Effects of Intratracheal Mesenchymal Stromal Cell Therapy during Recovery and Resolution after Ventilator-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 , P insp 35 cm H 2 O,) 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 × 10 6 cells, n = 8); (4) intratracheal MSCs (4 × 10 6 cells, n = 8); (5) intratracheal conditioned medium (300 µl, n = 8); or (6) intravenous MSCs (4 × 10 6 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 H 2 O −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

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

“…Mesenchymal stromal cells (MSCs) are increasingly recognized as a promising candidate therapy for ARDS (6). We and others have reported that MSCs improve survival, reduce inflammation, and enhance bacterial clearance in preclinical models of lung injury (7)(8)(9)(10)(11)(12)(13)(14). Secretion of paracrine factors, modulation of host cells via secretion of extracellular vesicles (EVs), and mitochondrial transfer were shown to be important for the therapeutic effects of MSCs in these studies.…”

Adult stem cells: potential implications for perioperative medicine

“…For example, in a preclinical model of ventilator-induced lung injury, MSCs administered intratracheally or intravenously reduced pro-inflammatory cytokine production and improved arterial oxygenation and lung compliance. 11 Similarly, MSCs delivered in several large animal models of myocardial infarction have increased ejection fraction and decreased scar size. 12 Mesenchymal stromal cells have also proven useful in preclinical acute kidney injury where they displayed potent anti-apoptotic and cytoprotective effects.…”

“…In preclinical models of acute lung injury, it has been shown that these MSC culture media concentrates may be as effective as MSCs themselves in reducing inflammation. 11,19 Future research will be needed for further characterization of the therapeutic factors released by MSCs.…”

“…Par exemple, dans un modèle préclinique de lésion pulmonaire induite par la ventilation, les CSM administrées par voie intra-trachéale ou intraveineuse ont réduit la production de cytokines pro-inflammatoires et amélioré l'oxygénation artérielle et la compliance pulmonaire. 11 De la même façon, les CSM administrées dans plusieurs importants modèles animaux d'infarctus du myocarde ont augmenté la fraction d'éjection et réduit la taille de la cicatrice. 12 Les cellules stromales mésenchymateuses se sont également avérées utiles dans le traitement des lésions rénales aiguës précliniques, où elles ont démontré d'importants effets anti-apoptotiques et cytoprotecteurs.…”

“…Dans des modèles précliniques de lésion pulmonaire aiguë, il a été démontré que ces concentrés de milieux de culture de CSM pouvaient être aussi efficaces que les CSM pour réduire l'inflammation. 11,19 Des recherches supplémentaires seront nécessaires afin de mieux caractériser les facteurs thérapeutiques libérés par les CSM. 21 Dans une étude semblable, lorsque des CSM ont été exposées à la bupivacaïne, à la ropivacaïne ou à la lidocaïne, on a observé que l'administration de lidocaïne avait un effet cytotoxique significatif.…”