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Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease
Accepted Manuscript Pathophysiology of pulmonary hypertension in chronic parenchymal lung disease Inderjit Singh, MBBch PII:
S0002-9343(15)30025-5
DOI:
10.1016/j.amjmed.2015.11.026
Reference:
AJM 13289
To appear in:
The American Journal of Medicine
Received Date: 26 October 2015 Revised Date:
2 November 2015
Accepted Date: 3 November 2015
Please cite this article as: Singh I, Pathophysiology of pulmonary hypertension in chronic parenchymal lung disease, The American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2015.11.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Pathophysiology of pulmonary hypertension in chronic parenchymal lung disease Inderjit Singh MBBch1, Kevin Cong Ma MD1, and David Adam Berlin MD1 1Department
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Corresponding author information: Inderjit Singh, Department of Medicine, Division of Pulmonary and Critical Care, Weill Cornell Medical Center, 1300 York Avenue, Box 96 New York, New York, 10065. E-mail: [email protected]
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of Medicine, Division of Pulmonary and Critical Care, Weill Cornell Medical Center, New York, New York, 10065.
ABSTRACT
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The authors of this article report no conflicts of interest. No funding was required for this article. This article/abstract was not submitted or presented to prior publication or presentation respectively. All authors had access to the data and a role in writing the manuscript; article type. Key words: pulmonary hypertension; idiopathic pulmonary fibrosis; pulmonary fibrosis; chronic obstructive pulmonary disease; COPD; sarcoidosis Running head: introduction; pathophysiology of pulmonary hypertension in interstitial lung disease and chronic obstructive pulmonary disease; conclusion
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Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease (COPD) and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease associated pulmonary hypertension. This review will focus on the pathophysiology of three forms of chronic lung disease: idiopathic pulmonary fibrosis, COPD, and sarcoidosis.
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INTRODUCTION
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Chronic obstructive pulmonary disease (COPD) and interstitial lung diseases are commonly associated with pulmonary hypertension. The current consensus definition for pulmonary hypertension in chronic respiratory disease is: 1. Chronic lung disease with pulmonary hypertension when mean pulmonary arterial pressure ≥ 25 mm Hg 2. Chronic lung disease with severe pulmonary hypertension when the mean pulmonary arterial pressure is ≥ 35 mm Hg, or greater ≥ 25 but ≤ 35 mm Hg with low cardiac index (< 2 L/min/m2) (1).
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The prevalence of pulmonary hypertension in chronic lung disease varies widely depending on the diagnostic method, the definition of pulmonary hypertension used, and the patient population studied (2-11). Patients with chronic lung disease-associated pulmonary hypertension have a significantly worse prognosis compared to patients without pulmonary hypertension (2, 4, 6, 12, 13). This review will focus on the pathophysiology of three forms of chronic lung disease: idiopathic pulmonary fibrosis, COPD, and sarcoidosis.
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Nearly the entire cardiac output normally flows through the pulmonary circuit. Despite this, the pulmonary vascular pressure and resistance are much less than the systemic circulation. This is because the pulmonary circulation adapts to large changes in cardiac output by distending and/or recruiting previously under perfused pulmonary capillaries. Thus, pulmonary vascular resistance decreases as pulmonary blood flow increases. Pulmonary vascular resistance is expressed as: =
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Unlike the systemic circulation with its greater vasomotor activity, the pulmonary circulation has limited ability to control regional pulmonary blood flow and is greatly influenced by various other active and passive factors (table 1). The pulmonary arteries and arterioles with their muscular walls, are mainly extra-alveolar and regulate pulmonary vascular resistance via active nervous, humoral, or gaseous mechanisms. In contrast, the pulmonary capillaries lie adjacent to alveolar walls and the resistance of these alveolar vessels is therefore greatly influenced by alveolar pressure and volume. Thus, in the normal pulmonary circulation, vessels devoid of active vasoconstriction plays a pivotal role in regulating pulmonary vascular resistance and the distribution of pulmonary blood flow (14).
