- Email: [email protected]
World Health Organization Class III COPD-Associated Pulmonary Hypertension
2 Romero-Candeira S, Fernandez C, Martin C, et al. Influence of diuretics on the concentration of proteins and other components of pleural transudates in patients with heart failure. Am J Med 2001; 110:681– 686 3 Light RW. Pleural diseases. 5th ed. Baltimore, MD: Lippincott, Williams and Wilkins, 2007 4 Burgess LJ, Maritz FJ, Taljaard JJ. Comparative analysis of the biochemical parameters used to distinguish between pleural transudates and exudates. Chest 1995; 107:1604 –1609 5 Porcel JM, Vives M, Cao G, et al. Measurement of pro-brain natriuretic peptide in pleural fluid for the diagnosis of pleural effusions due to heart failure. Am J Med 2004; 15:116:417– 420 6 Kolditz M, Halank M, Schiemanck CS, et al. High diagnostic accuracy of NT-proBNP for cardiac origin of pleural effusions. Eur Respir J 2006; 28:144 –150 7 Liao H, Na MJ, Dikensoy O, et al. Diagnostic value of pleural fluid N-terminal pro-brain natriuretic peptide levels in patients with cardiovascular diseases. Respirology 2008; 13:53–57 8 Sanz MP, Borque L, Rus A, et al. Comparison of BNP and NT-proBNP assays in the approach to the emergency diagnosis of acute dyspnea. J Clin Lab Anal 2006; 20:227–232 9 Porcel JM, Martinez-Alonsa M, Cao G, et al. Biomarkers of heart failure in pleural fluid. Chest 2009; 136:671– 677
World Health Organization Class III COPD-Associated Pulmonary Hypertension Are We There Yet in Understanding the Pathobiology of the Disease? hypertension (PH) associated with respiP ulmonary ratory lung diseases that create a hypoxic milieu,
such as with COPD, are regarded as separate entities according to the World Health Organization (WHO) classification (WHO group III).1 For a long time, it has been postulated that hypoxia has a major impact on the pulmonary circulation, while factors such as polycythemia and hypercapnia have relatively minor roles in the development of PH.2,3 The original description by Von Euler and Liljestrand4 of the adaptation of perfusion to ventilation in lung physiology, observed that hypoxic pulmonary vasoconstriction is one of the major components to maintain adequate alveolar capillary gas exchange. In this manner, pulmonary blood flow is directed preferentially to well-ventilated areas of the lung at rest, and to alterations in these regional areas when changing from a supine to prone position or when under stress, such as with exercise. While acute hypoxic vasoconstrictive adjustments to maintain adequate perfusion and ventilation ratios are integral to a healthy, functioning lung, chronic hypoxia may lead to the development of PH. PH has been found in about a third of patients with COPD,5 while close to 91% of patients with COPD have exercise-induced PH.6 Severe PH de-
velops in only 5 to 20% of patients, however,7,8 and these patients tend to have more moderate airway obstruction, significant hypoxia, less hypercapnia, and significantly impaired survival.9 The development of increased pulmonary vascular resistance in this select group of patients with COPD has historically been thought to be in part due to the loss of a significant portion of the pulmonary vascular bed and in part due to poor oxygenation of the remaining alveolar capillary units, resulting in hypoxic pulmonary vasoconstriction. However, oxygen therapy fails to reverse PH in these patients,10 and pathologic studies reveal that there is pulmonary artery wall remodeling with intimal thickening11 in the setting of significant inflammation.12 Recent evidence13 from a murine model supports a role for proinflammatory cytokine interleukin (IL)-6 in the development of pulmonary vascular remodeling. However, the relationship among IL-6, COPD, and PH remains to be determined. In this issue of CHEST (see page 678), Chaouat et al14 help to answer this question. In a study that consecutively enrolled 148 patients with COPD and 180 control patients without COPD from two centers within France, the authors assessed the presence of PH (defined by a mean pulmonary artery pressure [mPAP] of ⬎25 mm Hg as determined by right heart catheterization), and correlated the cytokine plasma levels and gene polymorphisms of IL-6, IL-1B, and monocyte chemotactic protein-1 in each of the following groups: COPD patients with PH; COPD patients without PH; non-COPD smokers; and nonCOPD nonsmokers. In addition, they measured the levels of IL-6 messenger RNA in human pulmonary artery smooth muscle cells under normoxic and hypoxic conditions. They found that patients with COPD and PH were more likely to have lower Pao2 and elevated levels of IL-6 than those without PH, and that pulmonary function tests and CT scan emphysema scores were nondiscriminatory in detecting COPD patients with associated PH. They also noted that patients with the IL-6 GG genotype had a higher mPAP than other genotypes; however, IL-6 plasma protein levels did not correlate. Patients with homozygosity for both the serotonin transporter genotype 5-HTT LL and the genotype IL-6 GG were additively more likely to have PH. There was a twofold increase in IL-6 messenger RNA levels in vitro in human pulmonary artery smooth muscle cells exposed to hypoxic conditions. To my knowledge, this is the first study to investigate the role that the inflammatory cytokine IL-6 may play at the level of the protein, message, and gene in patients with COPD and PH. One must, however, remain cautious in interpreting these data
