© 2004 American Thoracic Society
Angiogenesis and Pulmonary FibrosisFeast or Famine?Pulmonary and Critical Care Medicine David Geffen School of Medicine at UCLA Los Angeles, California The existence of neovascularization in idiopathic pulmonary fibrosis was originally identified in 1963 by Turner-Warwick, who demonstrated that within areas of pulmonary fibrosis there was extensive neovascularization with anastamoses between the systemic and pulmonary microvasculature (1). Recently, an imbalance in the levels of angiogenic chemokines, as compared with angiostatic chemokines, that favors net angiogenesis has been demonstrated in both animal models and tissue specimens from patients with idiopathic pulmonary fibrosis (2–5). Renzoni and coworkers have demonstrated vascular remodeling in both idiopathic pulmonary fibrosis and fibrosing alveolitis associated with systemic sclerosis (6). In this issue of the Journal (pp. 242–251), Cosgrove and coworkers provide further support for the concept of vascular remodeling in idiopathic pulmonary fibrosis (7). Pigment epithelium–derived factor is an inhibitor of new vessel formation. In contrast, vascular endothelial growth factor is a promoter of angiogenesis. The relative expression of these two proteins has been implicated in neovascularization associated with retinal disorders, such as macular degeneration and diabetic retinopathy. In the current study, Cosgrove and colleagues studied the expression of pigment epithelium–derived factor and vascular endothelial growth factor in lung specimens of patients with idiopathic pulmonary fibrosis. Immunolocalization demonstrated a relative absence of vessels in the fibroblastic foci of idiopathic pulmonary fibrosis. This appeared to correlate with increased expression of pigment epithelium–derived factor in the fibroblastic foci. Interestingly, they also noted significant vascularity in the areas of fibrosis around the fibroblastic foci with numerous abnormal vessels in the regions of severe architectural distortion. These findings are similar to those of Renzoni and coworkers (6) and supports the concept of regional heterogeneity of vascularity in idiopathic pulmonary fibrosis. This heterogeneity is not surprising as usual interstitial pneumonia, which is the pathological description of idiopathic pulmonary fibrosis, is defined by its regional and temporal heterogeneity. Although Cosgrove and coworkers found decreased levels of vascular endothelial growth factor in bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis, they did not find any significant difference in levels in lung tissue as compared with control subjects. The lack of increase in vascular endothelial growth factor does not necessarily correlate with a reduction in angiogenesis. It has been well described in other fibroproliferative disorders, such as the acute respiratory distress syndrome, in which angiogenesis plays a role, that vascular endothelial growth factor has a less important role than other angiogenic factors (8). To gain some insight into the angiogenic potential of lung tissue from patients with idiopathic pulmonary fibrosis the authors looked at the ability of lung homogenates to induce new vessel formation. They found net angiogenic activity of idiopathic pulmonary fibrosis lung tissue to be decreased. This is in contrast to previous work describing increased net angiogenic activity in lung homogenates from patients with idiopathic pulmonary fibrosis (2, 5). This lack of angiogenic activity is surprising given the fact that the authors demonstrate that transforming growth factor ß, which has angiogenic as well as fibrotic actions, is a significant inducer of pigment epithelial–derived factor and is significantly elevated in idiopathic pulmonary fibrosis. Similarly, it is well documented that angiogenic chemokines are elevated in idiopathic pulmonary fibrosis lung tissue, and one would expect that that would promote increased angiogenic activity (2, 5, 9). There are several possible explanations for the disparity. First, Cosgrove and coworkers chose to use an in vitro assay of angiogenesis, which is less robust than the in vivo rat corneal micro pocket assay used in previous studies. Second, idiopathic pulmonary fibrosis by definition demonstrates regional and temporal heterogeneity. Biopsies from different lobes can demonstrate significant pathological differences; therefore, it is logical to expect heterogeneity in terms of angiogenic activity (10). The authors provide evidence to support this concept of vascular heterogeneity with the lack of vascularity within the fibroblastic focus and increased vascularity in the surrounding areas. There are mixed reports as to the prognostic significance of the fibroblastic focus in usual interstitial pneumonia, some investigators have found a correlation between the number of fibroblastic foci and outcome whereas others have found no correlation (11, 12). The findings of Cosgrove and coworkers call into question the popular hypothesis that the fibroblastic focus is the leading edge of fibrosis. Studies of the mechanisms of wound repair in the skin show the central role of new vessel formation in association with granulation tissue in normal repair. Similarly, in the current study Cosgrove and coworkers show that vessels were prominent in the Massons bodies of tissue specimens from patients with cryptogenic organizing pneumonia. This is consistent with the findings in cutaneous wound repair including the exuberant repair associated with keloid formation. The lack of vessels in the fibroblastic foci begs the question as to how active these lesions really are. If they are truly at the leading edge of fibrosis where do they get their nutrients from? Similar to fibroblast cell lines, primary lung fibroblasts constitutively produced pigment epithelium–derived factor. They differed, however, by virtue of the fact that primary fibroblasts did not increase the expression after transforming growth factor ß stimulation. Furthermore, there was no difference in the expression of pigment epithelium–derived factor between primary fibroblasts from normal and idiopathic pulmonary fibrosis lung. If the fibroblast was the most prominent source of pigment epithelium–derived factor one might expect differences between normal and idiopathic pulmonary fibrosis fibroblasts. Previous work has demonstrated phenotypic differences in fibroblasts isolated from patients with usual interstitial pneumonia as compared with controls (2, 13). It has been shown that conditioned media from fibroblasts from patients with idiopathic pulmonary fibrosis stimulates angiogenesis (2). Moreover, in the current study epithelial cells appeared to be an equally important source of pigment epithelium–derived factor. Epithelial cells are a rich source of cytokines, including the angiogenic chemokine CXCL5, and play an important role in vascular remodeling in idiopathic pulmonary fibrosis (5). Further work will be required to define the relative and specific role of fibroblasts and epithelial cells in angiogenesis in idiopathic pulmonary fibrosis. So where do we stand with regard to angiogenesis and pulmonary fibrosis? Is there too much or too little? The study of Cosgrove and coworkers and previous work would indicate that in fact there is both a feast and a famine, with heterogeneity in vascularization in idiopathic pulmonary fibrosis. This heterogeneity may on the one hand support fibroproliferation and on the other hand inhibit normal repair mechanisms. Furthermore, this abnormal vasculature and the pulmonary systemic anastamoses described by Turner-Warwick are likely a significant contributor to the refractory hypoxemia that is seen in many patients with idiopathic pulmonary fibrosis. Further work in this field may lead to novel therapies for this dismal disease. FOOTNOTES Conflict of Interest Statement: M.P.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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