Intrapulmonary Delivery of Bone Marrow-Derived Mesenchymal Stem Cells Improves Survival and Attenuates Endotoxin-Induced Acute Lung Injury in Mice 1 (original) (raw)
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American Journal of Physiology-lung Cellular and Molecular Physiology, 2007
Bone marrow-derived mesenchymal stem cells (BMDMSCs) appear to be important in repair of the chronic lung injury caused by bleomycin in mice. To determine effects of these BMDMSCs on an acute inflammatory response, we injected C57BL/6 mice intraperitoneally with 1mg/kg endotoxin followed either by intravenous infusion of 5 x10 5 BMDMSCs, the same number of lung fibroblasts or an equal volume of normal saline solution. Lungs harvested 6, 24 and 48 hours and 14 days after endotoxin showed that BMDMSC administration prevented endotoxin induced lung inflammation, injury and edema. Although we were able to detect donor cells in the lungs at 1 day after endotoxin, by 14 days no donor cells were detected. BMDMSC administration suppressed the endotoxin induced increase in circulating pro-inflammatory cytokines without decreasing circulating levels of anti-inflammatory mediators. Ex vivo cocultures of BMDMSC and lung cells from endotoxemic animals demonstrated a bilateral conversation in which lung cells stimulated proliferation and migration of stem cells and suppressed pro-inflammatory cytokine production by lung cells. We conclude that BMDMSCs decrease both the systemic and local inflammatory responses induced by endotoxin. These effects do not require either lung engraftment or differentiation of the stem cells and are due at least in part to the production of stem cell chemoattractants by the lungs and to humoral and physical interactions between stem cells and lung cells. We speculate that mobilization of this population of BMDMSCs may be a general mechanism for modulating an acute inflammatory response.
Aim: This study evaluated the potential of bone marrow derived mesenchymal stem cells (MSCs) to regulate cytokines and remodel the lung induced by lipopolysaccharide (LPS; O-antigen). Materials & methods: A group of mice (n = 21) was inoculated intraperitoneally with one dose 0.1 ml containing 0.025 mg LPS/mouse, and another treated intravenously with one dose of labeling bone marrow derived MSCs at 7.5 × 10 5 cell/mouse 4 h after LPS injection. All animals were sacrificed on the 1st, 7th and 14th days post-injection. Results: MSCs increased the level of IL-10 with suppression of TNF-α, decrease of collagen fibers and renewal of alveolar type I cells, together with lung tissue remodeling. Conclusion: MSCs were shown to modulate inflammatory cytokines (TNF-α and IL-10) and to differentiate into alveolar type I cells, which prevented fibrosis in lung tissue from LPS-treated mice. Lay abstract: This study sought to confirm the remodeling effect of mesenchymal stem cells (MSCs) on lungs injury resulting from lipopolysaccharide infection, as lipopolysaccharide has an important role in acute lung injury pathogenesis. MSCs decreased the level of TNF-α and increased the level of antinflammatory cells (IL-10), leading to prevention of fibrosis with renewal of alveolar type I cells. This research aids our understanding of the utility of MSCs in chronic lung injury treatment.
