© 2005 American Thoracic Society doi: 10.1164/rccm.2507006
Is Cell Therapy in Acute Lung Injury a Realistic Dream?Tohoku University School of Medicine, Sendai, Japan Acute lung injury and acute respiratory distress syndrome (ARDS) still have a poor prognosis in spite of the recent development of new therapeutic strategies. Modulating the repair process of injured lungs would be a therapeutic target to decrease high mortality (1). It is believed that tissue stem cells contribute to injured alveolar epithelial and capillary endothelial repair. However, a growing body of evidence suggests that some of the stem cells are mobilized from bone marrow into the circulation and sequester in the injured organ, where they contribute to tissue repair processes. One of the well-characterized bone marrow–derived progenitor cells is the circulating endothelial progenitor cell (EPC). EPCs are present in peripheral blood, and can differentiate into mature endothelial cells (2). The lack of a sufficient number of progenitor cells may contribute to an impaired repair process in acute lung injury (3). Therefore, EPCs can play a role in the repair of damaged pulmonary and systemic endothelium, and may be important for recovery from acute lung injury and ARDS. The number of circulating EPCs is different in each individual and condition. Several circumstances play a role in defining this number, such as age, cancer, diabetes, and inflammation (4, 5). Clinically, low levels of EPCs correlate with the risk of coronary diseases and atherosclerosis (4, 6). In addition, functional impairment of EPCs was observed in patients with myocardial infarction (7). These reports suggest that both sufficient numbers and proper function of EPCs are necessary for a good prognosis in cardiovascular diseases. In pulmonary diseases, Yamada and coworkers demonstrated that circulating EPCs increased in patients with acute community-acquired pneumonia, and that scar-like fibrotic changes in the lungs remained in patients with low levels of circulating EPCs, suggesting an important role of EPCs in lung repair (5). In this issue of the Journal (pp. 854–860), Burnham and colleagues report the relationship between circulating EPCs and survival in the patients with acute lung injury (8). They found that the number of circulating EPCs increased in patients with acute lung injury and ARDS, indicating that EPCs are mobilized from the bone marrow under inflammatory conditions. More interestingly, the patients who had a higher number of circulating EPCs had a better prognosis, suggesting that EPC could be a prognostic biological marker for patients with acute lung injury. The study by Burnham and coworkers opens a new area of work in acute lung injury research and raises many interesting questions and therapeutic ideas. Why can some patients increase the number of EPCs in circulation, but some cannot? Is this insufficient availability of EPCs caused by an impaired function of the bone marrow, or by inadequate cytokines influencing EPC mobilization? Increasing circulating numbers of EPCs is a result of two steps. The first is increasing the levels of EPC proliferation and differentiation within the bone marrow, and the second is increasing the degree of EPC mobilization from bone marrow. Many cytokines, such as vascular endothelial growth factor, hepatocyte growth factor, and granulocyte colony-stimulating factor, increase in the lungs during acute lung injury (9–11). These cytokines are also known to induce EPC mobilization and differentiation in vivo and in vitro (2, 12). It is possible that differences in the levels of such cytokines are present in the high-EPC and low-EPC groups of patients. Is it simply the number of available EPCs that contributes to mortality? Functional differences in EPCs may be another key to the discrepancy in prognosis. Impaired EPC function has been reported in patients with cardiovascular diseases, and functional EPCs improve angiogenesis (7). In addition, a recent study has shown that the role of EPC is not only to repair or regenerate damaged vasculature, but also to produce several growth factors and cytokines (13). Impairment in these factors may also have an impact on the maintenance and repair of injured vasculature. EPCs are not the only progenitor cells that come from bone marrow. Based on studies in patients who underwent bone marrow transplantation from sex-mismatched donors, Suratt and colleagues reported that donor-derived epithelial cells are also present in alveoli, suggesting the bone marrow origin of epithelium (14). The number of other bone marrow–derived progenitor cells may also decline in circulation in patients with low levels of EPCs. Efficient alveolar epithelial repair is an important factor for the resolution of acute lung injury (15). Increased numbers of bone marrow–derived progenitor cells may contribute to alveolar repair and survival in acute lung injury patients. The origin of alveolar epithelium is still under discussion (16), therefore we need more work in this field. Is cell therapy in acute lung injury a realistic dream? In addition to all the questions that can be raised concerning the pathophysiologic role of EPCs in acute lung injury, it is appealing to consider EPCs as a potential therapeutic application. If the EPCs play a critical role in survival from acute lung injury, would it be possible to use them as a therapeutic tool? If we could increase circulating EPCs in patients with low levels of EPCs, would their prognosis be improved? How can we recruit EPCs to the proper injured tissue? What is the key factor for proper differentiation to mature cells? It is probably too early to discuss cell therapy in acute lung injury. In addition, the area of lung stem cell research area is very controversial and needs more careful analysis. However, Burnham and colleagues' work gives us a new point of view for understanding the pathophysiology of acute lung injury. Such novel cell-based approaches are likely to lead to new therapies in the near future. FOOTNOTES Conflict of Interest Statement: H.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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