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Translating Basic Research Into Clinical Practice |

Pulmonary Vascular Involvement in COPD FREE TO VIEW

Víctor I. Peinado, PhD; Sandra Pizarro, MD; Joan Albert Barberà, MD
Author and Funding Information

*From the Department of Pulmonary Medicine, Hospital Clínic, Universitat de Barcelona; Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); and Ciber de Enfermedades Respiratorias, Barcelona, Spain.

Correspondence to: Joan Albert Barberà, MD, Servei de Pneumologia, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: jbarbera@clinic.ub.es


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.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2008;134(4):808-814. doi:10.1378/chest.08-0820
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Alterations in pulmonary vessel structure and function are highly prevalent in patients with COPD. Vascular abnormalities impair gas exchange and may result in pulmonary hypertension, which is one of the principal factors associated with reduced survival in COPD patients. Changes in pulmonary circulation have been identified at initial disease stages, providing new insight into their pathogenesis. Endothelial cell damage and dysfunction produced by the effects of cigarette smoke products or inflammatory elements is now considered to be the primary alteration that initiates the sequence of events resulting in pulmonary hypertension. Cellular and molecular mechanisms involved in this process are being extensively investigated. Progress in the understanding of the pathobiology of pulmonary hypertension associated with COPD may provide the basis for a new therapeutic approach addressed to correct the imbalance between endothelium-derived vasoactive agents. The safety and efficacy of endothelium-targeted therapy in COPD-associated pulmonary hypertension warrants further investigation in randomized clinical trials.

Figures in this Article

COPD is defined in terms of airflow obstruction that results from an inflammatory process affecting the airways and lung parenchyma. Despite major abnormalities taking place in the airway side, changes in pulmonary vessels represent an important component of the disease. Alterations in vessel structure are highly prevalent, and abnormalities in their function impair gas exchange and result in pulmonary hypertension, which is one of the principal factors associated with reduced survival in COPD patients.1

The etiopathogenic mechanisms that are responsible for pulmonary vascular abnormalities in COPD patients remain incompletely understood, but they have been extensively investigated over the past few years. Studies24 conducted in patients with mild COPD that revealed significant structural and functional abnormalities in their pulmonary vessels have opened a new avenue for a better understanding of the pathogenesis of these changes, which might translate into clinical practice. In this review, we will examine the contributions of the last studies on the pathobiology of pulmonary vascular abnormalities that are associated with COPD, and will discuss the potential clinical implications in terms of diagnosis and treatment.

Remodeling is a process that causes thickening of the arterial wall and is thought to increase resistance by causing the vessel wall to encroach into the lumen and reduce its diameter. In COPD patients, pulmonary vascular remodeling affects small and precapillary arteries, and has been identified at different degrees of disease severity. Intimal enlargement is the most prominent feature of pulmonary vascular remodeling. It is apparent in arteries of different sizes, although it is more pronounced in small muscular arteries (ie, those < 500 μm in diameter).2,3,5 In addition, there is muscularization of arterioles that also show intimal enlargement. Changes in the tunica media are less conspicuous, and the majority of studies2,3,5 have failed to show striking differences in the thickness of the muscular layer in COPD patients.

Remodeling of pulmonary arteries is not restricted to patients with an established diagnosis of COPD. Indeed, intimal thickening, the magnitude of which does not differ from that seen in patients with mild COPD, also occurs in heavy smokers with normal lung function.3

Intimal hyperplasia has the following two components: cellular and extracellular. The majority of cells proliferating in hyperplasic intimas of pulmonary muscular arteries are smooth muscle cells (SMCs), as shown by positive immunoreaction to α-smooth muscle actin.4 Comparative analyses of serial sections show that some SMCs in the intima do not express desmin filaments, whereas all them express vimentin filaments.4 The expression pattern of both intermediate filaments may discriminate between a synthetic phenotype for SMCs and the contractile phenotype observed in mature cells.6,7 Accordingly, vimentin-positive, desmin-negative SMCs represent a subpopulation of less differentiated SMCs that may possess synthetic capacity and take part in an ongoing process of vascular remodeling.8 These findings are consistent with previous observations in patients with advanced COPD showing muscle deposition in pulmonary muscular arteries and the formation of a definite muscle layer in small arterioles.9,10 Newly formed smooth muscle bounds adopt a longitudinal disposition that differs from the circumferential disposition of normal smooth muscle.