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Hypoxic pulmonary vasoconstriction also plays a major role in the active regulation of pulmonary vascular resistance and pulmonary blood flow. This regional reflexive mechanism is an adaptive response to divert pulmonary blood flow away from regions of low oxygen tension and plays an integral part in optimizing ventilation / perfusion matching. Reflexive hypoxic pulmonary vasoconstriction has multiple mechanisms resulting from the direct effects of hypoxia on pulmonary vascular smooth muscle cells (15-17), impaired release of endothelium derived vasodilators such as nitric oxide and prostaglandin (18), and increased expression of the vasoconstrictive peptide, endothelin (19, 20).
ACCEPTED MANUSCRIPT Various patho-physiologic pathways account for the development of pulmonary hypertension in patients with chronic lung disease. Normally, the thin wall of the pulmonary arteries and arterioles, and the non-muscularized pulmonary capillaries allow the vessels to distend rather than actively constrict or dilate (21). In pulmonary hypertension, pulmonary vascular remodeling thickens the arterial wall and increases resistance by reducing the luminal diameter. This reduces the ability of the vessel to distend passively and also potentiates the further increase in pulmonary vascular resistance produced by active vasoconstriction (22, 23).
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Pathophysiology of pulmonary hypertension in interstitial lung disease and chronic obstructive pulmonary disease
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Pathophysiology of pulmonary hypertension in chronic obstructive pulmonary disease
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In patients with COPD, the elevation in pulmonary vascular resistance is the result of a complex interaction between mechanical factors, reflexive hypoxic pulmonary vasoconstriction, and pulmonary vascular remodeling (table 2). In chronic bronchitis, expiratory airflow limitation increases alveolar air volume, resulting in dynamic hyperinflation. As the alveoli expands, the adjacent intra-alveolar pulmonary capillaries are stretched and their diameter decreases. The resistance to pulmonary blood flow increases greatly as the intra-alveolar pressure increases because the adjacent vessels become longer (resistance is directly proportional to length) and their radii become smaller (resistance is inversely proportional to radius to the fourth power). Additionally, over-expansion of the alveoli may also directly compress these capillaries further contributing to the increase in pulmonary vascular resistance (24).
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Contrary to prior notion, emphysematous destruction of the pulmonary vascular bed plays a less significant role in the development of pulmonary hypertension amongst COPD patients. In COPD patients, there is no significant correlation between pulmonary arterial pressure or resistance and the extent of emphysema as measured by CT lung density (25). The obliteration of alveolar vessels that is seen in emphysema is typically associated with normal resting pulmonary arterial pressure until the very late stages, when pulmonary vascular destruction leads to severe diffusion limitation with resting arterial hypoxemia. However, loss of pulmonary vascular bed does contribute to the increase in pulmonary vascular resistance during exercise in such patients because the inability to recruit and/or distend under-perfused vessels (26).
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The lack of reversibility in response to oxygen therapy or nitric oxide (NO) inhalation suggests that a more chronic structural change rather than the acute hypoxic pulmonary vasoconstriction mechanism accounts for pulmonary hypertension development in COPD patients (27-31). This process of pulmonary vascular remodeling involves mainly the small pulmonary arteries and is characterized by neomuscularization, intimal thickening, and medial hypertrophy (23). Many pathophysiologic mechanisms have been implicated in pulmonary vascular remodeling amongst COPD patients with pulmonary hypertension. These include chronic hypoxia, cigarette smoking injury (32-35), and airway and vascular wall inflammation (36, 37). All of these factors lead to vascular endothelial damage and subsequent structural changes within the vascular wall. Chronic hypoxia contributes to pulmonary vascular remodeling through production of Hypoxia Induced Mitogenic Factor (HIMF) and interleukin-6 (IL-6), both of which promotes vascular endothelial cell proliferation (38, 39). Recently, increased expression of adenosine A2B receptor (ADORA2B) and hyaluronan have also been implicated (40). Recent studies have also demonstrated that COPD patients with LL-genotype of serotonin (5-HT), a potent stimulator of vascular smooth muscle hyperplasia, are at greater risk of developing higher pulmonary arterial pressure compared with other polymorphisms (41, 42). There is also evidence evoking the role of bone marrow derived
ACCEPTED MANUSCRIPT endothelial progenitor cells (EPCs) in the progression and maintenance of pulmonary vascular remodeling (23). In response to vascular endothelial injury, these cells infiltrate the intima of pulmonary arteries further contributing to the remodeling process (43, 44). The resulting pulmonary vascular remodeling causes impaired endothelium-dependent vasodilation (33, 45) from reduced expression of endothelial nitric oxide synthase (eNOS) enzyme (34, 46) and decrease release of prostacyclin metabolites (47, 48). This produces an imbalance that favors an increase in pulmonary vascular tone and a proliferative state within the pulmonary vascular wall.