Critical Care, 2018
Background: Lung diseases such as acute respiratory distress syndrome (ARDS) have a high incidence worldwide. The current drug therapies for ARDS have supportive effects, making them inefficient. New methods such as stromal cell therapy are needed for this problem. Methods: This research was performed with ten New Zealand rabbits in two groups. Bone marrow aspiration was performed on the treated group, and mesenchymal stem cells were isolated and cultured. The experimental model of ARDS was induced using LPS from Escherichia coli strain O55:B5. Then, 10 10 bone marrow mesenchymal stem cells (BM-MSCs) were autologously transplanted intrapulmonary in the treatment group, and 1-2 ml of PBS in the control group. The clinical signs, computed tomographic (CT) scans, echocardiography, blood gas analysis, complete blood count, and cytokine levels were measured before and at 3, 6, 12, 24, 48, 72, and 168 h after BM-MSC transplant. Finally, the rabbits were killed, and histopathological examination was performed. Results: The results showed that BM-MSCs decreased the severity of clinical symptoms, the number of white blood cells and heterophils in the blood, the total cell count, and number of heterophils and macrophages in bronchoalveolar lavage, and balanced the values of arterial blood gases (increase in partial pressure of oxygen and O 2 saturation and decrease in the partial pressure of carbon dioxide). They also downregulated the tumor necrosis factor (TNF)-α and interleukin (IL)-6 concentrations and increased the IL-10 concentrations at different times compared with time 0 and in the control group, significantly. In the CT scan, a significant decrease in the Hounsfield units and total lung volume was found by echocardiography, and in comparing the two groups, a significant difference in the parameters was noticed. The histopathology demonstrated that the BM-MSCs were able to reduce the infiltration of inflammatory cells and pulmonary hemorrhage and edema. Conclusions: This study indicated that BM-MSCs play a significant role in the repair of lung injury.
Intensive Care Medicine Experimental, 2015
Background: The potential for mesenchymal stem cells (MSCs) to reduce the severity of experimental lung injury has been established in several pre-clinical studies. We have recently demonstrated that MSCs, and MSC-secreted factors (secretome), enhance lung repair and regeneration at 48 h following ventilation-induced lung injury (VILI). We wished to determine the potential for MSC therapy to exert beneficial effects in the early recovery phase following VILI when ongoing injury coexists with processes of repair, and to compare the efficacy of MSC therapy to the use of the secretome alone. Methods: Male Sprague-Dawley rats were anesthetized, oro-tracheally intubated, and subjected to high stretch mechanical ventilation until lung compliance had declined by 50 % of baseline. Animals were then weaned from mechanical ventilation, and anesthesia discontinued. Once awake and spontaneously ventilating, animals received an intravenous injection of either rodent MSCs (10 million/kg), MSC-conditioned medium, fibroblasts (10 million/kg), or vehicle. Thereafter, the animals were allowed to recover and the extent of lung injury/repair was determined after 4 h. Results: Treatment with MSCs diminished injury and enhanced recovery following VILI to a greater extent compared to MSC-conditioned medium, with fibroblasts proving ineffective. MSCs, but not their conditioned medium, attenuated indices of lung injury including oxygenation, respiratory compliance, and lung edema. Total lung water as assessed by wet:dry ratio, bronchoalveolar lavage total inflammatory cell, neutrophil counts, and alveolar IL-6 concentrations were reduced in the animals that received MSC therapy. Conclusions: The immunomodulating and/or reparative effect of MSCs is evident early after VILI in this model. MSC-conditioned medium was not as effective as the cells themselves in diminishing injury and restoring lung structure and function.
Cell Transplantation, 2010
The aim of this study was to test the hypothesis that bone marrow mononuclear cell (BMDMC) therapy led an improvement in lung mechanics and histology in endotoxin-induced lung injury. Twenty-four C57BL/6 mice were randomly divided into four groups ( n = 6 each). In the acute lung injur;y (ALI) group, Escherichia coli lipopolysaccharide (LPS) was instilled intratracheally (40 μg, IT), and control (C) mice received saline (0.05 ml, IT). One hour after the administration of saline or LPS, BMDMC (2 × 107 cells) was intravenously injected. At day 28, animals were anesthetized and lung mechanics [static elastance ( Est), resistive (Δ P1), and viscoelastic (Δ P2) pressures] and histology (light and electron microscopy) were analyzed. Immunogold electron microscopy was used to evaluate if multinucleate cells were type II epithelial cells. BMDMC therapy prevented endotoxin-induced lung inflammation, alveolar collapse, and interstitial edema. In addition, BMDMC administration led to epithelia...