COPD is an inflammatory disease, hence, inflammatory cells might contribute to the alterations of pulmonary vessels. Indeed, the extent of pulmonary vascular remodeling correlates with the severity of inflammatory cell infiltrate in small airways.2,11 Patients with COPD have an increased number of inflammatory cells infiltrating the adventitia of pulmonary muscular arteries, compared with nonsmokers.12 This inflammatory infiltrate is largely constituted by activated T lymphocytes with a predominance of the CD8+ T-cell subset.12,13 By contrast, the numbers of neutrophils, macrophages, and B lymphocytes are minimal and do not differ from those of control subjects.

In patients with mild-to-moderate COPD, the intensity of the inflammatory cell infiltrate in pulmonary arteries correlates with the degree of airflow obstruction, suggesting that, as the disease progresses, the inflammatory reaction in pulmonary arteries may become more severe.12 Interestingly, smokers with normal lung function also show an increased number of CD8+ T cells in the arterial adventitia, with a reduction of the CD4+/CD8+ ratio, compared with nonsmokers, that does not differ from that of patients with mild-to-moderate COPD.12

Endothelial cells play a crucial role in the regulation of vascular homeostasis.14 In pulmonary vessels, endothelial cells contribute to the reduced vascular tone,15 regulate vessel adaptation to increased flow,16 and modulate hypoxic vasoconstriction.17,18 Endothelial dysfunction of the pulmonary arteries has been shown with different degrees of COPD severity, as follows: patients with end-stage COPD who had undergone lung transplantation19; and patients with mild-to-moderate COPD.3 The impairment of endothelial function may be associated with or result from changes in the expression or the balanced release of vasoactive mediators with vasodilator properties, such as nitric oxide (NO) or prostacyclin, and mediators with vasoconstrictive properties, such as endothelin-1 (ET-1) or angiotensin (Fig 1).

Figure Jump LinkFigure 1 Major pathways involved in the regulation of pulmonary vascular tone. Substances with vasorelaxing action also possess antiproliferative effects on SMCs, whereas vasoconstrictive agents promote the proliferation of SMCs. ECE = endothelin-converting enzyme; ETA = endothelin receptor A; ETB = endothelin receptor B; sGC = soluble guanylate cyclase; GTP = guanosine triphosphate; GMP = guanosine monophosphate; cGMP = cyclic GMP; PDE = phosphodiesterase; PGH2 = prostaglandin H2; PGI2 = prostacyclin; PGI2S = prostacyclin synthase; ATP = adenosine triphosphate; AC = adenylate cyclase; AMP = adenosine monophosphate; cAMP = cyclic AMP.Grahic Jump Location

Giaid and Saleh20 showed a significant reduction of endothelial NO synthase (eNOS) expression in pulmonary arteries in patients with severe forms of both primary and secondary pulmonary hypertension (including patients with COPD), thereby suggesting that the down-regulation of NO might contribute to the development of pulmonary hypertension. The reduced expression of eNOS has also been shown21 in the pulmonary arteries of smokers without or with minimal airflow obstruction. More recent data22 have demonstrated that eNOS expression in pulmonary arteries is more markedly reduced in patients with greater COPD severity. Nana-Sinkam et al23 have recently shown that the expression of prostacyclin synthase is also reduced in the pulmonary arteries of patients with severe emphysema. Furthermore, Giaid et al24 showed that the expression of ET-1 in pulmonary arteries was increased in both primary and secondary forms of pulmonary hypertension (including patients with COPD).

