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Original Research: Diffuse Lung Disease |

Nicotine Treatment Improves Toll-Like Receptor 2 and Toll-Like Receptor 9 Responsiveness in Active Pulmonary SarcoidosisNicotine Treatment in Pulmonary Sarcoidosis

Mark W. Julian, MS; Guohong Shao, MD; Larry S. Schlesinger, MD; Qin Huang, MD; David G. Cosmar, BA; Nitin Y. Bhatt, MD; Daniel A. Culver, MD, FCCP; Robert P. Baughman, MD, FCCP; Karen L. Wood, MD, FCCP; Elliott D. Crouser, MD
Author and Funding Information

From the Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine (Messrs Julian and Cosmar and Drs Shao, Huang, Bhatt, Wood, and Crouser), the Dorothy M. Davis Heart and Lung Research Institute, and the Department of Microbial Infection and Immunity and the Center for Microbial Interface Biology (Dr Schlesinger), Wexner Medical Center at The Ohio State University, Columbus; the Department of Pulmonary, Allergy and Critical Care Medicine (Dr Culver), Cleveland Clinic Foundation, Cleveland; and the Division of Pulmonary and Critical Care Medicine (Dr Baughman), University of Cincinnati Medical Center, Cincinnati, OH.

Correspondence to: Elliott D. Crouser, MD, Wexner Medical Center at The Ohio State University, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, 201F Dorothy M. Davis Heart and Lung Research Institute, 473 W 12th Ave, Columbus, OH 43210-1252; e-mail: Elliott.Crouser@osumc.edu


Funding/Support: This work was supported by the American Thoracic Society and the Foundation for Sarcoidosis Research.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(2):461-470. doi:10.1378/chest.12-0383
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Background:  New evidence links nicotine to the regulation of T cell-mediated inflammation via α7 nicotinic cholinergic receptor activation, and chronic nicotine exposure (smoking) reduces the incidence of granulomatous diseases. We sought to determine whether nicotine treatment was well tolerated while effectively normalizing immune responses in patients with active pulmonary sarcoidosis.

Methods:  Consenting adults with symptomatic sarcoidosis (n = 13) were randomly assigned to receive 12 weeks of nicotine treatment plus conventional therapy or conventional therapy alone. Obtained blood cells were evaluated for their responsiveness to selected Toll-like receptor (TLR) and nucleotide oligomerization domain-like receptor ligands and T cell surface marker expression before and after nicotine treatment. Asymptomatic patients (n = 6) and disease-free subjects (n = 6) served as comparative control subjects. Adverse events were monitored for the duration of the study.

Results:  Compared with the asymptomatic group, symptomatic patients had impaired peripheral responses to TLR2, TLR4, and TLR9 ligands (anergy) and reduced peripheral populations of CD4+FoxP3+ regulatory T cells (Tregs). Nicotine treatment was associated with restoration of TLR2 and TLR9 responsiveness, and expansion of Tregs, including the CD4+CD25FoxP3+ phenotype. There were no serious adverse events or signs of nicotine dependency.

Conclusions:  Nicotine treatment in active pulmonary sarcoidosis was well tolerated and restored peripheral immune responsiveness to TLR2 and TLR9 agonists and expansion of FoxP3+ Tregs, including a specific “preactivated” (CD25) phenotype. The immune phenotype of patients with symptomatic sarcoidosis treated with nicotine closely resembled that of asymptomatic patients, supporting the notion that nicotine treatment may be beneficial in this patient population.

Trial registry:  ClinicalTrials.gov; No.: NCT00701207; URL: www.clinicaltrials.gov

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