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Editorials
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
for several reasons. First, at the protein level, plasma IL-6 levels were significantly elevated in patients with COPD-associated PH; however, there was a weak association (r ⫽ 0.39) with significant scatter whereby some patients may have high mPAP with low plasma IL-6 levels and vice versa. It is thus hard to determine whether following plasma IL-6 levels is clinically and pathobiologically relevant. Furthermore, the pulmonary capillary wedge pressure correlated with the elevation in mPAP, suggesting that the weak association may be due to unknown confounders, such as coexistent left heart disease in patients with COPD. Second, in the authors’ efforts to determine biological plausibility that inflammatory IL-6 is integral to the pathogenesis of PH in patients with COPD, they were unable to show a positive correlation between increased IL-6 GG gene expression with increased IL-6 protein expression. Without further investigation, we cannot be sure whether there may have been modification at the DNA-RNA transcription step or posttranslational modification of the protein in vivo. In vitro, however, there appears to be a definite correlation between hypoxic conditions and IL-6 production in pulmonary artery smooth muscle cells at the level of messenger RNA. In addition, the relatively small sample size may have had an impact on the lack of correlation between the gene expression of IL-6 GG and the protein expression of IL-6, despite their efforts to test their findings in two separate French cohorts.15 Adequately powered cohorts are key in eliminating false-positive results when genetic association analyses are studied as was noted with idiopathic PH (WHO Class I) and 5-HTT.15 Third, their cohort of patients with COPD-associated PH had relatively mild PH (mPAP, 26 mm Hg; range, 22 to 31 mm Hg). Posttranslational protein expression may be positively correlated with gene expression if investigators had targeted the 5 to 20% of COPD patients with severe PH. This is supported by the author’s observation that there was a relatively small mPAP difference between patients with IL-6 gene polymorphism GG and those with CG and CC gene polymorphisms. Despite these limitations, this observational study brings us forward in understanding the pathogenesis of the development of PH in patients with COPD. This study provides further evidence that inflammation, and specifically IL-6, in addition to hypoxia may be contributing to the pathobiology of PH in patients with COPD and that individual genetic susceptibility may be why severe PH develops in only 5 to 20% of patients with COPD. M. Kathryn Steiner, MD Worcester, MA www.chestjournal.org
Dr. Steiner is Assistant Professor of Medicine, Lung, Allergy and Critical Care Medicine, University of Massachusetts Memorial Medical Center, Worcester, MA. The author has 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. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: M. Kathryn Steiner, MD, UMass Memorial Medical Center, Medicine, 55 Lake Ave North, Worcester, MA 01655; e-mail: [email protected] DOI: 10.1378/chest.09-0896
References 1 Simmoneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:5S– 12S 2 Ooi H, Cadogan E, Sweeney M, et al. Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling. Am J Physiol Heart Circ Physiol 2000; 278:H331–H338 3 Weissmann N, Manz D, Buchspies D, et al. Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia. Thromb Haemost 2005; 94:630 – 638 4 Von Euler US, Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 1946; 12:301–320 5 Weiztenblum E. Chronic cor pulmonale. Heart 2003; 89:225– 230 6 Scharf SM, Iqbal M, Keller C, et al. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med 2002; 166:314 –322 7 Chaouat A, Bugnet AS, Kadaoui N, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 172:189 –194 8 Kessler R, Faller M, Weitzenblum E, et al. “Natural History” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med 2001; 164:219 –224 9 Weitzenblum E, Chaouat A. Severe pulmonary hypertension in COPD: is it a distinct disease? Chest 2005; 127:1480 –1482 10 Oswald-Mammosser M, Weitzenblum E, Quoix E, et al. Prognostic factors in COPD patients receiving long-term oxygen therapy: importance of pulmonary artery pressure. Chest 1995; 107:1193–1198 11 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 12 Walter RE, Wilk JB, Larson MG. Systemic inflammation and COPD: the Framingham Heart Study. Chest 2008; 133:19 –25 13 Steiner MK, Syrkina OL, Kolliputi N, et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 2009; 104:236 –244 14 Chaouat A, Savale L, Chouaid C, et al. Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 2009; 136: 678 – 687 15 Machado RD, Koehler R, Glissmeyer E, et al. Genetic association of the serotonin transporter in pulmonary artery hypertension. Am J Respir Crit Care Med 2006; 173:793–797 CHEST / 136 / 3 / SEPTEMBER, 2009
