Role for interleukin-6 in COPD-related pulmonary hypertension.
BACKGROUND
Pulmonary artery remodeling triggered by alveolar hypoxia is considered the main mechanism of pulmonary hypertension (PH) in COPD patients. We hypothesized that the risk for PH in COPD is increased by an elevation in the proinflammatory cytokines interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and IL-1beta, as well as by specific genetic polymorphisms of these cytokines.


METHODS
We assessed cytokine plasma levels and the polymorphisms G(-174)C IL-6, C(-511)T IL-1beta, and A(-2518)G MCP-1 in 148 COPD patients (recruited at two centers) with right heart catheterization data and 180 control subjects including smokers and nonsmokers. Human pulmonary artery smooth muscle cells (PA-SMCs) were cultured for IL-6 messenger RNA assays under normoxic and hypoxic conditions.


RESULTS
Patients with PH (mean pulmonary artery pressure [PAP], >or= 25 mm Hg) had lower Pao(2) and higher plasma IL-6 values than those without PH; there were no differences in terms of pulmonary function test results or CT scan emphysema scores. Plasma IL-6 correlated with mean PAP (r = 0.39; p < 0.001) and was included in a multiple stepwise regression analysis, with mean PAP as the dependent variable. In patients with the IL-6 GG genotype, the mean PAP value was significantly higher and PH was more common than in CG or CC patients (adjusted odds ratio, 4.32; 95% confidence interval, 1.96 to 9.54). Exposure to 4 h of hypoxia led to an about twofold increase in IL-6 messenger RNA in cultured human PA-SMCs.


CONCLUSIONS
Inflammation, most likely involving IL-6, may contribute substantially to PH complicating COPD.
Chaouat
Ari
A
Service des Maladies Respiratoires et Réanimation Respiratoire, Hôpital de Brabois, Centre Hospitalier Régional Universitaire Nancy, Vandoeuvre-lès-Nancy, France; Département de Pneumologie, Nouvel Hôpital Civil, Centre Hospitalier Régional Universitaire Strasbourg, Strasbourg, France. Electronic address: a.chaouat@chu-nancy.fr.
Savale
Laurent
L
Service de Physiologie Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France; Institut National de la Santé et de la Recherche Médicale U841, Faculté de Médecine de Créteil, Créteil, France.
Chouaid
Christos
C
Service de Pneumologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France.
Tu
Ly
L
Institut National de la Santé et de la Recherche Médicale U841, Faculté de Médecine de Créteil, Créteil, France.
Sztrymf
Benjamin
B
Service de Physiologie Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France; Institut National de la Santé et de la Recherche Médicale U841, Faculté de Médecine de Créteil, Créteil, France.
Canuet
Matthieu
M
Département de Pneumologie, Nouvel Hôpital Civil, Centre Hospitalier Régional Universitaire Strasbourg, Strasbourg, France.
Maitre
Bernard
B
Institut National de la Santé et de la Recherche Médicale U841, Faculté de Médecine de Créteil, Créteil, France; Service de Pneumologie et de Pathologie Professionnelle, Centre Hospitalier Intercommunal de Créteil, Créteil, France.
Housset
Bruno
B
Service de Pneumologie et de Pathologie Professionnelle, Centre Hospitalier Intercommunal de Créteil, Créteil, France.
Brandt
Christian
C
Centre Hospitalier Régional Universitaire Strasbourg, Hôpital Civil, Centre d'Investigation Clinique, Strasbourg, France.
Le Corvoisier
Philippe
P
Centre d'Investigation Clinique, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France; Institut National de la Santé et de la Recherche Médicale U841, Faculté de Médecine de Créteil, Créteil, France.
Weitzenblum
Emmanuel
E
Département de Pneumologie, Nouvel Hôpital Civil, Centre Hospitalier Régional Universitaire Strasbourg, Strasbourg, France.
Eddahibi
Saadia
S
Institut National de la Santé et de la Recherche Médicale U841, Faculté de Médecine de Créteil, Créteil, France.
Adnot
Serge
S
Service de Physiologie Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France; Institut National de la Santé et de la Recherche Médicale U841, Faculté de Médecine de Créteil, Créteil, France.
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics; D016009:Chi-Square Distribution; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000209:etiology* / Q000235:genetics; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000235:genetics; D012044:Regression Analysis; D012129:Respiratory Function Tests; D018709:Statistics, Nonparametric
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D015850:Interleukin-6