The idea of a maintenance program in the adult lung has emerged in the past few years.25 The lung copes with external challenges by inhaled particles, toxic gases, and invading microorganisms. The defense against this external injury depends on immune mechanisms and an efficient system for removing and replacing apoptotic cells. Stem cells may play a critical role in lung homeostasis since they retain their ability to replicate and differentiate into structural cells. Both resident and bone marrow-derived stem cells may play such a role in the lung.

There is evidence indicating that the bone marrow is a source of endothelial progenitor cells (EPCs), which are mobilized into the peripheral blood in response to cytokines or tissue injury, and are recruited into the lung,26,27 eventually contributing to the lung maintenance program. Although there is no doubt that these cells may play a role in tissue repair, given the potential for differentiation to endothelial cells, they might also participate in the progression or maintenance of preexisting lesions.28 In the pulmonary circulation of COPD patients, this hypothesis is supported by a study showing an increase in the number of cells positive for CD133, which is a marker of bone marrow origin, infiltrating the hyperplasic intima of pulmonary arteries, very close to denuded areas of the endothelium.29 In that study, the number of progenitor cells attached to the endothelium correlated with the thickness of the arterial wall, suggesting a potential association with the severity of the remodeling process. More recently, it has been shown30 that CD133+ cells have the ability to migrate into the intima of pulmonary arteries and differentiate into SMCs, further supporting the idea of their participation in pulmonary vascular remodeling in COPD.

Hypoxia has been classically considered to be the major pathogenic mechanism of pulmonary hypertension in COPD. However, its role is currently being reconsidered because pulmonary vascular remodeling and endothelial dysfunction can be observed in patients with mild COPD who do not have hypoxemia and in smokers with normal lung function,2,4,12 and because long-term oxygen therapy does not reverse pulmonary hypertension.31

Observations1 point out that cigarette smoke products might be at the origin of pulmonary vascular impairment in COPD patients. This suggestion arises from the observation that smokers with normal lung function show prominent changes in pulmonary arteries, such as SMC proliferation,3,4 impairment of endothelial function,3 reduced expression of eNOS,21 increased expression of growth factors,32 and inflammatory cell infiltrate,12 which are indistinguishable from those seen in COPD patients, and clearly differ from those in nonsmokers.

Furthermore, pulmonary hypertension and vessel remodeling33 develop in guinea pigs that have been exposed over a long period to cigarette smoke. These changes appear when there is no evidence of emphysema, indicating that cigarette smoke-induced vascular abnormalities antecede its development.34 In this animal model, cigarette smoke exposure induces rapid changes in the gene expression of vascular endothelial growth factor (VEGF), VEGF receptor-1, ET-1, and inducible nitric oxide synthase,35 which are mediators that regulate vascular cell growth and vessel contraction, and are likely involved in the pathogenesis of pulmonary vascular changes in COPD patients. In addition, the exposure of pulmonary artery endothelial cells to cigarette smoke extract causes an irreversible inhibition of eNOS activity, which is due to a diminished level of protein content and messenger RNA.36 Cigarette smoke contains a number of products that have the potential to produce endothelial injury, among which the aldehyde acrolein seems to play a prominent role since it reduces the expression of prostacyclin synthase in endothelial cells.23

In summary, there is compelling evidence suggesting that the initial event in the natural history of pulmonary hypertension in COPD patients could be the injury of the pulmonary endothelium by cigarette smoke products. Indeed, lesions in endothelial cells in pulmonary arteries from COPD patients can be identified by microscopic observation as areas of denuded endothelium (Fig 2). More subtle, but no less important, is the alteration of the endothelial synthesis and the release of vasoactive mediators associated with habitual smoking.21 One of the consequences of endothelial dysfunction is the impairment of the reactivity of pulmonary arteries to hypoxia,10,37,38 thereby contributing to ventilation-perfusion mismatching and promoting the development of arterial hypoxemia. Endothelial damage also results in an imbalance among the factors that regulate cell growth, thereby favoring the proliferation of SMCs and extracellular matrix deposition (Fig 3). The up-regulation of VEGF, which is enhanced by endothelial dysfunction,32 might also contribute to the stimulatation of inflammatory cell release from bone marrow and homing at the sites of vascular damage. All of these changes may contribute to intimal hyperplasia with the ensuing reduction of the arterial lumen, which increases pulmonary vascular resistance.

