Mairead Hayes

Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat

Background Bone-marrow derived mesenchymal stem cells (MSCs) reduce the severity of evolving acute lung injury (ALI), but their ability to repair the injured lung is not clear. A study was undertaken to determine the potential for MSCs to enhance repair after ventilator-induced lung injury (VILI) and elucidate the mechanisms underlying these effects. Methods Anaesthetised rats underwent injurious ventilation which produced severe ALI. Following recovery, they were given an intravenous injection of MSCs (2×106 cells) or vehicle immediately and a second dose 24 h later. The extent of recovery following VILI was assessed after 48 h. Subsequent experiments examined the potential for non-stem cells and for the MSC secretome to enhance VILI repair. The contribution of specific MSC-secreted mediators was then examined in a wound healing model. Results MSC therapy enhanced repair following VILI. MSCs enhanced restoration of systemic oxygenation and lung compliance, reduced total lung water, decreased lung inflammation and histological lung injury and restored lung structure. They attenuated alveolar tumour necrosis factor α concentrations while increasing concentrations of interleukin 10. These effects were not seen with non-stem cells (ie, rat fibroblasts). MSC-secreted products also enhanced lung repair and attenuated the inflammatory response following VILI. The beneficial effect of the MSC secretome on repair of pulmonary epithelial wounds was attenuated by prior depletion of keratinocyte growth factor. Conclusion MSC therapy enhances lung repair following VILI via a paracrine mechanism that may be keratinocyte growth factor-dependent.

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

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-&agr; (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.

Clinical review: Stem cell therapies for acute lung injury/acute respiratory distress syndrome - hope or hype?

A growing understanding of the complexity of the pathophysiology of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), coupled with advances in stem cell biology, has led to a renewed interest in the therapeutic potential of stem cells for this devastating disease. Mesenchymal stem cells appear closest to clinical translation, given the evidence that they may favourably modulate the immune response to reduce lung injury, while maintaining host immune-competence and also facilitating lung regeneration and repair. The demonstration that human mesenchymal stem cells exert benefit in the endotoxin-injured human lung is particularly persuasive. Endothelial progenitor cells also demonstrate promise in reducing endothelial damage, which is a key pathophysiological feature of ALI. Embryonic and induced pluripotent stem cells are at an earlier stage in the translational process, but offer the hope of directly replacing injured lung tissue. The lung itself also contains endogenous stem cells, which may ultimately offer the greatest hope for lung diseases, given their physiologic role in replacing and regenerating native lung tissues. However, significant deficits remain in our knowledge regarding the mechanisms of action of stem cells, their efficacy in relevant pre-clinical models, and their safety, particularly in critically ill patients. These gaps need to be addressed before the enormous therapeutic potential of stem cells for ALI/ARDS can be realised.

Can ‘Permissive’ Hypercapnia Modulate the Severity of Sepsis-induced ALI/ARDS?

Ventilatory strategies that reduce lung stretch by reducing tidal and minute ventilation, which results in a ‘permissive’ hypercapnic acidosis, improve outcome in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) [1], [2]. Reassuringly, evidence from clinical studies attests to the safety and lack of detrimental effects of hypercapnic acidosis [2]. Of particular importance, a secondary analysis of data from the ARDSnet tidal volume study [1] demonstrated that the presence of hypercapnic acidosis at the time of randomization was associated with improved patient survival in patients who received high tidal volume ventilation [3]. These findings have resulted in a shift in paradigms regarding hypercapnia — from avoidance to tolerance — with hypercapnia increasingly permitted in order to realize the benefits of low lung stretch. Consequently, low tidal and minute volume ventilation and the accompanying ‘permissive’ hypercapnia are now the standard of care for patients with ALI/ARDS, and are increasingly used in the ventilatory management of a diverse range of diseases leading to acute severe respiratory failure, including asthma and chronic obstructive pulmonary disease.

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

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.

Mesenchymal stem cells - a promising therapy for Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS) constitutes a spectrum of severe acute respiratory failure in response to a variety of inciting stimuli that is the leading cause of death and disability in the critically ill. Despite decades of research, there are no therapies for ARDS, and management remains supportive. A growing understanding of the complexity of the pathophysiology of ARDS, coupled with advances in stem cell biology, has lead to a renewed interest in the therapeutic potential of mesenchymal stem cells for ARDS. Recent evidence suggests that mesenchymal stem cells can modulate the immune response to reduce injury and also increase resistance to infection, while also facilitating regeneration and repair of the injured lung. This unique combination of effects has generated considerable excitement. We review the biological characteristics of mesenchymal stem cells that underlie their therapeutic potential for ARDS. We also summarise existing pre-clinical evidence, evaluate the potential and pitfalls of using mesenchymal stem cells for treatment, and examine the likely future directions for mesenchymal stem cells in ARDS.

Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia

IntroductionNuclear factor (NF)-κB is central to the pathogenesis of inflammation in acute lung injury, but also to inflammation resolution and repair. We wished to determine whether overexpression of the NF-κB inhibitor IκBα could modulate the severity of acute and prolonged pneumonia-induced lung injury in a series of prospective randomized animal studies.MethodsAdult male Sprague-Dawley rats were randomized to undergo intratracheal instillation of (a) 5 × 109 adenoassociated virus (AAV) vectors encoding the IκBα transgene (5 × 109 AAV-IκBα); (b) 1 × 1010 AAV-IκBα; (c) 5 × 1010 AAV-IκBα; or (d) vehicle alone. After intratracheal inoculation with Escherichia coli, the severity of the lung injury was measured in one series over a 4-hour period (acute pneumonia), and in a second series after 72 hours (prolonged pneumonia). Additional experiments examined the effects of IκBα and null-gene overexpression on E. coli-induced and sham pneumonia.ResultsIn acute pneumonia, IκBα dose-dependently decreased lung injury, improving arterial oxygenation and lung static compliance, reducing alveolar protein leak and histologic injury, and decreasing alveolar IL-1β concentrations. Benefit was maximal at the intermediate (1 × 1010) IκBα vector dose; however, efficacy was diminished at the higher (5 × 1010) IκBα vector dose. In contrast, IκBα worsened prolonged pneumonia-induced lung injury, increased lung bacterial load, decreased lung compliance, and delayed resolution of the acute inflammatory response.ConclusionsInhibition of pulmonary NF-κB activity reduces early pneumonia-induced injury, but worsens injury and bacterial load during prolonged pneumonia.

Mesenchymal Stem/Stromal Cells: Opportunities and Obstacles in ARDS

The acute respiratory distress syndrome (ARDS) constitutes a major cause of death in critical care worldwide, with mortality rates of 40–60 % even with ongoing advances in care. Despite being the focus of ongoing intensive research efforts for over four decades, there are no pharmacologic therapies for acute lung injury (ALI)/ARDS. The lack of success to date with standard ‘pharmacologic’ approaches suggests the need to consider more complex therapeutic approaches, aimed at reducing early injury while maintaining host immune competence, and facilitating (or at least not inhibiting) lung regeneration and repair.