Acute respiratory distress syndrome (ARDS) is a pulmonary syndrome with growing prevalence and high mortality and morbidity that increase with age. There is no current therapy able to restore pulmonary function in ARDS patients. Preclinical models of ARDS have demonstrated that intratracheal or systemic administration of mesenchymal stem cells (MSCs) protects the lung against injury. The mechanisms responsible for the protective effects are multiple, including the secretion of multiple paracrine factors capable of modulating the immune response and restoring epithelial and endothelial integrity. Recent studies have demonstrated that MSCs can also control oxidative stress, transfer functional mitochondria to the damaged cells, and control bacterial infection by secretion of antibacterial peptides. These characteristics make MSCs promising candidates for ARDS therapy.

1.
Rincon F, et al: Impact of acute lung injury and acute respiratory distress syndrome after traumatic brain injury in the United States. Neurosurgery 2012;71:795-803.
2.
Angus DC, et al: Healthcare costs and long-term outcomes after acute respiratory distress syndrome: a phase III trial of inhaled nitric oxide. Crit Care Med 2006;34:2883-2890.
3.
Walkey AJ, et al: Acute respiratory distress syndrome: epidemiology and management approaches. Clin Epidemiol 2012;4:159-169.
4.
Serpa Neto A, et al: Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA 2012;308:1651-1659.
5.
Hayes M, et al: Clinical review: stem cell therapies for acute lung injury/acute respiratory distress syndrome - hope or hype? Crit Care 2012;16:205.
6.
Rubenfeld GD, et al: Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:1685-1693.
7.
Davidson TA, et al: The effect of acute respiratory distress syndrome on long-term survival. Am J Respir Crit Care Med 1999;160:1838-1842.
8.
Herridge MS, et al: Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364:1293-1304.
9.
Ranieri VM, et al: Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307:2526-2533.
10.
Ferguson ND, et al: The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 2012;38:1573-1582.
11.
Berger G, et al: Sepsis impairs alveolar epithelial function by downregulating Na-K-ATPase pump. Am J Physiol Lung Cell Mol Physiol 2011;301:L23-L30.
12.
Vadasz I, Weiss CH, Sznajder JI: Ubiquitination and proteolysis in acute lung injury. Chest 2012;141:763-771.
13.
Piantadosi CA, Schwartz DA: The acute respiratory distress syndrome. Ann Intern Med 2004;141:460-470.
14.
Ware LB, Matthay MA: Clinical practice. Acute pulmonary edema. N Engl J Med 2005;353:2788-2796.
15.
Erickson SE, et al: Recent trends in acute lung injury mortality: 1996-2005. Crit Care Med 2009;37:1574-1579.
16.
Proudfoot AG, Hind M, Griffiths MJ: Biomarkers of acute lung injury: worth their salt? BMC Med 2011;9:132.
17.
Tzouvelekis A, Pneumatikos I, Bouros D: Serum biomarkers in acute respiratory distress syndrome an ailing prognosticator. Respir Res 2005;6:62.
18.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-1308.
19.
Wiedemann HP, et al: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564-2575.
20.
Numata M, et al: Inhibition of inducible nitric oxide synthase prevents LPS-induced acute lung injury in dogs. J Immunol 1998;160:3031-3037.
21.
Camamo JM, McCoy RH, Erstad BL: Retrospective evaluation of inhaled prostaglandins in patients with acute respiratory distress syndrome. Pharmacotherapy 2005;25:184-190.
22.
Treml B, et al: Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med 2010;38:596-601.
23.
Khilnani GC, Hadda V: Corticosteroids and ARDS: a review of treatment and prevention evidence. Lung India 2011;28:114-119.
24.
Lewis JF, Veldhuizen RA: The future of surfactant therapy during ALI/ARDS. Semin Respir Crit Care Med 2006;27:377-388.
25.
Combes A, et al: Extracorporeal membrane oxygenation for respiratory failure in adults. Curr Opin Crit Care 2012;18:99-104.
26.
Barbas CS, et al: Goal-oriented respiratory management for critically ill patients with acute respiratory distress syndrome. Crit Care Res Pract 2012;2012:952168.
27.
Ware LB, et al: Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest 2010;137:288-296.
28.
McCulloch EA, Till JE: Perspectives on the properties of stem cells. Nat Med 2005;11:1026-1028.
29.
Dominici M, et al: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315-317.
30.
Wu Y, Zhao RC: The role of chemokines in mesenchymal stem cell homing to myocardium. Stem Cell Rev 2012;8:243-250.
31.
Shim W, et al: G-CSF for stem cell therapy in acute myocardial infarction: friend or foe? Cardiovasc Res 2011;89:20-30.
32.
Bartsch K, et al: Mesenchymal stem cells remain host-derived independent of the source of the stem-cell graft and conditioning regimen used. Transplantation 2009;87:217-221.
33.
Schenk S, et al: Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor. Stem Cells 2007;25:245-251.
34.
Ji JF, et al: Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells 2004;22:415-427.