Figure Jump LinkFigure 2 Scanning electron microscopy of the endothelial surface of pulmonary arteries. Top, A: endothelium of a nonsmoker subject showing a smooth and continuous appearance. Bottom, B: endothelial surface of a patient with COPD showing a denuded area where endothelial cells have detached from subendothelial tissue.Grahic Jump Location
Figure Jump LinkFigure 3 Proposed pathobiology of pulmonary hypertension in COPD patients. Cigarette smoke components or inflammation products may initiate the sequence of changes by damaging endothelial cells and producing endothelial dysfunction. This results in an imbalance between vasoactive and growth factors that promotes SMC proliferation. Additional factors such as hypoxia, inflammation, and shear stress amplify and perpetuate these effects, further contributing to the development of pulmonary hypertension. PAP = pulmonary artery pressure. See the legend of Figure 1 for abbreviation not used in the text.Grahic Jump Location

Arteries with endothelial dysfunction are more susceptible to the action of additional factors. Among those, sustained arterial hypoxemia and alveolar hypoxia in poorly ventilated lung units play a crucial role, since they may induce further endothelial impairment and vessel remodeling, either directly or through VEGF-dependent mechanisms, thus amplifying the initial effects of cigarette smoke products. Similar effects might be produced by cytokine release by inflammatory cells and by shear stress induced by increased vascular resistance (Fig 3).

The results of basic research into the vascular biology of the pulmonary circulation in COPD patients have identified the following several issues having potential clinical relevance: (1) structural and functional changes in pulmonary vessels are highly prevalent in all disease stages; (2) in patients with mild-to-moderate disease, these changes may not cause pulmonary hypertension at rest but might produce it during exercise and, eventually, may contribute to exercise limitation; (3) the impairment of endothelial function in pulmonary vessels appears to be at the origin of the pathogenesis of pulmonary hypertension in COPD patients and might constitute a potential therapeutic target; (4) endothelial dysfunction might be associated with impaired reactivity to hypoxic stimulus, thereby altering ventilation-perfusion matching and producing hypoxemia; and (5) cigarette smoke products appear to be the causative agents of the initial changes in pulmonary circulation through a direct effect on endothelial cells.

The treatment options for COPD-associated pulmonary vascular abnormalities are limited. To date, long-term oxygen therapy for the treatment of hypoxemia is the only treatment that has demonstrated efficacy in slowing down or reversing the progression of pulmonary hypertension.31 Nevertheless, pulmonary arterial pressure rarely returns to normal values, and the structural abnormalities of pulmonary vessels remain unaltered.9 Treatment with conventional vasodilators, such as calcium channel blockers or angiotensin-II antagonists, is not recommended because of their potential detrimental effects on gas exchange, due to the inhibition of hypoxic pulmonary vasoconstriction,18 and their lack of efficacy after long-term treatment.39,40

Experience gathered in patients with pulmonary arterial hypertension (PAH) suggests that treatments addressed to correct the fundamental disturbance that produces pulmonary hypertension, namely, endothelial cell dysfunction and/or destruction, might to some extent reverse its progression.41 Three major pathways are involved in the pathobiology of PAH at the endothelial level, which represent the following important therapeutic targets in this condition: NO-cyclic guanosine monophosphate; prostacyclin-cyclic adenosine monophosphate; and ET-1 pathways41 (Fig 1). Currently, the following three classes of drugs that exert an effect in these pathways are available: prostanoids; ET-1 receptor antagonists; and phosphodiesterase-5 inhibitors.41 These drugs (in what is called targeted pulmonary hypertension therapy) provide substantial beneficial effects in patients with PAH in terms of survival, symptom improvement, exercise tolerance, and pulmonary hemodynamics.4244