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Other factors that have been implicated in pulmonary hypertension development COPD patients include increase blood viscosity from secondary polycythemia (49) and the synergetic effects of hypoxia with the accompanying increase in hydrogen ion concentration seen in hypercapnic acidosis (26).
Pathophysiology of pulmonary hypertension in idiopathic pulmonary fibrosis
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The pulmonary vasculopathy of idiopathic pulmonary fibrosis in areas of fibrosis are pathologically similar to those in COPD patients (31, 50, 51). However, in addition to neomuscularization and medial hypertrophy, patients with idiopathic pulmonary fibrosis also demonstrate intimal fibrosis with resulting vascular lumen obliteration. The fibrotic areas also demonstrate vascular regression, whereas the non-fibrotic areas have increased growth of structurally abnormal vasculature that may contribute to increased vascular resistance (50).
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Similar to COPD and pulmonary hypertension, patients with idiopathic pulmonary fibrosis may also exhibit increases in mean pulmonary arterial pressure measurements during exercise. This exertional increase in mean pulmonary arterial pressure is related to inadequate pulmonary capillary recruitment (52). The pattern of vascular remodeling, the lack of reversibility with oxygen, and the occurrence of pulmonary hypertension in patients with only mild hypoxemia suggest factors other than hypoxia as the primary cause of pulmonary hypertension in idiopathic pulmonary fibrosis.
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Endothelin-1, a potent vasoconstrictive agent and mediator of vascular smooth proliferation has been implicated in the development of pulmonary hypertension amongst patients with idiopathic pulmonary fibrosis. Endothelin-1 is highly expressed in airway epithelium, type II pneumocytes, and endothelial cells in patients with idiopathic pulmonary fibrosis compared with control subjects and patients with non-specific fibrosis (53). Similarly, elevated levels of endothelin-1 are also seen in lung tissues of patients with scleroderma-associated pulmonary fibrosis (54).
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Other factors that contribute to pulmonary vascular remodeling in pulmonary fibrosis include transforming growth factor alpha (TGF- α) (50, 55), 5-lipoxygenase, platelet-derived growth factor, fibroblast growth factor (56, 57), and autoantibodies such as anti-endothelial cells and antifibrillin seen in systemic sclerosis mediated lung fibrosis (58).
Pathophysiology of pulmonary hypertension in sarcoidosis There are various patho-physiologic mechanisms that contribute to pulmonary hypertension development in sarcoidosis (table 3). While fibrotic ablation of the pulmonary vasculature and parenchymal destruction is an important contributor to pulmonary hypertension development, the finding of pulmonary hypertension in sarcoidosis patients with preserved lung architecture and normal pulmonary function suggests other potential mechanisms (table 3) (59). This includes granulomatous infiltration of the pulmonary vasculature. Intrinsic pulmonary vaso-occlusion from granulomatous infiltration can occur at all levels from the large pulmonary arteries to venules. This granulomatous vascular involvement tends to occur in a heterogeneous manner and more
ACCEPTED MANUSCRIPT commonly involves the small arteries and pulmonary venules (60). Involvement of the pulmonary venules can result in a pulmonary veno-occlusive disease-like phenotype (59, 61-63).
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On a molecular level, levels of endothelin-1 levels are elevated in broncho-alveolar lavage fluid (64) and plasma (65) of patients with severe sarcoidosis and pulmonary hypertension (64). Additionally, pulmonary vasodilators such as NO and prostacyclin are decreased presumably from granulomatous mediated endothelial destruction (66). This heterogeneous mechanism of pulmonary hypertension occurrence in sarcoidosis complicates the use of pulmonary vasodilatory therapies and likely accounts for the difference in gas exchange outcomes seen with the various different pulmonary vasodilators.
