Angiogenesis in Chronic Lung Disease

doi:10.1378/chest.06-2453

Chest

Volume 131, Issue 3, March 2007, Pages 874-879

https://doi.org/10.1378/chest.06-2453 Get rights and content

Abstract

Chronic lung diseases like COPD, severe progressive pulmonary hypertension (PH), and interstitial lung diseases all have a lung vascular disease component. Cellular and molecular mechanisms of pulmonary vascular remodeling have been experimentally explored in many animal models, and it is now clear that microvessels are involved. In emphysema patients, there is a loss of lung microvessels, and in many forms of severe PH there is obliteration of precapillary arterioles by angioproliferation. Thus, COPD/emphysema and severe angioproliferative PH are on the opposite ends of a spectrum of vascular biology responses. Animal experiments have provided insight regarding some of the initiating events that shape the various forms of pulmonary vascular remodeling. In pulmonary fibrosis and in the postinjury phase of acute lung injury, the angiogenic/angiostatic balance is also affected. This review will therefore discuss angiogenesis in several chronic lung diseases and will speculate on how altered vascular homeostasis may contribute to lung disease development.

Section snippets

Severe Angioproliferative PH

Elevated pulmonary artery pressures in patients with PH have been largely attributed to vasoconstriction. However, in the past 10 years there has been emerging evidence that exuberant angioproliferation is also an important contributor to vascular resistance. Tuder et al²first reported in 1994 that exuberant endothelial cell growth and elements of inflammation were present in PH-associated plexiform lesions. As evidence for a process of disordered angiogenesis, Tuder and coworkers²demonstrated

Airspace Enlargement/Emphysema

In contrast to many forms of PH that are characterized by increased angiogenesis, emphysema is remarkable for a relative paucity of blood vessels. COPD patients have a significantly reduced capillary length and length density.¹²VEGF receptor blockade in an experimental emphysema model of COPD¹³induced the loss of microvessels and was associated with alveolar septal cell apoptosis and airspace enlargement. This result suggests that a normal alveolar structure is not maintained without capillary

Asthma

Angiogenesis has only been appreciated in more recent years as an important contributor to airway remodeling in patients with bronchial asthma. Engorgement of dilated and remodeled vessels is a consistent feature in the airways of patients with fatal asthma.¹⁹Both adults20, 21and children²²with mild-to-moderate asthma have an increased number of subepithelial bronchial vessels compared with nonasthmatic subjects, suggesting that angiogenesis is potentially a central component in the progression

Pulmonary Fibrosis

Although it has been acknowledged that some patients with interstitial lung disease have a pulmonary vascular disease component, usually characterized by the muscularization of small arteries, relatively little attention has been paid to the microvasculature. Cosgrove et al²⁴examined lung tissue samples obtained from patients with interstitial lung disease. They examined histochemically the vascular density in the fibroblastic foci and found that the vessel density was decreased in association

Angiogenesis and Repair in Late-Phase Acute Lung Injury

The aftermath of acute lung injury (ALI)/ARDS is typically characterized by the resolution of inflammation by apoptosis and phagocytic clearance of dead cells, and epithelial and endothelial proliferation with the reestablishment of a functional gas-exchanging alveolar-capillary interface. Hyperactivation of the LSMP, however, may account for the progression to fibroproliferative ARDS with progressive intraalveolar and intraseptal angiofibroproliferation.²⁸The result is chronic lung disease

Conclusions

Angiogenesis is a fundamental principle of vascular remodeling and repair. However, the association of pulmonary vascular cell apoptosis as an initiating mechanism for angiogenesis in chronic lung disorders has not been widely appreciated. This review has described in a broad fashion how disordered angiogenesis may be implicated in the disease pathogenesis of PH, emphysema, asthma, pulmonary fibrosis, and late-phase ARDS, and in regulation of the progression to chronic lung disease. An emerging

References (48)

RO Achcar et al.
Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension
Chest
(2006)
PD Wagner et al.
Muscle-targeted deletion of VEGF and exercise capacity in mice
Respir Physiol Neurobiol
(2006)
JF Tomashefski
Pulmonary pathology of the adult respiratory distress syndrome
Clin Chest Med
(1990)
TA Neff et al.
Long-term assessment of lung function in survivors of severe ARDS
Chest
(2003)
K Hirota et al.
Regulation of angiogenesis by hypoxia-inducible factor 1
Crit Rev Oncol Hematol
(2006)
SE Fligiel et al.
Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury
Hum Pathol
(2006)
B Li et al.
VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization
FASEB J
(2006)
RM Tuder et al.
Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension
Am J Pathol
(1994)
AA Liebow
Pulmonary emphysema with special reference to vascular changes
Am Rev Respir Dis
(1959)
NF Voelkel et al.
Vascular endothelial growth factor in the lung
Am J Physiol Lung Cell Mol Physiol
(2006)

RW Vandivier et al.

