© 2004 American Thoracic Society
Neovascularization in Idiopathic Pulmonary FibrosisToo Much or too Little?Royal Brompton Hospital London, United Kingdom Idiopathic pulmonary fibrosis is characterized by tissue damage and an aberrant healing response leading to severe and progressive disruption of lung architecture (1). Angiogenesis, the formation of new vessels from preexisting vasculature, is an integral part of physiologic and pathologic tissue repair responses, which can be beneficial or detrimental depending upon context. The relative roles played by new vessel formation and vascular regression in idiopathic pulmonary fibrosis are unclear; understanding the contribution of vascular abnormalities to the fibrotic process is likely to lead to valuable pathogenetic insights. In this issue of the Journal (pp. 1203–1208), Ebina and coworkers (2) evaluate interstitial capillary density, as assessed by image analysis of CD34-positive and von Willebrand factor staining, against the histologic severity of idiopathic pulmonary fibrosis. Compared with control lungs, capillary density was increased in areas of minimal fibrosis, but decreased in the most extensively fibrotic lesions. In areas of higher capillary density, there was increased endothelial cell proliferation and increased staining for vascular endothelial growth factor and interleukin-8, two potent angiogenic factors, localized to both capillary endothelial cells and alveolar type II epithelial cells. By contrast, immunoreactivity for vascular endothelial growth factor and interleukin-8 was minimal in highly fibrotic regions. The study by Ebina and coworkers (2) reconciles apparently contradictory findings regarding vascular remodeling and angiogenesis in idiopathic pulmonary fibrosis. Several studies have suggested that angiogenesis might be important. Turner-Warwick identified new vessel formation in this disease, demonstrating anastomoses between the systemic and pulmonary microvasculature (3). Wells and coworkers suggested that the greater gas exchange impairment in idiopathic pulmonary fibrosis compared with the pulmonary fibrosis associated with systemic sclerosis (after adjustment for disease extent) could be the result of angiogenesis (4). An imbalance between proangiogenic and angiostatic CXC chemokines, favoring net angiogenic activity, was reported in idiopathic pulmonary fibrosis (5). By contrast, vascular density is strikingly decreased in fibrotic areas of idiopathic pulmonary fibrosis (6–8); in particular, fibroblastic foci, present at the leading edge of fibrosis and linked to disease progression, are characterized by an almost complete absence of capillaries (2, 8, 9, 11). Decreased levels of vascular endothelial growth factor have been found in bronchoalveolar lavage (10) and increased levels of potent angiostatic factors in tissue biopsy homogenates (11) of idiopathic pulmonary fibrosis. Lastly, substantial neovascularization occurs in the fibromyxoid lesions of organizing pneumonia, a disorder that does not usually progress to irreversible fibrosis (9). The observation by Ebina and coworkers (2) that both increased capillary density and vascular regression are found within the same disease, according to extent of tissue fibrosis, indicates that a striking heterogeneity in vessel turnover is a characteristic of idiopathic pulmonary fibrosis. These findings pose a new dilemma in the field, which has hitherto been largely overlooked: the study by Ebina and coworkers (2) highlights the need to take disease severity into account, both for regional differences, in biopsy studies, and for disease extent, as assessed by imaging and/or lung function tests in the study of biomarkers. Perhaps the most interesting question raised by Ebina and coworkers (2) is whether the increase in capillary density observed in the least fibrotic areas is actively involved in the development of the fibrogenic process, whether it is a consequence or whether it prevents it. The fibrotic process of idiopathic pulmonary fibrosis might thrive on the absence of microvessels. The increased capillary density could be a compensatory response to the striking hypovascularity of the fibroblastic foci and the more fibrotic areas. Ebina and coworkers hypothesize that the increased vascular density in the least fibrotic areas has a role in the regeneration of alveolar septa damaged by the fibrotic process. This is an interesting hypothesis, but needs supporting evidence. Verifying whether such an increase in vascularization also occurs in the normal or near-normal lung adjacent to fibrotic areas in other fibrosing lung diseases would establish whether the increased capillary density observed by Ebina and coworkers (2) is an adaptive mechanism common to fibrosis or whether it is disease-specific. Another interesting feature described by Ebina and coworkers (2) is the predominance of venules with von Willebrand factor–positive cells compared with the CD34-positive capillaries in the walls of the most fibrotic lesions. The authors provide a 3-dimensional reconstruction that shows that the small von Willebrand Factor–positive venules at the center of the fibrotic lesions are slightly increased compared with those of a control lung (even though these findings were not formally quantified). An increase in von Willebrand Factor–positive vessels in idiopathic pulmonary fibrosis was also suggested by Keane and coworkers (5). The vascular phenotype could be abnormal in idiopathic pulmonary fibrosis. Phenotypically different vessels were observed in the areas adjacent to fibroblastic foci and may contribute to abnormal matrix remodeling and impaired gas exchange (8). Future studies are needed to elucidate possible functional consequences of differences in the morphophysiology and distribution of microvessels in idiopathic pulmonary fibrosis. It is uncertain whether the primary vascular abnormality in idiopathic pulmonary fibrosis is a lack or an excess of neovascularization. Answering this question has clear therapeutic implications. If neovascularization plays a key role in the exaggerated/dysregulated matrix remodeling, the neutralization of proangiogenic factors should be pursued. In the animal model of bleomycin-induced lung fibrosis, inhibition of an angiogenic chemokine or administration of an angiostatic chemokine reduced lung collagen deposition (12, 13). Findings obtained in the bleomycin model of lung fibrosis, however, may not be applicable to human disease. It remains possible that the increased capillary density in the least fibrotic regions reported by Ebina and coworkers (2) is merely a compensatory response. In this case, the primary deficiency could be an inability to form new vessels in areas of established fibrosis and inhibition of angiogenesis could actually be detrimental. Further work is needed to establish whether insufficient or abnormal angiogenesis is pathogenetically linked to aberrant matrix remodeling in idiopathic pulmonary fibrosis. FOOTNOTES Conflict of Interest Statement: E.A.R. 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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