Conclusion
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Pulmonary hypertension is a common and significant complication of interstitial lung disease and COPD. The presence of pulmonary hypertension signifies a poorer functional and survival outcome in these patients. In order to understand the complex and variable pathophysiology of pulmonary hypertension complicating lung disease, it is important to understand the various physiological determinants of the normal pulmonary circulation. Derangements in any of these factors increase the pulmonary vascular resistance.
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Gravity / body position
Decreases in gravity dependent regions of the lungs Increases Increases
Hydrostatic effects leading to recruitment and distension of previously under perfused vessels.
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Viscosity directly increases resistance. Increased alveolar pressure with compression and lengthening of alveolar vessels. Increased intra-pleural pressure with compression of extra-alveolar vessels. Reduces venous return resulting in decreased pulmonary blood flow and derecruitment. FRC: functional residual capacity; PVR: pulmonary vascular resistance
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Increased blood viscosity Positive-pressure ventilation
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Table 1(a): Passive factors influencing pulmonary vascular resistance Passive factors Effect on PVR Mechanism of increased PVR Increased lung volume (above FRC) Increases Lengthening and compression of alveolar vessels. Decreased lung volume (below FRC) Increases Compression of extra-alveolar vessels. Increased pulmonary arterial pressure Decreases Recruitment and distension of previously under Increased left atrial pressure perfused vessels. Increased pulmonary blood volume Increased cardiac output
Table 1(b): Active factors influencing pulmonary vascular resistance
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Active factors that increases PVR Active factors that decreases PVR Neural factors: Neural factors: • Sympathetic nervous system stimulation • Parasympathetic nervous system stimulation • Sympathomimetics: NE, epinephrine, and • Parasympathomimetics: Ach alpha- agonists • Sympathomimetic: Beta-2-agonists Gaseous factors: Gaseous factor: • Alveolar hypoxia and hypercapnia • Nitric oxide Other factors: Other factors: • Thromboxane • Prostacyclin • Endothelin • Bradykinin • Angiotensin • PG-E1 • PG-F2aplha and PG-E2 • Low pH of mixed venous blood PVR: pulmonary vascular resistance; NE: norepinephrine; Ach: acetylcholine: PG: prostaglandin
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Table 2: Factors contributing to elevation in pulmonary vascular resistance in chronic obstructive pulmonary disease CONTRIBUTING FACOTRS CONSEQUNCE Expiratory airflow obstruction
Alveolar hyperinflation
Pulmonary vascular remodeling
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Chronic hypoxia LL-genotype polymorphism of 5-HT Increased expression of ADORA2B Proliferation of bone marrow EPCs Cigarette smoking injury Airway and vascular wall inflammation Hypoxia and acidosis
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Reflexive pulmonary vascular constriction
Polycythemia
Increased blood viscosity
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5-HT: serotonin; PCWP: pulmonary capillary wedge pressure; ADORA2B: adenosine A2B receptor; HIMF: hypoxia induced mitogenic factor; EPCs: endothelial progenitor cells
Table 3: Potential mechanisms of sarcoidosis-associated pulmonary hypertension
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Fibrotic ablation of pulmonary vasculature and lung parenchyma Left ventricular systolic or diastolic dysfunction Granulomatous pulmonary vasculopathy Extrinsic compression of pulmonary vasculature by lymphadenopathy or mediastinal fibrosis Pulmonary vasculitis Pulmonary veno-occlusive disease Increase pulmonary vasoreactivity Porto-pulmonary hypertension
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CLINICAL SIGNIFICANCE
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Regulation of blood flow in the normal pulmonary circulation occurs at the level of the pulmonary capillaries. In patients with chronic parenchymal lung disease, pulmonary hypertension (PH) carries a worse prognosis. Chronic parenchymal lung disease-associated PH is the result of interactions between mechanical factors, reflexive hypoxic pulmonary vasoconstriction, and pulmonary vascular remodeling. The heterogeneous mechanism of PH occurrence in chronic parenchymal lung disease complicates the use of pulmonary vasodilators.