The challenges of chronic obstructive pulmonary disease (COPD): a perspective

COPD

(2005)

N Voelkel et al.

Emphysema: an autoimmune vascular disease?

Proc Am Thorac Soc

(2005)

RM Tuder et al.

Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis

J Pathol

(2001)

SD Lee et al.

Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension

J Clin Invest

(1998)

ME Yeager et al.

Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension

Circ Res

(2001)

S Ameshima et al.

Peroxisome proliferator-activated receptor γ (PPARγ) expression is decreased in pulmonary hypertension and affects endothelial cell growth

Circ Res

(2003)

BM Wiebe et al.

Lung morphometry by unbiased methods in emphysema: bronchial and blood vessel volume, alveolar surface area and capillary length

APMIS

(1998)

Y Kasahara et al.

Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

J Clin Invest

(2000)

L Taraseviciene-Stewart et al.

Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease?

Proc Am Thorac Soc

(2006)

Y Kasahara et al.

Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema

Am J Respir Crit Care Med

(2001)

K Imai et al.

Correlation of lung surface area to apoptosis and proliferation in human emphysema

Eur Respir J

(2005)

K Morimoto et al.

Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease

J Immunol

(2006)

K Kuwano et al.

Small airways dimensions in asthma and in chronic obstructive pulmonary disease

Am Rev Respir Dis

(1993)

X Li et al.

Increased vascularity of the bronchial mucosa in mild asthma

Am J Respir Crit Care Med

(1997)