As alluded to above, some of these endothelium-related pathways are also altered in patients with COPD-associated pulmonary hypertension.21,23 Furthermore, the concept that pulmonary hypertension might arise from endothelial damage produced by cigarette smoke products or inflammatory mediators, rather than from hypoxia-induced vasoconstriction, opens a new approach to its treatment.1 Accordingly, it is conceivable that drugs that may correct the endothelial vasoconstrictor-dilator imbalance could be of clinical benefit in the treatment of COPD. Published information on the use of these drugs for the treatment of pulmonary hypertension in COPD patients is scarce and consists essentially of case reports or uncontrolled studies in a reduced number of subjects. Therefore, it is not possible to establish a recommendation on the use of these drugs in COPD patients. The safety and efficacy of endothelium-targeted therapy for the treatment of pulmonary vascular abnormalities needs to be clarified in properly conducted randomized controlled trials.

Repopulation of the pulmonary circulation with normally functioning endothelial cells by means of EPCs is also theoretically attractive. The expanding clinical applications of bone-marrow derived stem cells, along with a better understanding of the pathobiology of tissue repair will offer novel treatment strategies for lung regeneration in COPD. In fact, EPCs have been used for the treatment of pulmonary hypertension in animal models.4547 In the mice, IV administration of bone marrow cells attenuates the pulmonary hypertension induced by the administration of monocrotaline.47 Rats treated with monocrotaline receiving EPCs transduced with human eNOS also exhibited reversal of pulmonary hypertension.46 These studies have increased the expectancy to reverse pulmonary hypertension in humans. However, great caution must be taken with the eventual therapeutic use of stem cells due to their potential for carcinogenic transformation or, less dramatically, their contribution to intimal hyperplasia and pulmonary vascular remodeling, as alluded above.

Structural and functional impairment of pulmonary vessels are early phenomena in the natural history of COPD. Cigarette smoke products are now identified as the most likely causative agents of the initial changes in pulmonary circulation through either a direct effect on endothelial cells or an inflammatory mechanism. The combination of endothelial dysfunction, vessel remodeling and inflammatory cell infiltrate conform the basis for the development of pulmonary hypertension in COPD. Treatment options for this complication are limited. Experience gathered in PAH suggests that treatments addressed to correct the fundamental disturbance that produces pulmonary hypertension, namely endothelial cell dysfunction and/or destruction might be clinically useful.

Currently, there is no adequate information on the safety and efficacy of this approach in COPD and proper evidence should be gathered in randomized clinical trials. Furthermore, cell therapy with bone marrow-derived EPCs is hampered by their potential involvement in pulmonary vascular remodeling.

eNOS

endothelial nitric oxide synthase

EPC

endothelial progenitor cell

ET

endothelin

NO

nitric oxide

PAH

pulmonary arterial hypertension

SMC

smooth muscle cell

VEGF

vascular endothelial growth factor

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Santos S, Peinado VI, Ramirez J, et al. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J. 2002;19:632-638. [PubMed]
 
Magee F, Wright JL, Wiggs BR, et al. Pulmonary vascular structure and function in chronic obstructive pulmonary disease. Thorax. 1988;43:183-189. [PubMed]
 
Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995;75:487-517. [PubMed]
 
van der Loop FT, Gabbiani G, Kohnen G, et al. Differentiation of smooth muscle cells in human blood vessels as defined by smoothelin, a novel marker for the contractile phenotype. Arterioscler Thromb Vasc Biol. 1997;17:665-671. [PubMed]
 
Gabbiani G, Rungger-Brandle E, de Chastonay C, et al. Vimentin-containing smooth muscle cells in aortic intimal thickening after endothelial injury. Lab Invest. 1982;47:265-269. [PubMed]
 
