Editorial Views  |   June 2012
Cell-based Therapy for Acute Lung Injury: Are We There Yet?
Author Affiliations & Notes
  • Jae-Woo Lee, M.D.
  • Yinggang Zhu, M.D.
  • Michael A. Matthay, M.D.
  • *Department of Anesthesiology and Cardiovascular Research Institute, University of California San Francisco, San Francisco, California. . Department of Pulmonary Medicine, Fudan University, Shanghai, China. Department of Anesthesiology and Cardiovascular Research Institute and Department of Medicine, University of California San Francisco.
Article Information
Editorial Views / Respiratory System
Editorial Views   |   June 2012
Cell-based Therapy for Acute Lung Injury: Are We There Yet?
Anesthesiology 6 2012, Vol.116, 1189-1191. doi:10.1097/ALN.0b013e3182567fc5
Anesthesiology 6 2012, Vol.116, 1189-1191. doi:10.1097/ALN.0b013e3182567fc5
ACUTE lung injury (ALI) and acute respiratory distress syndrome remain one of the most common causes of acute respiratory failure in critically ill patients.1 Despite extensive research, current treatment options remain primarily supportive with lung protective ventilation and a fluid conservative strategy. Recently, the potential use of cell-based therapy has generated considerable interest for the treatment of lung diseases, including ALI.2 In this month's issue of ANESTHESIOLOGY, Cao et al.  add to the literature by studying the potential therapeutic role of circulating autologous endothelial progenitor cells (EPC) in endotoxin-induced ALI in rabbits.3 
“Recently, the potential use of cell-based therapy has generated considerable interest for the treatment of lung diseases, including [acute lung injury].”
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Much of the initial interest in cell-based therapy for treatment of ALI originated from the multipotent nature of bone-marrow–derived cells. In 2001, Krause et al.  4 reported that a single bone-marrow–derived hematopoietic stem cell in mice could give rise to cells of multiple different organs, including the lung. The authors reported up to 20% engraftment of bone-marrow–derived cells in the lung, including epithelial cells, from a single hematopoietic precursor. This report stimulated additional investigations into the possibility that adult bone-marrow–derived stem cells might be able to regenerate the lung epithelium and/or endothelium. Initially, the regenerative potential of bone-marrow–derived EPC was studied predominantly in models of endothelial injury from cardiovascular disease, particularly after myocardial infarction or pulmonary arterial hypertension.5  9 More recently, several investigators demonstrated an improvement in pulmonary alveolar-capillary barrier function in lung injury models, including oleic acid in rabbits and endotoxin in rats after EPC therapy.10,11 However, subsequent studies indicate that the level of engraftment of bone-marrow–derived cells in lung injury was low, with observed rates of less than 5%.12  16 
In their study, Cao et al.  found that intravenous infusion of EPC 4 h after the induction of endotoxin-induced injury significantly improved oxygenation (ratio of partial pressure of oxygen to fraction of inspired oxygen ratio) and histologic indices of lung injury, including the infiltration of polymorphonuclear cells, the extent of hyaline membrane formation and hemorrhage, and the lung wet-to-dry ratio as a measure of pulmonary edema at 48 h. EPC infusion suppressed the concentrations of the inflammatory cytokine, IL-1β, and an adhesion molecule, ICAM-1, and also reduced concentrations of reactive oxygen species, nitric oxide and malondialdehyde. The authors speculated that the therapeutic effect of EPC could be attributable to endothelial repair of the damaged pulmonary vascular wall by intercalating of the EPC into the injured capillaries or immunomodulation of the inflammatory and oxidant responses, including release of the antiinflammatory cytokine IL-10 and induction of higher concentrations of superoxide dismutase. The authors studied the trafficking of the EPC to the lung with immunohistochemistry and fluorescence-conjugated cell tracers for 48 h. However, because of the short time period of injury studied and the fact that the intravenous infusion of bone-marrow–derived cells typically are initially trapped in the pulmonary microcirculation, additional studies are needed to determine the contribution of engraftment in the therapeutic response of EPC. Cao et al.  also identified the immunomodulatory properties of EPC as another potential therapeutic mechanism underlying the beneficial effect of EPC in lung injury.
The article by Cao et al.  has several limitations. First, the authors were not able to identify the mechanisms of benefit of EPC in these studies but provided circumstantial data suggesting engraftment or antioxidant or antiinflammatory effects. Second, an autologous source of the EPC was used for therapy, suggesting that an allogeneic source may cause an immune reaction in the host in a clinical setting. It is unclear if EPC are immunoprivileged in a manner similar to that of other adult stem cells, lacking in major histocompatibility complex I or II antigen expression, and able to evade a host response. Patients with ALI or acute respiratory distress syndrome usually experience rapid lung injury, so it would not be practical to harvest and culture circulating EPC from the patient before clinical use. In addition, the underlying causes of ALI, including infection, might alter the phenotype or number of circulating EPC or EPC from the bone marrow. For example, Burnham et al.  found a higher number of colony-forming units of EPC from patients with ALI compared with healthy control subjects, and in patients with ALI, an increased number of circulating EPC were associated with improved survival, suggesting that circulating EPC were mobilized from the bone marrow to replenish the injured endothelium.17 Would these circulating EPC behave in a manner similar to that of circulating EPC or EPC from the bone marrow from otherwise healthy patients?