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Immunoglobulin A (IgA) is important in local immunity and is also abundant in the blood. This study aimed to evaluate the effects of serum IgA on cultured lung microvascular endothelial cells (HMVEC-Ls), which are involved in the pathogenesis of inflammatory lung diseases. Serum IgA induced adhesion molecules and inflammatory cytokine production from HMVEC-Ls, and enhanced adhesion of peripheral blood mononuclear cells to HMVEC-Ls. In contrast, migration, proliferation, and tube formation of HMVEC-Ls were significantly suppressed by serum IgA. Experiments with siRNAs and western blotting revealed that two known IgA receptors, β1,4-galactosyltransferase 1 (b4GALT1) and asialoglycoprotein receptor 1 (ASGR1), and mitogen-activated protein kinase and nuclear factor-kappa B pathways were partly involved in serum IgA-induced cytokine production by HMVEC-Ls. Collectively, serum IgA enhanced cytokine production and adhesiveness of HMVEC-L, with b4GALT1 and ASGR1 partially being involved, and suppressed angiogenesis. Thus, serum IgA may be targeted to treat inflammatory lung diseases.
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We then looked into another application of hFLO, a model for hypoxia-induced angiogenesis [65] which can mature to full perfusability [66]. Blood vessel formation is an important process which affects several lung diseases including cancer [67] and pulmonary hypertension [68]. Previous vascular organoid methods use of hypoxia (5% O2) and supplementation of proangiogenic factors vascular endothelial growth factor (VEGF) and fibroblasts growth factor 2 (FGF2) to induce vascular endothelial branching, differentiation and maturation [69].
Micropatterned suspension culture creates consistently sized and shaped cell aggregates but has not produced organotypic structures from stable cells, thus restricting its use in accurate disease modeling. Here, we show that organotypic structure is achieved in hybrid suspension culture via supplementation of soluble extracellular matrix (ECM). We created a viable lung organoid from epithelial, endothelial, and fibroblast human stable cell lines in suspension culture. We demonstrate the importance of soluble ECM in organotypic patterning with the emergence of lumen-like structures with airspace showing feasible gas exchange units, formation of branching, perfusable vasculature, and long-term 70-day maintenance of lumen structure. Our results show a dependent relationship between enhanced fibronectin fibril assembly and the incorporation of ECM in the organoid. We successfully applied this technology in modeling lung fibrosis via bleomycin induction and test a potential antifibrotic drug in vitro while maintaining fundamental cell-cell interactions in lung tissue. Our human fluorescent lung organoid (hFLO) model represents features of pulmonary fibrosis which were ameliorated by fasudil treatment. We also demonstrate a 3D culture method with potential of creating organoids from mature cells, thus opening avenues for disease modeling and regenerative medicine, enhancing understanding of lung cell biology in health and lung disease.
Therapeutic targets in lung tissue remodelling and fibrosis
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Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.
Group 3 PH: Clinical Features and Treatment
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Cdc42 regulates LPS-induced proliferation of primary pulmonary microvascular endothelial cells via ERK pathway
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Citation Excerpt :
Thus, the complete rehabilitation of PMVECs after injury mainly depends on cell proliferation around the lesions. However, some investigators have suggested that there is a pulmonary structure homeostasis, or balance, in which endothelial cells are continuously cycled through proliferation and apoptosis (Gargett and Rogers, 2001; Voelkel et al., 2007). Disruptions to this balance are thought to lead to chronic pulmonary or vascular disease.
After stimulation due to injury, cell division cycle protein 42 (Cdc42) restores and enhances barrier functions by strengthening intercellular adherens junctions; however, its influence on cell proliferation after injury remains unknown.
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We stimulated PMVECs with different doses of LPS and evaluated the effects on cell proliferation. We also constructed a primary gene-knockout cell line lacking Cdc42 to verify the role of Cdc42 in regulating the proliferation of PMVECs that were stimulated using LPS and to explore related signaling pathways.
Stimulating PMVECs with small doses of LPS increased proliferation. Cdc42 is involved in regulating this process, which was mediated by the extracellular regulated protein kinase (ERK) pathway.
Cdc42 plays a role in regulating the proliferation of PMVECs stimulated with small doses of LPS, and this regulation involves the ERK pathway.
A method for evaluating the murine pulmonary vasculature using micro-computed tomography
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The lung is a complex organ that is composed of airways, blood vessels, and parenchyma. Acquired diseases such as emphysema and bronchopulmonary dysplasia, and congenital diseases such as congenital diaphragmatic hernia, congenital heart disease, and primary pulmonary hypertension may have alterations in the pulmonary vasculature from vessel wall remodeling and reduction in vessel numbers due to vessel rarefaction or failed angiogenesis.1-6 Pulmonary hypertension is a source of significant morbidity and mortality.
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: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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Chest

Translating Basic Research Into Clinical PracticeAngiogenesis in Chronic Lung Disease

Abstract

Section snippets

Severe Angioproliferative PH

Airspace Enlargement/Emphysema

Asthma

Pulmonary Fibrosis

Angiogenesis and Repair in Late-Phase Acute Lung Injury

Conclusions

Chest

Respir Physiol Neurobiol

Clin Chest Med

Chest

Crit Rev Oncol Hematol

Hum Pathol

VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization

FASEB J

Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension

Am J Pathol

Pulmonary emphysema with special reference to vascular changes

Am Rev Respir Dis

Vascular endothelial growth factor in the lung

Am J Physiol Lung Cell Mol Physiol

The challenges of chronic obstructive pulmonary disease (COPD): a perspective

COPD

Emphysema: an autoimmune vascular disease?

Proc Am Thorac Soc

Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis

J Pathol

Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension

J Clin Invest

Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension

Circ Res

Peroxisome proliferator-activated receptor γ (PPARγ) expression is decreased in pulmonary hypertension and affects endothelial cell growth

Circ Res

Lung morphometry by unbiased methods in emphysema: bronchial and blood vessel volume, alveolar surface area and capillary length

APMIS

Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

J Clin Invest

Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease?

Proc Am Thorac Soc

Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema

Am J Respir Crit Care Med

Correlation of lung surface area to apoptosis and proliferation in human emphysema

Eur Respir J

Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease

J Immunol

Small airways dimensions in asthma and in chronic obstructive pulmonary disease

Am Rev Respir Dis

Increased vascularity of the bronchial mucosa in mild asthma

Am J Respir Crit Care Med

Translating Basic Research Into Clinical Practice
Angiogenesis in Chronic Lung Disease