Chest
Volume 136, Issue 3, September 2009, Pages 678-687
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Original Research
Pulmonary Hypertension
Role for Interleukin-6 in COPD-Related Pulmonary Hypertension

https://doi.org/10.1378/chest.08-2420Get rights and content

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-1β, 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-1β, 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], ≥ 25 mm Hg) had lower Pao2 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.

Section snippets

Materials and Methods

This study was approved by the review board of the Henri Mondor Teaching Hospital. All patients and control subjects signed an informed consent document before being included in the study.

Clinical Characteristics of the Study Population

Table 1 shows the characteristics of the 148 patients with COPD. Most patients were men, and the age range was 42 to 79 years. Current smokers made up 23% of the patient group; all the other patients were ex-smokers. Current smokers had less severe airway obstruction compared to ex-smokers (data not shown). Airflow limitation was moderate to severe. PH (mean PAP ≥ 25 mm Hg) was present in 58 patients (39%). The 57 patients with no available plasma samples for cytokine assays were not

Discussion

The results of the present study point to a role for inflammation, and more specifically for IL-6, in the pathogenesis of PH in patients with COPD. In patients with COPD, circulating IL-6 levels correlated with mean PAP. PAP was higher in patients who had the GG genotype of the G(−174)C IL-6 polymorphism than in patients who had the GC or CC genotype. Cultured human PA-SMCs constitutively expressed IL-6, and the expression level increased under hypoxia. Furthermore, the IL-6 and 5-HTT gene

Acknowledgments

Author contributions: Drs. Chaouat, Eddahibi, and Adnot conceived the study. Drs. Chaouat, Canuet, Brandt, and Weitzenblum performed the clinical work in Strasbourg. Drs. Savale, Chouaid, Sztrymf, Maitre, Housset, Le Corvoisier, and Adnot performed the clinical work in Créteil and Paris. Mr. Tu, and Drs. Eddahibi and Adnot carried out the laboratory investigations.

Financial/nonfinancial contributions: The authors have reported to the ACCP that no significant conflicts of interest exist with any

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Funding/Support: This study was supported by grants from the Institut National de la Santé et de la Recherche Médicale, Ministère de la Recherche, Institut des Maladies Rares (GIS), and Délégation à la Recherche Clinique de l'Assistance Publique-Hôpitaux de Paris. Financial support was received also from the European Commission under the sixth Framework Program (contract No. LSHM-CT-2005-018725, pulmotension).

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

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