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American Journal of Respiratory Cell and Molecular Biology. Vol. 35, pp. 403-404, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.F319

Correspondence

Pathophysiology of Circulating Progenitor Cells in Pulmonary Disease and Parallels with Cardiovascular Disease

Gian Paolo Fadini, M.D., Angelo Avogaro, M.D., Ph.D. and Carlo Agostini, M.D.

Department of Clinical and Experimental Medicine, University of Padova, Medical School, Padova, Italy

To the Editor:

We read with great interest the Editorial of the April issue concerning the emerging roles of stem cells in pulmonary medicine (1). We would like to discuss briefly some aspects related to the research on extrapulmonary progenitor cells, sharing our feelings about some impressive similarities in the behavior of circulating progenitor cells between pulmonary disease (PD) and cardiovascular disease (CVD).

In the last decade, a number of experimental data and clinical observations have suggested that bone marrow represents a reservoir of immature cells that participate in regeneration and repair of many peripheral tissues (2). By far the most widely characterized circulating progenitors are endothelial progenitor cells (EPCs), and there has been a special interest in examining the relationships between EPC alterations and the pathogenesis of most CVD (3). In particular, data obtained in animal models have convincingly demonstrated that EPCs are involved in endothelial homeostasis and take part in neovascularization processes (4, 5). Depletion of the circulating EPC pool has been associated with cardiovascular risk factors (6), and it has been shown that patients with chronic CVD display a strong reduction and/or dysfunction of EPCs (7, 8). On the basis of these data it has been proposed that EPC alterations may have a causative role in CVD. On the other hand, acute myocardial infarction is followed by EPC increase, like a reflection of the homeostatic attempt to overcome vascular obstruction (9), and the extent of EPC mobilization is a crucial determinant of myocardial function during the follow-up of myocardial infarction (10).

More recently, the interest in EPC biology has extended to the field of respiratory medicine and there are data suggesting the existence of strong similarities between cardiovascular and pulmonary pathophysiology in terms of EPC regulation. For instance, cigarette smoking, as a potent causal and risk factor for both chronic obstructive PD and CVD, leads to a reversible EPC decrease and dysfunction (12, 13). Moreover, we have recently demonstrated that patients with chronic obstructive and restrictive lung diseases have a severe depletion of circulating EPCs, associated with an excess in apoptotic cell death (14). We recently reviewed our case series of patients with CVD (n = 65) and PD (n = 35). Figure 1 depicts the levels of circulating EPCs in patients with CVD and PD compared with healthy subjects: progenitor cells are reduced in a similar manner in patients with CVD and PD, irrespective of the fact that case series were heterogeneous, since patients with CVD included both peripheral and coronary atherosclerosis, while patients with PD included both obstructive and restrictive patterns. Thus, EPC pathophysiology seems to be quite similar in PD and in CVD. To explain this surprising parallelism, we suggest a number of hypotheses. It is possible that long-lasting hypoxia, acting locally in CVD or favored by the reduction of pulmonary function in PD, may induce continuous bone marrow stimulation for EPC release, progressively leading to an exhaustion of the precursor pool in both CVD and PD. Alternatively, EPC reduction in peripheral blood might reflect localization of progenitor cells in the tissues involved by CVD or PD. Finally, as we have recently demonstrated in patients with PD, an increase in apoptotic cell death may account for the reduction in progenitor cell levels. Taking advantage of animal models in our lab, we are investigating putative causes that favor the depletion of progenitor cells in these disorders.


Figure 1
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  		Figure 1. Circulating progenitor cells were measured by flow cytometry using FITC-conjugated anti-CD34 (Becton Dickinson, Franklin Lakes, NJ), APC-conjugated CD133 (Miltenyi Biotec, Bergisch Gladbach, Germany), and PE-conjugated anti-KDR (R&D Systems, Minneapolis, MN) monoclonal antibodies in 137 middle-aged healthy subjects, 62 patients affected by cardiovascular disease (CVD, meant as stable coronary or peripheral arterial disease), and 35 patients affected by chronic pulmonary diseases (PD, meant as oxygen-dependent obstructive or restrictive pulmonary disease). Progenitor cell reduction was mainly due to decrease in the CD34+ and CD34+KDR+ fractions. Difference between groups was assessed by two-tailed Student's t test with Bonferroni correction for multiple testing (* significantly different versus healthy subjects after {alpha}-adjusting).

 
In any case, it is easy to anticipate that the evaluation of therapeutic potentiality of EPCs administration in humans with PD or CVD will represent a major challenge to researchers involved in the clinical management of these disorders. As a matter of the fact, clinical trials of cell therapy for acute and chronic CVD have been initiated, with some promising results (11). Unfortunately, there remain relevant methodologic issues to be resolved, such as characterization of cells to be used (15), procedures for the ex vivo expansion of EPCs, and routes of administration. There are also important clinical questions to be answered, such as optimal patient selection and possible harmful side effects (16). Finally, we must recognize that subjects who would receive most benefits from this therapeutic approach are those in whom progenitor cells are not only reduced but also functionally impaired (17). Obviously, this may represent a strong limitation to the potentialities of cellular therapy in these diseases.

Footnotes

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

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  14. Fadini GP, Schiavon M, Cantini M, Basso I, Facco M, Miorin M, Tassinato M, de Kreutzenberg SV, Avogaro A, Agostini C. Circulating progenitor cells are reduced in patients with severe lung disease. Stem Cells 2006;24:1806–1813.[Abstract/Free Full Text]
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  17. Werner N, Nickenig G. Influence of Cardiovascular Risk Factors on Endothelial Progenitor Cells. Limitations for Therapy? Arterioscler Thromb Vasc Biol, 2005




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Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2006 American Thoracic Society.