Chest
Volume 142, Issue 1, July 2012, Pages 200-207
Journal home page for Chest

Translating Basic Research into Clinical Practice
Angiogenesis in Pulmonary Fibrosis: Too Much or Not Enough?

https://doi.org/10.1378/chest.11-1962Get rights and content

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal disease, based on a multifaceted and incompletely understood pathogenesis. Some of the cellular and molecular mechanisms of vascular remodeling have been experimentally explored, and it is obvious that alterations of microvessels are involved in IPF. These can, among others, lead to the development of pulmonary hypertension. In order to understand the process of vascular integrity and repair, it is necessary to identify the factors associated with angiogenesis in IPF. A delicate balance of angiogenic and angiostatic factors regulates vessel homeostasis in normal physiologic conditions in the lungs. Although earlier studies have proposed that IPF is associated with an increase of angiogenesis, there is some more recent evidence that angiogenesis in fibrotic lungs may actually be decreased, causing some controversy in the literature in this area. This review, therefore, discusses the concept of angiogenesis in pulmonary fibrosis and speculates on how the spatial and temporal heterogeneity of IPF might explain the controversial findings about vessel density in fibrotic lungs.

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

References (64)

  • L Farkas et al.

    Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors

    Am J Respir Cell Mol Biol

    (2011)
  • A Golden et al.

    Diffuse interstitial fibrosis of lungs; a form of diffuse interstitial angiosis and reticulosis of the lungs

    AMA Arch Intern Med

    (1953)
  • M Turner-Warwick

    Precapillary systemic-pulmonary anastomoses

    Thorax

    (1963)
  • NR Simler et al.

    Angiogenic cytokines in patients with idiopathic interstitial pneumonia

    Thorax

    (2004)
  • M Ebina et al.

    Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2004)
  • GP Cosgrove et al.

    Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis

    Am J Respir Crit Care Med

    (2004)
  • M Sumi et al.

    Increased serum levels of endostatin in patients with idiopathic pulmonary fibrosis

    J Clin Lab Anal

    (2005)
  • M Selman et al.

    Emerging drugs for idiopathic pulmonary fibrosis

    Expert Opin Emerg Drugs

    (2011)
  • ER Parra et al.

    Heterogeneous remodeling of lung vessels in idiopathic pulmonary fibrosis

    Lung

    (2005)
  • EA Renzoni et al.

    Interstitial vascularity in fibrosing alveolitis

    Am J Respir Crit Care Med

    (2003)
  • MN Peão et al.

    Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin

    Anat Rec

    (1994)
  • MP Keane et al.

    The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis

    J Immunol

    (1997)
  • KR Flaherty et al.

    Histopathologic variability in usual and nonspecific interstitial pneumonias

    Am J Respir Crit Care Med

    (2001)
  • MP Keane et al.

    IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis

    J Immunol

    (1999)
  • MP Keane et al.

    Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis

    J Immunol

    (1999)
  • JA Belperio et al.

    CXC chemokines in angiogenesis

    J Leukoc Biol

    (2000)
  • RC Russo et al.

    Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis

    Am J Respir Cell Mol Biol

    (2009)
  • S Srisuma et al.

    Identification of genes promoting angiogenesis in mouse lung by transcriptional profiling

    Am J Respir Cell Mol Biol

    (2003)
  • RM Strieter et al.

    The role of CXC chemokines in pulmonary fibrosis

    J Clin Invest

    (2007)
  • KH Plate et al.

    Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo

    Nature

    (1992)
  • WT Monacci et al.

    Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues

    Am J Physiol

    (1993)
  • H Fehrenbach et al.

    Differential immunolocalization of VEGF in rat and human adult lung, and in experimental rat lung fibrosis: light, fluorescence, and electron microscopy

    Anat Rec

    (1999)
  • Cited by (0)

    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.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

    View full text