35.
Munoz-Elias G, et al: Adult bone marrow stromal cells in the embryonic brain: engraftment, migration, differentiation, and long-term survival. J Neurosci 2004;24:4585-4595.
36.
De Bari C, et al: Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane. J Cell Biol 2003;160:909-918.
37.
Morigi M, et al: Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol 2004;15:1794-1804.
38.
Xu J, et al: Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol 2007;293:L131-L141.
39.
Akiyama K, et al: Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 2012;10:544-555.
40.
Grove DA, et al: Attenuation of early airway obstruction by mesenchymal stem cells in a murine model of heterotopic tracheal transplantation. J Heart Lung Transplant 2011;30:341-350.
41.
Li TS, et al: Regeneration of infarcted myocardium by intramyocardial implantation of ex vivo transforming growth factor-beta-preprogrammed bone marrow stem cells. Circulation 2005;111:2438-2445.
42.
Miyahara Y, et al: Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 2006;12:459-465.
43.
Iso Y, et al: Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment. Biochem Biophys Res Commun 2007;354:700-706.
44.
Lee RH, et al: Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009;5:54-63.
45.
Ortiz LA, et al: Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 2003;100:8407-8411.
46.
Rojas M, et al: Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 2005;33:145-152.
47.
Luan Y, et al: Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism. Int Immunopharmacol 2012;14:432-437.
48.
Kim KC, et al: Changes of gene expression after bone marrow cell transfusion in rats with monocrotaline-induced pulmonary hypertension. J Korean Med Sci 2012;27:605-613.
49.
Stewart DJ, Mei SH: Cell-based therapies for lung vascular diseases: lessons for the future. Proc Am Thorac Soc 2011;8:535-540.
50.
Luan Y, et al: Implantation of mesenchymal stem cells improves right ventricular impairments caused by experimental pulmonary hypertension. Am J Med Sci 2012;343:402-406.
51.
de Faria CA, et al: Experimental basis and new insights for cell therapy in chronic obstructive pulmonary disease. Stem Cell Rev 2012;8:1236-1244.
52.
Guan XJ, et al: Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors. J Cell Biochem 2013;114:323-335.
53.
Huh JW, et al: Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol 2011;301:L255-L266.
54.
Lee RH, et al: Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci USA 2006;103:17438-17443.
55.
Nemeth K, et al: Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009;15:42-49.
56.
Mei SH, et al: Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010;182:1047-1057.
57.
Firinci F, et al: Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma. Int Immunopharmacol 2011;11:1120-1126.
58.
Parekkadan B, et al: Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS One 2007;2:e941.
59.
Togel F, et al: Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005;289:F31-F42.
60.
Ionescu L, et al: Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am J Physiol Lung Cell Mol Physiol 2012;303:L967-L977.
61.
Xu YL, et al: Intravenous transplantation of mesenchymal stem cells attenuates oleic acid induced acute lung injury in rats. Chin Med J (Engl) 2012;125:2012-2018.
62.
Lee JW, et al: Potential application of mesenchymal stem cells in acute lung injury. Expert Opin Biol Ther 2009;9:1259-1270.
63.
Matthay MA: Treatment of acute lung injury: clinical and experimental studies. Proc Am Thorac Soc 2008;5:297-299.
64.
Mei SH, et al: Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med 2007;4:e269.
65.
Stolzing A, et al: Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev 2008;129:163-173.
66.
Bork S, et al: DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell 2010;9:54-63.
67.
Roobrouck VD, Ulloa-Montoya F, Verfaillie CM: Self-renewal and differentiation capacity of young and aged stem cells. Exp Cell Res 2008;314:1937-1944.
68.
Choumerianou DM, et al: Comparative study of stemness characteristics of mesenchymal cells from bone marrow of children and adults. Cytotherapy 2010;12:881-887.
69.
Zhou S, et al: Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 2008;7:335-343.
70.
Alt EU, et al: Aging alters tissue resident mesenchymal stem cell properties. Stem Cell Res 2012;8:215-225.
71.
Stolzing A, Bauer E, Scutt A: Suspension cultures of bone-marrow-derived mesenchymal stem cells: effects of donor age and glucose level. Stem Cells Dev 2012;21:2718-2723.
72.
Gorskaya YF, Danilova TA, Nesterenko VG: Age-associated reduction of the count and functional activity of stromal precursor cells can be caused by both true reduction (exhaustion) of cell pool and regulatory effects of the organism. Bull Exp Biol Med 2011;151:210-214.
73.
Mansilla E, et al: Could metabolic syndrome, lipodystrophy, and aging be mesenchymal stem cell exhaustion syndromes? Stem Cells Int 2011;2011:943216.
74.
Shao L, et al: Reactive oxygen species and hematopoietic stem cell senescence. Int J Hematol 2011;94:24-32.
75.
Kucia M, et al: Reduced number of VSELs in the bone marrow of growth hormone transgenic mice indicates that chronically elevated Igf1 level accelerates age-dependent exhaustion of pluripotent stem cell pool: a novel view on aging. Leukemia 2011;25:1370-1374.