Sincerely,
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Inderjit Singh, MBBch Department of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, 1300 York Avenue, Box 96, New York, New York, 10065. E-mail: [email protected]
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S0002-9343(15)30025-5
DOI:
10.1016/j.amjmed.2015.11.026
Reference:
AJM 13289
To appear in:
The American Journal of Medicine
Received Date: 26 October 2015 Revised Date:
2 November 2015
Accepted Date: 3 November 2015
Please cite this article as: Singh I, Pathophysiology of pulmonary hypertension in chronic parenchymal lung disease, The American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2015.11.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Pathophysiology of pulmonary hypertension in chronic parenchymal lung disease Inderjit Singh MBBch1, Kevin Cong Ma MD1, and David Adam Berlin MD1 1Department
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Corresponding author information: Inderjit Singh, Department of Medicine, Division of Pulmonary and Critical Care, Weill Cornell Medical Center, 1300 York Avenue, Box 96 New York, New York, 10065. E-mail: [email protected]
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of Medicine, Division of Pulmonary and Critical Care, Weill Cornell Medical Center, New York, New York, 10065.
ABSTRACT
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The authors of this article report no conflicts of interest. No funding was required for this article. This article/abstract was not submitted or presented to prior publication or presentation respectively. All authors had access to the data and a role in writing the manuscript; article type. Key words: pulmonary hypertension; idiopathic pulmonary fibrosis; pulmonary fibrosis; chronic obstructive pulmonary disease; COPD; sarcoidosis Running head: introduction; pathophysiology of pulmonary hypertension in interstitial lung disease and chronic obstructive pulmonary disease; conclusion
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Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease (COPD) and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease associated pulmonary hypertension. This review will focus on the pathophysiology of three forms of chronic lung disease: idiopathic pulmonary fibrosis, COPD, and sarcoidosis.
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INTRODUCTION
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Chronic obstructive pulmonary disease (COPD) and interstitial lung diseases are commonly associated with pulmonary hypertension. The current consensus definition for pulmonary hypertension in chronic respiratory disease is: 1. Chronic lung disease with pulmonary hypertension when mean pulmonary arterial pressure ≥ 25 mm Hg 2. Chronic lung disease with severe pulmonary hypertension when the mean pulmonary arterial pressure is ≥ 35 mm Hg, or greater ≥ 25 but ≤ 35 mm Hg with low cardiac index (< 2 L/min/m2) (1).
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The prevalence of pulmonary hypertension in chronic lung disease varies widely depending on the diagnostic method, the definition of pulmonary hypertension used, and the patient population studied (2-11). Patients with chronic lung disease-associated pulmonary hypertension have a significantly worse prognosis compared to patients without pulmonary hypertension (2, 4, 6, 12, 13). This review will focus on the pathophysiology of three forms of chronic lung disease: idiopathic pulmonary fibrosis, COPD, and sarcoidosis.
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Nearly the entire cardiac output normally flows through the pulmonary circuit. Despite this, the pulmonary vascular pressure and resistance are much less than the systemic circulation. This is because the pulmonary circulation adapts to large changes in cardiac output by distending and/or recruiting previously under perfused pulmonary capillaries. Thus, pulmonary vascular resistance decreases as pulmonary blood flow increases. Pulmonary vascular resistance is expressed as: =
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Unlike the systemic circulation with its greater vasomotor activity, the pulmonary circulation has limited ability to control regional pulmonary blood flow and is greatly influenced by various other active and passive factors (table 1). The pulmonary arteries and arterioles with their muscular walls, are mainly extra-alveolar and regulate pulmonary vascular resistance via active nervous, humoral, or gaseous mechanisms. In contrast, the pulmonary capillaries lie adjacent to alveolar walls and the resistance of these alveolar vessels is therefore greatly influenced by alveolar pressure and volume. Thus, in the normal pulmonary circulation, vessels devoid of active vasoconstriction plays a pivotal role in regulating pulmonary vascular resistance and the distribution of pulmonary blood flow (14).