International Journal of Current Microbiology and Applied Sciences
Acute respiratory distress syndrome (ARDS) is among the most common causes of respiratory failure in critically ill patients. Despite extensive research, ARDS remains a major cause of morbidity and mortality, with no effective pharmacological treatment options. The present study was conducted to evaluate the efficacy of bone marrow-derived stem cells (BM-MSCs) compared with Dexamethasone (Dex) and Sodium bicarbonate (NaHCO 3) against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Rats were injected with 20µl of LPS of Escherichia coli in each nostril for two consecutive days. Treatments were carried out by administration of BM-MSCs (1 × 10 6 cells/rat), Dexamethasone (2mg/kg/i.p.) once before induction with LPS and sodium bicarbonate (10-15 ml/day for two consecutive days, while last dose was given 30 minutes before LPS inhalation). Treatment with BM-MSCs significantly decreased inflammatory influx, total leukocyte count in peripheral blood, reduction in oxidative stress, reversed depleted GSH in lung tissue, reduced inflammatory responses in rat nasal airways as detected by mucin rMuc-5AC gene expression in lung tissue when compared with LPS group. Moreover, BM-MSCs displayed signs of lung recovery and the severity of lung injury was significantly reduced when compared to the LPS group and restoring the normal histological picture of lung as well as apoptosis.
Stem Cell Reviews and Reports, 2013
We hypothesized that bone marrow-derived mesenchymal stem cells (BM-MSCs) would have a possible role in the treatment of acute respiratory distress syndrome (ARDS). ARDS disease model was developed in Wistar albino male rats by intratracheal instillation of physiological saline solution. Anesthezied and tracheotomized rats (n08) with ARDS were pressure-controlled ventilated. Isolated and characterized rat (r-) BM-MSCs were labeled with GFP gene, and introduced in the lungs of the ARDS ratmodel. After applying of MSCs, the life span of each rat was recorded. When rats died, their lung tissues were removed for histopathological examination. Also the tissue sections were analyzed for GFP labeled rBM-MSCs and stained for vimentin, CK19, proinflammatory (MPO, IL-1β, IL-6 and MIP-2) and anti-inflammatory [IL-1ra and prostaglandin E2 receptor (EP3)] cytokines. The histopathological signs of rat-model ARDS were similar to the acute phase of ARDS in humans. rBM-MSCs were observed to home in lung paranchyma. Although the infiltration of neutrophils slightly decreased in the interalveolar, peribronchial and perivascular area, a notable improvement was determined in the degree of hemorrhage, edema and hyaline membrane formation in rats treated with rBM-MSCs. Also decreased proinflammatory cytokines levels and increased the intensity of anti-inflammatory cytokines were established. Therefore MSCs could promote alveoar epithelial repair by mediating of cytokines from a proinflammatory to an antiinflammatory response. As a novel therapeutic approach, mesenchymal stem cell treatment with intratracheal injection could be helpful in the management of critically ill patients with ARDS.
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2012
Mortality and morbidity of acute lung injury and acute respiratory distress syndrome remain high because of the lack of pharmacological therapies to prevent injury or promote repair. Mesenchymal stem cells (MSCs) prevent lung injury in various experimental models, despite a low proportion of donor-derived cell engraftment, suggesting that MSCs exert their beneficial effects via paracrine mechanisms. We hypothesized that soluble factors secreted by MSCs promote the resolution of lung injury in part by modulating alveolar macrophage (AM) function. We tested the therapeutic effect of MSC-derived conditioned medium (CdM) compared with whole MSCs, lung fibroblasts, and fibroblast-CdM. Intratracheal MSCs and MSC-CdM significantly attenuated lipopolysaccharide (LPS)-induced lung neutrophil influx, lung edema, and lung injury as assessed by an established lung injury score. MSC-CdM increased arginase-1 activity and Ym1 expression in LPS-exposed AMs. In vivo, AMs from LPS-MSC and LPS-MSC CdM...