76.
Glauche I, Thielecke L, Roeder I: Cellular aging leads to functional heterogeneity of hematopoietic stem cells: a modeling perspective. Aging Cell 2011;10:457-465.
77.
Goldschmidt-Clermont PJ, et al: Inflammation, stem cells and atherosclerosis genetics. Curr Opin Mol Ther 2010;12:712-723.
78.
Chilosi M, et al: Epithelial stem cell exhaustion in the pathogenesis of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 2010;27:7-18.
79.
Durik M, et al: Nucleotide excision DNA repair is associated with age-related vascular dysfunction. Circulation 2012;126:468-478.
80.
Gregg SQ, et al: A mouse model of accelerated liver aging caused by a defect in DNA repair. Hepatology 2012;55:609-621.
81.
Gregg SQ, Robinson AR, Niedernhofer LJ: Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease. DNA Repair (Amst) 2011;10:781-791.
82.
Goss JR, et al: Premature aging-related peripheral neuropathy in a mouse model of progeria. Mech Ageing Dev 2011;132:437-442.
83.
Vo N, et al: Accelerated aging of intervertebral discs in a mouse model of progeria. J Orthop Res 2010;28:1600-1607.
84.
Lavasani M, et al: Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nat Commun 2012;3:608.
85.
Conboy IM, et al: Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 2005;433:760-764.
86.
Fan M, et al: The effect of age on the efficacy of human mesenchymal stem cell transplantation after a myocardial infarction. Rejuvenation Res 2010;13:429-438.
87.
Hermann A, et al: Age-dependent neuroectodermal differentiation capacity of human mesenchymal stromal cells: limitations for autologous cell replacement strategies. Cytotherapy 2010;12:17-30.
88.
Guillot PV, et al: Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC. Stem Cells 2007;25:646-654.
89.
Meisel R, et al: Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 2011;25:648-654.
90.
Krasnodembskaya A, et al: Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 2010;28:2229-2238.
91.
Nijnik A, Hancock RE: The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr Opin Hematol 2009;16:41-47.
92.
Vallabhaneni KC, Haller H, Dumler I: Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes. Stem Cells Dev 2012;21:3104-3113.
93.
Gupta N, et al: Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007;179:1855-1863.
94.
Yamada M, et al: Bone marrow-derived progenitor cells are important for lung repair after lipopolysaccharide-induced lung injury. J Immunol 2004;172:1266-1272.
95.
Eggenhofer E, et al: Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol 2012;3:297.
96.
Kang SK, et al: Journey of mesenchymal stem cells for homing: strategies to enhance efficacy and safety of stem cell therapy. Stem Cells Int 2012;2012:342968.
97.
Geiser T, et al: Pulmonary edema fluid from patients with acute lung injury augments in vitro alveolar epithelial repair by an IL-1beta-dependent mechanism. Am J Respir Crit Care Med 2001;163:1384-1388.
98.
Ajuebor MN, et al: Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: evidence for an inhibitory loop involving endogenous IL-10. J Immunol 1999;162:1685-1691.
99.
Takahata Y, et al: Functional expression of beta2 adrenergic receptors responsible for protection against oxidative stress through promotion of glutathione synthesis after Nrf2 upregulation in undifferentiated mesenchymal C3H10T1/2 stem cells. J Cell Physiol 2009;218:268-275.
100.
Iyer SS, et al: Cysteine redox potential determines pro-inflammatory IL-1beta levels. PLoS One 2009;4:e5017.
101.
Spees JL, et al: Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci USA 2006;103:1283-1288.
102.
Islam MN, et al: Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012;18:759-765.
103.
Gupta N, et al: Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax 2012;67:533-539.
104.
Matthay MA, Wiener-Kronish JP: Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Respir Dis 1990;142:1250-1257.
105.
Ware LB, Matthay MA: Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;163:1376-1383.
106.
Xu J, et al: Mesenchymal stem cell-based angiopoietin-1 gene therapy for acute lung injury induced by lipopolysaccharide in mice. J Pathol 2008;214:472-481.
107.
Lee JW, et al: Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci USA 2009;106:16357-16362.
108.
Ortiz LA, et al: Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 2007;104:11002-11007.
109.
Zhao F, et al: Therapeutic effects of bone marrow-derived mesenchymal stem cells engraftment on bleomycin-induced lung injury in rats. Transplant Proc 2008;40:1700-1705.
110.
Lee SH, et al: Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis. Respir Res 2010;11:16.
111.
Gonzalez-Rey E, et al: Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009;58:929-939.
112.
Iyer SS, et al: Effect of bone marrow-derived mesenchymal stem cells on endotoxin-induced oxidation of plasma cysteine and glutathione in mice. Stem Cells Int 2010;2010:868076.
113.
Danchuk S, et al: Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-alpha-induced protein 6. Stem Cell Res Ther 2011;2:27.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.