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Translating Basic Research into Clinical PracticeAngiogenesis in Pulmonary Fibrosis: Too Much or Not Enough?
Section snippets
Concept of Angiogenesis in Pulmonary Fibrosis
The earlier work suggested an increase of angiogenesis in fibrotic lungs, which was conceptually explained by hypoxic tissue conditions triggering angiogenic signals to stimulate vessel growth and thereby counteracting the hypoxia. Although this clearly follows a fair logic, recent morphometric and mechanistic studies in human and animal lung have challenged this concept and caused some controversy over the extent and functional role of neovascularization in the pathogenesis of IPF. It has been
Angiogenic and Angiostatic Factors in Pulmonary Fibrosis
Complex life forms cannot exist without blood vessels and angiogenesis, and, therefore, it is not surprising that evolution has created numerous mechanisms and molecules with angiogenic and angiostatic properties. Chemokines belong to a superfamily of homologous 8- to 10-kDa heparin-binding cytokine molecules. They are chemoattractants that act on specific transmembrane receptors and modulate angiogenesis via interaction with leukocytes, endothelial cells, and fibroblasts. CXC chemokines are
Matrix and Its Degradation in Pulmonary Fibrotic Angiogenesis
The ECM is a dynamic structure requiring a tightly regulated coordination between the different ECM components (collagens, elastin, glycoproteins, and proteoglycans), integrins, growth factors, and parenchymal cells to maintain the normal structure and function of the lung. IPF is characterized by an excessive and abnormal ECM. The mechanism of ECM homeostasis and tissue remodeling in fibrosis involves proteolysis by MMPs, which are regulated by tissue inhibitors of metalloproteinases (TIMPs).51
Therapeutic Approaches—Are We Ready to Target Angiogenesis in Pulmonary Fibrosis?
As described in detail, it is too early to clearly state whether there is too much or not enough angiogenesis in IPF lungs or even to decide if altered angiogenesis is good or bad. The abnormality in vascularization in fibrotic lungs may on one hand support fibroproliferation and inhibit normal repair mechanisms, but on the other hand it may also be a compensatory mechanism to limit progressive fibrogenesis (with the downside of secondary pulmonary hypertension). The yet-unanswered question is
Summary
The last decade has highlighted the complexity of the pathogenetic mechanisms of pulmonary fibrosis. The concepts have been moving from a rather simple chronic inflammatory process to one that involves abnormal wound healing, aberrant crosstalk between epithelial and mesenchymal cells, and lately even bone marrow-derived progenitor cells for fibroblasts. Now, looking at the vessel compartment in the lung tissue seems to make this even more complex and difficult to understand. Is there too much
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Kolb received consultancy fees from GlaxoSmithKline, Boehringer Ingelheim GmbH, and InterMune, and an unrestricted research grant from GlaxoSmithKline. Drs Hanumegowda and Farkas have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Role of sponsors: The sponsor had no role in the design
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Funding/Support: This study was funded by a Research Fellowship of the Deutsche Forschungsgemeinschaft for Dr Farkas, funded by the Canadian Institute for Health Research.
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