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Hypoxic pulmonary vasoconstriction also plays a major role in the active regulation of pulmonary vascular resistance and pulmonary blood flow. This regional reflexive mechanism is an adaptive response to divert pulmonary blood flow away from regions of low oxygen tension and plays an integral part in optimizing ventilation / perfusion matching. Reflexive hypoxic pulmonary vasoconstriction has multiple mechanisms resulting from the direct effects of hypoxia on pulmonary vascular smooth muscle cells (15-17), impaired release of endothelium derived vasodilators such as nitric oxide and prostaglandin (18), and increased expression of the vasoconstrictive peptide, endothelin (19, 20).
ACCEPTED MANUSCRIPT Various patho-physiologic pathways account for the development of pulmonary hypertension in patients with chronic lung disease. Normally, the thin wall of the pulmonary arteries and arterioles, and the non-muscularized pulmonary capillaries allow the vessels to distend rather than actively constrict or dilate (21). In pulmonary hypertension, pulmonary vascular remodeling thickens the arterial wall and increases resistance by reducing the luminal diameter. This reduces the ability of the vessel to distend passively and also potentiates the further increase in pulmonary vascular resistance produced by active vasoconstriction (22, 23).
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Pathophysiology of pulmonary hypertension in interstitial lung disease and chronic obstructive pulmonary disease
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Pathophysiology of pulmonary hypertension in chronic obstructive pulmonary disease
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In patients with COPD, the elevation in pulmonary vascular resistance is the result of a complex interaction between mechanical factors, reflexive hypoxic pulmonary vasoconstriction, and pulmonary vascular remodeling (table 2). In chronic bronchitis, expiratory airflow limitation increases alveolar air volume, resulting in dynamic hyperinflation. As the alveoli expands, the adjacent intra-alveolar pulmonary capillaries are stretched and their diameter decreases. The resistance to pulmonary blood flow increases greatly as the intra-alveolar pressure increases because the adjacent vessels become longer (resistance is directly proportional to length) and their radii become smaller (resistance is inversely proportional to radius to the fourth power). Additionally, over-expansion of the alveoli may also directly compress these capillaries further contributing to the increase in pulmonary vascular resistance (24).
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Contrary to prior notion, emphysematous destruction of the pulmonary vascular bed plays a less significant role in the development of pulmonary hypertension amongst COPD patients. In COPD patients, there is no significant correlation between pulmonary arterial pressure or resistance and the extent of emphysema as measured by CT lung density (25). The obliteration of alveolar vessels that is seen in emphysema is typically associated with normal resting pulmonary arterial pressure until the very late stages, when pulmonary vascular destruction leads to severe diffusion limitation with resting arterial hypoxemia. However, loss of pulmonary vascular bed does contribute to the increase in pulmonary vascular resistance during exercise in such patients because the inability to recruit and/or distend under-perfused vessels (26).
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The lack of reversibility in response to oxygen therapy or nitric oxide (NO) inhalation suggests that a more chronic structural change rather than the acute hypoxic pulmonary vasoconstriction mechanism accounts for pulmonary hypertension development in COPD patients (27-31). This process of pulmonary vascular remodeling involves mainly the small pulmonary arteries and is characterized by neomuscularization, intimal thickening, and medial hypertrophy (23). Many pathophysiologic mechanisms have been implicated in pulmonary vascular remodeling amongst COPD patients with pulmonary hypertension. These include chronic hypoxia, cigarette smoking injury (32-35), and airway and vascular wall inflammation (36, 37). All of these factors lead to vascular endothelial damage and subsequent structural changes within the vascular wall. Chronic hypoxia contributes to pulmonary vascular remodeling through production of Hypoxia Induced Mitogenic Factor (HIMF) and interleukin-6 (IL-6), both of which promotes vascular endothelial cell proliferation (38, 39). Recently, increased expression of adenosine A2B receptor (ADORA2B) and hyaluronan have also been implicated (40). Recent studies have also demonstrated that COPD patients with LL-genotype of serotonin (5-HT), a potent stimulator of vascular smooth muscle hyperplasia, are at greater risk of developing higher pulmonary arterial pressure compared with other polymorphisms (41, 42). There is also evidence evoking the role of bone marrow derived
ACCEPTED MANUSCRIPT endothelial progenitor cells (EPCs) in the progression and maintenance of pulmonary vascular remodeling (23). In response to vascular endothelial injury, these cells infiltrate the intima of pulmonary arteries further contributing to the remodeling process (43, 44). The resulting pulmonary vascular remodeling causes impaired endothelium-dependent vasodilation (33, 45) from reduced expression of endothelial nitric oxide synthase (eNOS) enzyme (34, 46) and decrease release of prostacyclin metabolites (47, 48). This produces an imbalance that favors an increase in pulmonary vascular tone and a proliferative state within the pulmonary vascular wall.