Finally, would EPC be the most effective cellular therapy for ALI. Another bone-marrow–derived adult stem or progenitor cell, mesenchymal stem cells (MSC), has been studied extensively in lung injury models. MSC secrete multiple paracrine factors that can regulate endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth.18 In preclinical animal models and in an isolated perfused human lung preparation, MSC have been effective in both endotoxin and live Escherichia coli  bacteria pneumonia-induced lung injury, in part through the secretion of growth factors, such as keratinocyte growth factor, and antiinflammatory cytokines, IL-10.19  21 There are currently more than 200 clinical trials registered with  testing MSC in a variety of disorders, including graft versus  host disease, Crohn's disease, acute myocardial infarction, and acute kidney failure. More recently, MSC have been tested in a clinical trial for chronic obstructive pulmonary disease and bronchopulmonary dysplasia.
In addition, endogenous adult human lung stem cells recently were described with reparative and regenerative properties. Kajstura et al.  reported a human c-KIT–positive adult lung stem cell that was clonogenic and able to regenerate the architecture of the lung bronchiole, alveoli, and arteriole after cryoablation injury in mice.22 However, the study needs to be replicated to determine the translational potential of these cells for acute or chronic lung diseases. Chapman et al.  discovered a subpopulation of mouse alveolar epithelial cells expressing the laminin receptor α6β4 that was capable of forming CC10-positive airway-like and SPC-positive saccular structures in a novel in vivo  embryonic lung organoid assay.23 Surprisingly, in a bleomycin mouse model of lung injury, the authors found that the majority of alveolar type II cells formed after injury were not derived from preexisting type II cells but from these α6β4 alveolar epithelial cells.
In conclusion, despite its limitations, the study by Cao et al.  raises several important questions concerning the use of cell-based therapy for lung injury. What is the contribution of engraftment (if any) and of immunomodulation by the release of paracrine effector molecules or microvesicles24 in the therapeutic effect of stem or progenitor cells? What is the most effective progenitor or stem cell to test clinically? In preclinical animal and human models of lung injury, both progenitor and adult stem cells have been shown to be effective in short-term models of ALI. In the clinical syndrome, ALI–acute respiratory distress syndrome, depending on the etiology and associated comorbidities, mortality rates range from 20 to 40%. Thus, innovative therapies are needed. In the future, well-designed clinical trials are warranted to test cell-based therapies for safety and efficacy.
Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 2000; 342:1334–49
Weiss DJ, Kolls JK, Ortiz LA, Panoskaltsis-Mortari A, Prockop DJ: Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc 2008; 5:637–67
Cao J-P, He X-Y, Xu H-T, Zhou Z, Shi X-Y: Autologous transplantation of peripheral blood-derived circulating endothelial progenitor cells attenuates endotoxin-induced acute lung injury in rabbits by direct endothelial repair and indirect immunomodulation. ANESTHESIOLOGY 2012; 116:1278–87
Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ: Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105:369–77
Kaushal S, Amiel GE, Guleserian KJ, Shapira OM, Perry T, Sutherland FW, Rabkin E, Moran AM, Schoen FJ, Atala A, Soker S, Bischoff J, Mayer JE Jr: Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo  . Nat Med 2001;7:1035–40
Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Böhm M, Nickenig G: Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005; 353:999–1007
Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM, REPAIR-AMI Investigators: Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006; 355:1210–21
Assmus B, Schächinger V, Teupe C, Britten M, Lehmann R, Döbert N, Grünwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM: Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 2002; 106:3009–17
Toya SP, Malik AB: Role of endothelial injury in disease mechanisms and contribution of progenitor cells in mediating endothelial repair. Immunobiology 2012; 217:569–80
Lam CF, Liu YC, Hsu JK, Yeh PA, Su TY, Huang CC, Lin MW, Wu PC, Chang PJ, Tsai YC: Autologous transplantation of endothelial progenitor cells attenuates acute lung injury in rabbits. ANESTHESIOLOGY 2008; 108:392–401
Mao M, Wang SN, Lv XJ, Wang Y, Xu JC: Intravenous delivery of bone marrow-derived endothelial progenitor cells improves survival and attenuates lipopolysaccharide-induced lung injury in rats. Shock 2010; 34:196–204
Wagers AJ, Sherwood RI, Christensen JL, Weissman IL: Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002; 297:2256–9
Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG: Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A 2003; 100:8407–11
Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL: Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 2005; 33:145–52
Kotton DN, Fabian AJ, Mulligan RC: Failure of bone marrow to reconstitute lung epithelium. Am J Respir Cell Mol Biol 2005; 33:328–34
Loi R, Beckett T, Goncz KK, Suratt BT, Weiss DJ: Limited restoration of cystic fibrosis lung epithelium in vivo  with adult bone marrow-derived cells. Am J Respir Crit Care Med 2006; 173:171–9
Burnham EL, Taylor WR, Quyyumi AA, Rojas M, Brigham KL, Moss M: Increased circulating endothelial progenitor cells are associated with survival in acute lung injury. Am J Respir Crit Care Med 2005; 172:854–60
Lee JW, Fang X, Krasnodembskaya A, Howard JP, Matthay MA: Concise review: Mesenchymal stem cells for acute lung injury: Role of paracrine soluble factors. Stem Cells 2011; 29:913–9
Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E: Bone marrow stromal cells attenuate sepsis via  prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009; 15:42–9
Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ: Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010; 182:1047–57
Lee JW, Fang X, Gupta N, Serikov V, Matthay MA: 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 U S A 2009; 106:16357–62
Kajstura J, Rota M, Hall SR, Hosoda T, D'Amario D, Sanada F, Zheng H, Ogórek B, Rondon-Clavo C, Ferreira-Martins J, Matsuda A, Arranto C, Goichberg P, Giordano G, Haley KJ, Bardelli S, Rayatzadeh H, Liu X, Quaini F, Liao R, Leri A, Perrella MA, Loscalzo J, Anversa P: Evidence for human lung stem cells. N Engl J Med 2011; 364:1795–806
Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, Sonnenberg A, Wei Y, Vu TH: Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Invest 2011; 121:2855–62
Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B, Tetta C, Camussi G: Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 2009; 20:1053–67
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