Wilkinson M, Langhorne CA, Heath D, et al. A pathophysiological study of 10 cases of hypoxic cor pulmonale. Q J Med. 1988;66:65-85. [PubMed]
 
Wright JL, Petty T, Thurlbeck WM. Analysis of the structure of the muscular pulmonary arteries in patients with pulmonary hypertension and COPD: National Institutes of Health Nocturnal Oxygen Therapy Trial. Lung. 1992;170:109-124. [PubMed]
 
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Figures

Figure Jump LinkFigure 1 Major pathways involved in the regulation of pulmonary vascular tone. Substances with vasorelaxing action also possess antiproliferative effects on SMCs, whereas vasoconstrictive agents promote the proliferation of SMCs. ECE = endothelin-converting enzyme; ETA = endothelin receptor A; ETB = endothelin receptor B; sGC = soluble guanylate cyclase; GTP = guanosine triphosphate; GMP = guanosine monophosphate; cGMP = cyclic GMP; PDE = phosphodiesterase; PGH2 = prostaglandin H2; PGI2 = prostacyclin; PGI2S = prostacyclin synthase; ATP = adenosine triphosphate; AC = adenylate cyclase; AMP = adenosine monophosphate; cAMP = cyclic AMP.Grahic Jump Location
Figure Jump LinkFigure 2 Scanning electron microscopy of the endothelial surface of pulmonary arteries. Top, A: endothelium of a nonsmoker subject showing a smooth and continuous appearance. Bottom, B: endothelial surface of a patient with COPD showing a denuded area where endothelial cells have detached from subendothelial tissue.Grahic Jump Location
Figure Jump LinkFigure 3 Proposed pathobiology of pulmonary hypertension in COPD patients. Cigarette smoke components or inflammation products may initiate the sequence of changes by damaging endothelial cells and producing endothelial dysfunction. This results in an imbalance between vasoactive and growth factors that promotes SMC proliferation. Additional factors such as hypoxia, inflammation, and shear stress amplify and perpetuate these effects, further contributing to the development of pulmonary hypertension. PAP = pulmonary artery pressure. See the legend of Figure 1 for abbreviation not used in the text.Grahic Jump Location

Tables

References

Barberà JA, Peinado VI, Santos S. Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J. 2003;21:892-905. [PubMed] [CrossRef]
 
Barberà JA, Riverola A, Roca J, et al. Pulmonary vascular abnormalities and ventilation-perfusion relationships in mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1994;149:423-429. [PubMed]
 
Peinado VI, Barberà JA, Ramírez J, et al. Endothelial dysfunction in pulmonary arteries of patients with mild COPD. Am J Physiol Lung Cell Mol Physiol. 1998;18:L908-L913
 
Santos S, Peinado VI, Ramirez J, et al. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J. 2002;19:632-638. [PubMed]
 
Magee F, Wright JL, Wiggs BR, et al. Pulmonary vascular structure and function in chronic obstructive pulmonary disease. Thorax. 1988;43:183-189. [PubMed]
 
Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995;75:487-517. [PubMed]
 
van der Loop FT, Gabbiani G, Kohnen G, et al. Differentiation of smooth muscle cells in human blood vessels as defined by smoothelin, a novel marker for the contractile phenotype. Arterioscler Thromb Vasc Biol. 1997;17:665-671. [PubMed]
 
Gabbiani G, Rungger-Brandle E, de Chastonay C, et al. Vimentin-containing smooth muscle cells in aortic intimal thickening after endothelial injury. Lab Invest. 1982;47:265-269. [PubMed]
 
Wilkinson M, Langhorne CA, Heath D, et al. A pathophysiological study of 10 cases of hypoxic cor pulmonale. Q J Med. 1988;66:65-85. [PubMed]
 
Wright JL, Petty T, Thurlbeck WM. Analysis of the structure of the muscular pulmonary arteries in patients with pulmonary hypertension and COPD: National Institutes of Health Nocturnal Oxygen Therapy Trial. Lung. 1992;170:109-124. [PubMed]
 
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