesis of VILI has been primarily studied in animal models using more or less injurious ventilator settings. However, we speculate that duration of MV also influences severity and character of VILI.Methods. Sixty-four healthy C57Bl/6 mice were mechanically ventilated for 5 or 12 hours, using lower tidal volumes with positive end-expiratory pressure (PEEP) or higher tidal volumes without PEEP. Fifteen nonventilated mice served as controls.Results. All animals remained hemodynamically stable and survived MV protocols. In both MV groups, PaO2to FiO2ratios were lower and alveolar cell counts were higher after 12 hours of MV compared to 5 hours. Alveolar-capillary permeability was increased after 12 hours compared to 5 hours, although differences did not reach statistical significance. Lung levels of inflammatory mediators did not further increase over time. Only in mice ventilated with increased strain, lung compliance declined and wet to dry ratio increased after 12 hours of MV compared to 5 hours.Conclusions. Deleterious effects of MV are partly dependent on its duration. Even lower tidal volumes with PEEP may initiate aspects of VILI after 12 hours of MV.

Syndecan-2–positive, Bone Marrow–derived Human Mesenchymal Stromal Cells Attenuate Bacterial-induced Acute Lung Injury and Enhance Resolution of Ventilator-induced Lung Injury in Rats

2018 ◽  
Vol 129 (3) ◽  
pp. 502-516 ◽  
Author(s):  
Claire Masterson ◽  
James Devaney ◽  
Shahd Horie ◽  
Lisa O’Flynn ◽  
Laura Deedigan ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Lung Injury ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Arterial Oxygenation ◽  
Human Mesenchymal Stromal Cells ◽  
Ventilator Induced Lung Injury ◽  
Enhanced Resolution ◽  
Macrophage Phagocytosis

Abstract What We Already Know about This Topic What This Article Tells Us That Is New Background Human mesenchymal stromal cells demonstrate promise for acute respiratory distress syndrome, but current studies use highly heterogenous cell populations. We hypothesized that a syndecan 2 (CD362)–expressing human mesenchymal stromal cell subpopulation would attenuate Escherichia coli–induced lung injury and enhance resolution after ventilator-induced lung injury. Methods In vitro studies determined whether CD362+ human mesenchymal stromal cells could modulate pulmonary epithelial inflammation, wound healing, and macrophage phagocytosis. Two in vivo rodent studies determined whether CD362+ human mesenchymal stromal cells attenuated Escherichia coli–induced lung injury (n = 10/group) and enhanced resolution of ventilation-induced injury (n = 10/group). Results CD362+ human mesenchymal stromal cells attenuated cytokine-induced epithelial nuclear factor kappa B activation, increased epithelial wound closure, and increased macrophage phagocytosis in vitro. CD362+ human mesenchymal stromal cells attenuated Escherichia coli–induced injury in rodents, improving arterial oxygenation (mean ± SD, 83 ± 9 vs. 60 ± 8 mmHg, P &lt; 0.05), improving lung compliance (mean ± SD: 0.66 ± 0.08 vs. 0.53 ± 0.09 ml · cm H2O−1, P &lt; 0.05), reducing bacterial load (median [interquartile range], 1,895 [100–3,300] vs. 8,195 [4,260–8,690] colony-forming units, P &lt; 0.05), and decreasing structural injury compared with vehicle. CD362+ human mesenchymal stromal cells were more effective than CD362− human mesenchymal stromal cells and comparable to heterogenous human mesenchymal stromal cells. CD362+ human mesenchymal stromal cells enhanced resolution after ventilator-induced lung injury in rodents, restoring arterial oxygenation (mean ± SD: 113 ± 11 vs. 89 ± 11 mmHg, P &lt; 0.05) and lung static compliance (mean ± SD: 0.74 ± 0.07 vs. 0.45 ± 0.07 ml · cm H2O−1, P &lt; 0.05), resolving lung inflammation, and restoring histologic structure compared with vehicle. CD362+ human mesenchymal stromal cells efficacy was at least comparable to heterogenous human mesenchymal stromal cells. Conclusions A CD362+ human mesenchymal stromal cell population decreased Escherichia coli–induced pneumonia severity and enhanced recovery after ventilator-induced lung injury.

scholarly journals Keratinocyte growth factor reduces alveolar epithelial susceptibility to in vitro mechanical deformation

2001 ◽  
Vol 281 (5) ◽  
pp. L1068-L1077 ◽  
Author(s):  
Jane Oswari ◽  
Michael A. Matthay ◽  
Susan S. Margulies
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Lung Injury ◽  
Keratinocyte Growth Factor ◽  
Alveolar Type ◽  
Alveolar Epithelial ◽  
Ventilator Induced Lung Injury ◽  
And Control

Keratinocyte growth factor (KGF) is a potent mitogen that prevents lung epithelial injury in vivo. We hypothesized that KGF treatment reduces ventilator-induced lung injury by increasing the alveolar epithelial tolerance to mechanical strain. We evaluated the effects of in vivo KGF treatment to rats on the response of alveolar type II (ATII) cells to in vitro controlled, uniform deformation. KGF (5 mg/kg) or saline (no-treatment control) was instilled intratracheally in rats, and ATII cells were isolated 48 h later. After 24 h in culture, both cell groups were exposed to 1 h of continuous cyclic strain (25% change in surface area); undeformed wells were included as controls. Cytotoxicity was evaluated quantitatively with fluorescent immunocytochemistry. There was >1% cell death in undeformed KGF-treated and control groups. KGF pretreatment significantly reduced deformation-related cell mortality to only 2.2 ± 1.3% (SD) from 49 ± 5.5% in control wells ( P < 0.001). Effects of extracellular matrix, actin cytoskeleton, and phenotype of KGF-treated and control cells were examined. The large reduction in deformation-induced cell death demonstrates that KGF protects ATII cells by increasing their strain tolerance and supports KGF treatment as a potential preventative measure for ventilator-induced lung injury.

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