© 2007 American Thoracic Society
Depletion of Endothelial Progenitor Cells May Link Pulmonary Fibrosis and Pulmonary HypertensionTo the Editor:In their pulmonary perspective, Nathan and colleagues hypothesize that an angiogenic imbalance links idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH) (1), while Thébaud and Abman, in their article, point out that normal angiogenesis sustains pulmonary architecture, suggesting that angiogenic cells and growth factors have a role in chronic lung disease (2). However, it is now clear that angiogenesis is driven not only by local humoral and cellular events but also by the contribution of circulating cells. Growth factors and chemokines stimulate mobilization and recruitment of endothelial progenitor cells (EPCs), which mediate intimal repair, prevent vascular remodeling, and stimulate angiogenesis. In the systemic circulation, endothelial damage leads to atherosclerosis (3), while in the pulmonary circulation, it sets the stage for the development of PAH. Animal studies have shown that EPC administration can prevent experimental PAH, and a pilot trial has confirmed this potential benefit in humans (4), suggesting that alteration of endogenous EPCs favors the development of PAH. We have previously shown that patients with chronic lung disease have a severe depletion of circulating EPCs (5). Herein, we would like to report the analysis of EPCs in 20 patients with IPF, 5 of whom developed PAH. In comparison with control subjects, patients with IPF showed a marked EPC depletion, which was more severe in the presence of PAH (Figure 1). In light of these data, we would like to suggest that inability to compensate for the decrease in EPCs could be the expression of the secondary marrow failure which often develops in patients with PAH (6) or a result of increased EPC apoptosis (5). In any case, we believe that a more pronounced EPC depression may link IPF to PAH, through disrupted vascular homeostasis. As a clinical implication, prevention of PAH in patients with IPF might be achieved using molecules that positively modulate EPCs, such as statins (3), which proved promising for PAH therapy in animal models and in observational case series.
A future major challenge will be to evaluate whether experimental therapies that have been proposed for phase III trials, such as bosentan and pirfenidone, are able to modulate levels of circulating EPCs in patients with IPF, preventing the development of PAH. An alternative explanation for our data is that reduction of EPCs in IPF reflects enhanced homing to the pulmonary vasculature. Obviously, this hypothesis would turn the role of EPCs from protective to pathogenic, augmenting our current uncertainties on the meaning of angiogenesis in IPF and PAH.
University of Padua Medical School, Padua, Italy 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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P < 0.05 comparing IPF+PAH versus IPF.