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
659
World Health Organization Class III COPD-Associated Pulmonary Hypertension Are We There Yet in Understanding the Pathobiology of the Disease? hypertension (PH) associated with respiP ulmonary ratory lung diseases that create a hypoxic milieu,
such as with COPD, are regarded as separate entities according to the World Health Organization (WHO) classification (WHO group III).1 For a long time, it has been postulated that hypoxia has a major impact on the pulmonary circulation, while factors such as polycythemia and hypercapnia have relatively minor roles in the development of PH.2,3 The original description by Von Euler and Liljestrand4 of the adaptation of perfusion to ventilation in lung physiology, observed that hypoxic pulmonary vasoconstriction is one of the major components to maintain adequate alveolar capillary gas exchange. In this manner, pulmonary blood flow is directed preferentially to well-ventilated areas of the lung at rest, and to alterations in these regional areas when changing from a supine to prone position or when under stress, such as with exercise. While acute hypoxic vasoconstrictive adjustments to maintain adequate perfusion and ventilation ratios are integral to a healthy, functioning lung, chronic hypoxia may lead to the development of PH. PH has been found in about a third of patients with COPD,5 while close to 91% of patients with COPD have exercise-induced PH.6 Severe PH de-
velops in only 5 to 20% of patients, however,7,8 and these patients tend to have more moderate airway obstruction, significant hypoxia, less hypercapnia, and significantly impaired survival.9 The development of increased pulmonary vascular resistance in this select group of patients with COPD has historically been thought to be in part due to the loss of a significant portion of the pulmonary vascular bed and in part due to poor oxygenation of the remaining alveolar capillary units, resulting in hypoxic pulmonary vasoconstriction. However, oxygen therapy fails to reverse PH in these patients,10 and pathologic studies reveal that there is pulmonary artery wall remodeling with intimal thickening11 in the setting of significant inflammation.12 Recent evidence13 from a murine model supports a role for proinflammatory cytokine interleukin (IL)-6 in the development of pulmonary vascular remodeling. However, the relationship among IL-6, COPD, and PH remains to be determined. In this issue of CHEST (see page 678), Chaouat et al14 help to answer this question. In a study that consecutively enrolled 148 patients with COPD and 180 control patients without COPD from two centers within France, the authors assessed the presence of PH (defined by a mean pulmonary artery pressure [mPAP] of ⬎25 mm Hg as determined by right heart catheterization), and correlated the cytokine plasma levels and gene polymorphisms of IL-6, IL-1B, and monocyte chemotactic protein-1 in each of the following groups: COPD patients with PH; COPD patients without PH; non-COPD smokers; and nonCOPD nonsmokers. In addition, they measured the levels of IL-6 messenger RNA in human pulmonary artery smooth muscle cells under normoxic and hypoxic conditions. They found that patients with COPD and PH were more likely to have lower Pao2 and elevated levels of IL-6 than those without PH, and that pulmonary function tests and CT scan emphysema scores were nondiscriminatory in detecting COPD patients with associated PH. They also noted that patients with the IL-6 GG genotype had a higher mPAP than other genotypes; however, IL-6 plasma protein levels did not correlate. Patients with homozygosity for both the serotonin transporter genotype 5-HTT LL and the genotype IL-6 GG were additively more likely to have PH. There was a twofold increase in IL-6 messenger RNA levels in vitro in human pulmonary artery smooth muscle cells exposed to hypoxic conditions. To my knowledge, this is the first study to investigate the role that the inflammatory cytokine IL-6 may play at the level of the protein, message, and gene in patients with COPD and PH. One must, however, remain cautious in interpreting these data
658
Editorials
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