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Other factors that have been implicated in pulmonary hypertension development COPD patients include increase blood viscosity from secondary polycythemia (49) and the synergetic effects of hypoxia with the accompanying increase in hydrogen ion concentration seen in hypercapnic acidosis (26).
Pathophysiology of pulmonary hypertension in idiopathic pulmonary fibrosis
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The pulmonary vasculopathy of idiopathic pulmonary fibrosis in areas of fibrosis are pathologically similar to those in COPD patients (31, 50, 51). However, in addition to neomuscularization and medial hypertrophy, patients with idiopathic pulmonary fibrosis also demonstrate intimal fibrosis with resulting vascular lumen obliteration. The fibrotic areas also demonstrate vascular regression, whereas the non-fibrotic areas have increased growth of structurally abnormal vasculature that may contribute to increased vascular resistance (50).
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Similar to COPD and pulmonary hypertension, patients with idiopathic pulmonary fibrosis may also exhibit increases in mean pulmonary arterial pressure measurements during exercise. This exertional increase in mean pulmonary arterial pressure is related to inadequate pulmonary capillary recruitment (52). The pattern of vascular remodeling, the lack of reversibility with oxygen, and the occurrence of pulmonary hypertension in patients with only mild hypoxemia suggest factors other than hypoxia as the primary cause of pulmonary hypertension in idiopathic pulmonary fibrosis.
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Endothelin-1, a potent vasoconstrictive agent and mediator of vascular smooth proliferation has been implicated in the development of pulmonary hypertension amongst patients with idiopathic pulmonary fibrosis. Endothelin-1 is highly expressed in airway epithelium, type II pneumocytes, and endothelial cells in patients with idiopathic pulmonary fibrosis compared with control subjects and patients with non-specific fibrosis (53). Similarly, elevated levels of endothelin-1 are also seen in lung tissues of patients with scleroderma-associated pulmonary fibrosis (54).
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Other factors that contribute to pulmonary vascular remodeling in pulmonary fibrosis include transforming growth factor alpha (TGF- α) (50, 55), 5-lipoxygenase, platelet-derived growth factor, fibroblast growth factor (56, 57), and autoantibodies such as anti-endothelial cells and antifibrillin seen in systemic sclerosis mediated lung fibrosis (58).
Pathophysiology of pulmonary hypertension in sarcoidosis There are various patho-physiologic mechanisms that contribute to pulmonary hypertension development in sarcoidosis (table 3). While fibrotic ablation of the pulmonary vasculature and parenchymal destruction is an important contributor to pulmonary hypertension development, the finding of pulmonary hypertension in sarcoidosis patients with preserved lung architecture and normal pulmonary function suggests other potential mechanisms (table 3) (59). This includes granulomatous infiltration of the pulmonary vasculature. Intrinsic pulmonary vaso-occlusion from granulomatous infiltration can occur at all levels from the large pulmonary arteries to venules. This granulomatous vascular involvement tends to occur in a heterogeneous manner and more
ACCEPTED MANUSCRIPT commonly involves the small arteries and pulmonary venules (60). Involvement of the pulmonary venules can result in a pulmonary veno-occlusive disease-like phenotype (59, 61-63).
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On a molecular level, levels of endothelin-1 levels are elevated in broncho-alveolar lavage fluid (64) and plasma (65) of patients with severe sarcoidosis and pulmonary hypertension (64). Additionally, pulmonary vasodilators such as NO and prostacyclin are decreased presumably from granulomatous mediated endothelial destruction (66). This heterogeneous mechanism of pulmonary hypertension occurrence in sarcoidosis complicates the use of pulmonary vasodilatory therapies and likely accounts for the difference in gas exchange outcomes seen with the various different pulmonary vasodilators.