for several reasons. First, at the protein level, plasma IL-6 levels were significantly elevated in patients with COPD-associated PH; however, there was a weak association (r ⫽ 0.39) with significant scatter whereby some patients may have high mPAP with low plasma IL-6 levels and vice versa. It is thus hard to determine whether following plasma IL-6 levels is clinically and pathobiologically relevant. Furthermore, the pulmonary capillary wedge pressure correlated with the elevation in mPAP, suggesting that the weak association may be due to unknown confounders, such as coexistent left heart disease in patients with COPD. Second, in the authors’ efforts to determine biological plausibility that inflammatory IL-6 is integral to the pathogenesis of PH in patients with COPD, they were unable to show a positive correlation between increased IL-6 GG gene expression with increased IL-6 protein expression. Without further investigation, we cannot be sure whether there may have been modification at the DNA-RNA transcription step or posttranslational modification of the protein in vivo. In vitro, however, there appears to be a definite correlation between hypoxic conditions and IL-6 production in pulmonary artery smooth muscle cells at the level of messenger RNA. In addition, the relatively small sample size may have had an impact on the lack of correlation between the gene expression of IL-6 GG and the protein expression of IL-6, despite their efforts to test their findings in two separate French cohorts.15 Adequately powered cohorts are key in eliminating false-positive results when genetic association analyses are studied as was noted with idiopathic PH (WHO Class I) and 5-HTT.15 Third, their cohort of patients with COPD-associated PH had relatively mild PH (mPAP, 26 mm Hg; range, 22 to 31 mm Hg). Posttranslational protein expression may be positively correlated with gene expression if investigators had targeted the 5 to 20% of COPD patients with severe PH. This is supported by the author’s observation that there was a relatively small mPAP difference between patients with IL-6 gene polymorphism GG and those with CG and CC gene polymorphisms. Despite these limitations, this observational study brings us forward in understanding the pathogenesis of the development of PH in patients with COPD. This study provides further evidence that inflammation, and specifically IL-6, in addition to hypoxia may be contributing to the pathobiology of PH in patients with COPD and that individual genetic susceptibility may be why severe PH develops in only 5 to 20% of patients with COPD. M. Kathryn Steiner, MD Worcester, MA www.chestjournal.org
Dr. Steiner is Assistant Professor of Medicine, Lung, Allergy and Critical Care Medicine, University of Massachusetts Memorial Medical Center, Worcester, MA. The author has 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. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: M. Kathryn Steiner, MD, UMass Memorial Medical Center, Medicine, 55 Lake Ave North, Worcester, MA 01655; e-mail: [email protected] DOI: 10.1378/chest.09-0896
References 1 Simmoneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:5S– 12S 2 Ooi H, Cadogan E, Sweeney M, et al. Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling. Am J Physiol Heart Circ Physiol 2000; 278:H331–H338 3 Weissmann N, Manz D, Buchspies D, et al. Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia. Thromb Haemost 2005; 94:630 – 638 4 Von Euler US, Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 1946; 12:301–320 5 Weiztenblum E. Chronic cor pulmonale. Heart 2003; 89:225– 230 6 Scharf SM, Iqbal M, Keller C, et al. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med 2002; 166:314 –322 7 Chaouat A, Bugnet AS, Kadaoui N, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 172:189 –194 8 Kessler R, Faller M, Weitzenblum E, et al. “Natural History” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med 2001; 164:219 –224 9 Weitzenblum E, Chaouat A. Severe pulmonary hypertension in COPD: is it a distinct disease? Chest 2005; 127:1480 –1482 10 Oswald-Mammosser M, Weitzenblum E, Quoix E, et al. Prognostic factors in COPD patients receiving long-term oxygen therapy: importance of pulmonary artery pressure. Chest 1995; 107:1193–1198 11 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 12 Walter RE, Wilk JB, Larson MG. Systemic inflammation and COPD: the Framingham Heart Study. Chest 2008; 133:19 –25 13 Steiner MK, Syrkina OL, Kolliputi N, et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 2009; 104:236 –244 14 Chaouat A, Savale L, Chouaid C, et al. Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 2009; 136: 678 – 687 15 Machado RD, Koehler R, Glissmeyer E, et al. Genetic association of the serotonin transporter in pulmonary artery hypertension. Am J Respir Crit Care Med 2006; 173:793–797 CHEST / 136 / 3 / SEPTEMBER, 2009
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
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