Conclusion
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Pulmonary hypertension is a common and significant complication of interstitial lung disease and COPD. The presence of pulmonary hypertension signifies a poorer functional and survival outcome in these patients. In order to understand the complex and variable pathophysiology of pulmonary hypertension complicating lung disease, it is important to understand the various physiological determinants of the normal pulmonary circulation. Derangements in any of these factors increase the pulmonary vascular resistance.
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Gravity / body position
Decreases in gravity dependent regions of the lungs Increases Increases
Hydrostatic effects leading to recruitment and distension of previously under perfused vessels.
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Viscosity directly increases resistance. Increased alveolar pressure with compression and lengthening of alveolar vessels. Increased intra-pleural pressure with compression of extra-alveolar vessels. Reduces venous return resulting in decreased pulmonary blood flow and derecruitment. FRC: functional residual capacity; PVR: pulmonary vascular resistance
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Increased blood viscosity Positive-pressure ventilation
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Table 1(a): Passive factors influencing pulmonary vascular resistance Passive factors Effect on PVR Mechanism of increased PVR Increased lung volume (above FRC) Increases Lengthening and compression of alveolar vessels. Decreased lung volume (below FRC) Increases Compression of extra-alveolar vessels. Increased pulmonary arterial pressure Decreases Recruitment and distension of previously under Increased left atrial pressure perfused vessels. Increased pulmonary blood volume Increased cardiac output
Table 1(b): Active factors influencing pulmonary vascular resistance
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Active factors that increases PVR Active factors that decreases PVR Neural factors: Neural factors: • Sympathetic nervous system stimulation • Parasympathetic nervous system stimulation • Sympathomimetics: NE, epinephrine, and • Parasympathomimetics: Ach alpha- agonists • Sympathomimetic: Beta-2-agonists Gaseous factors: Gaseous factor: • Alveolar hypoxia and hypercapnia • Nitric oxide Other factors: Other factors: • Thromboxane • Prostacyclin • Endothelin • Bradykinin • Angiotensin • PG-E1 • PG-F2aplha and PG-E2 • Low pH of mixed venous blood PVR: pulmonary vascular resistance; NE: norepinephrine; Ach: acetylcholine: PG: prostaglandin
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Table 2: Factors contributing to elevation in pulmonary vascular resistance in chronic obstructive pulmonary disease CONTRIBUTING FACOTRS CONSEQUNCE Expiratory airflow obstruction
Alveolar hyperinflation
Pulmonary vascular remodeling
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Chronic hypoxia LL-genotype polymorphism of 5-HT Increased expression of ADORA2B Proliferation of bone marrow EPCs Cigarette smoking injury Airway and vascular wall inflammation Hypoxia and acidosis
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Reflexive pulmonary vascular constriction
Polycythemia
Increased blood viscosity
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5-HT: serotonin; PCWP: pulmonary capillary wedge pressure; ADORA2B: adenosine A2B receptor; HIMF: hypoxia induced mitogenic factor; EPCs: endothelial progenitor cells
Table 3: Potential mechanisms of sarcoidosis-associated pulmonary hypertension
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Fibrotic ablation of pulmonary vasculature and lung parenchyma Left ventricular systolic or diastolic dysfunction Granulomatous pulmonary vasculopathy Extrinsic compression of pulmonary vasculature by lymphadenopathy or mediastinal fibrosis Pulmonary vasculitis Pulmonary veno-occlusive disease Increase pulmonary vasoreactivity Porto-pulmonary hypertension
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CLINICAL SIGNIFICANCE
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Regulation of blood flow in the normal pulmonary circulation occurs at the level of the pulmonary capillaries. In patients with chronic parenchymal lung disease, pulmonary hypertension (PH) carries a worse prognosis. Chronic parenchymal lung disease-associated PH is the result of interactions between mechanical factors, reflexive hypoxic pulmonary vasoconstriction, and pulmonary vascular remodeling. The heterogeneous mechanism of PH occurrence in chronic parenchymal lung disease complicates the use of pulmonary vasodilators.
Sincerely,
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Inderjit Singh, MBBch Department of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, 1300 York Avenue, Box 96, New York, New York, 10065. E-mail: [email protected]
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