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Human Neutrophil Peptides Stimulate Tumor Necrosis Factor-α Release by Alveolar Macrophages From Patients With Sarcoidosis FREE TO VIEW

Gregorino Paone, MD; Gabriele Lucantoni, MD; Alvaro Leone, MD; Paolo Graziano, MD; Rita Gasbarra, MD; Giovanni Galluccio, MD; Salvatore D'Antoni, MD; Giovanni Puglisi, MD; Enrico Girardi, MD; Giovanni Schmid, MD
Author and Funding Information

Affiliations: Carlo Forlanini Hospital Rome, Italy,  Istituto Nazionale per le Malattie Infettive “L. Spallanzani” Rome, Italy,  Don Gnocchi Foundation “Santa Maria Della Pace” Rome, Italy

Correspondence to: Gregorino Paone, MD, Forlanini Hospital, Via Portuense 332, 00149 Rome, Italy; e- mail: rpaone1023@yahoo.com


The authors have 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.

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


Chest. 2009;135(2):586-587. doi:10.1378/chest.08-2585
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To the Editor:

Sarcoidosis is a chronic multisystemic disorder of unknown etiology that is characterized by a protean clinical presentation and an increased immune response at the site of disease.1 Although any organ could be affected, the lungs are most frequently involved, with an enhanced recruitment of immunocompetent cells in the lower respiratory tract. Once activated, these cells may secrete proinflammatory mediators, which could play a role in the pathogenic mechanisms of this disorder, and may serve as indicators of disease clinical course or severity.24

Among these molecules, human neutrophil peptides (HNPs) are small cationic peptides that have been found to be increased in the BAL fluid of patients with sarcoidosis and are thought to be a key component of the enhanced antibacterial activity observed in the lungs of these individuals.5 To increase our knowledge of the role of HNP in sarcoidosis pathogenic mechanisms, we measured HNP levels in BAL fluid samples from 42 nontreated patients (25 patients with active disease and 17 patients with inactive disease) and in 12 healthy volunteers.6 All subjects were nonsmokers because of the influence of tobacco in BAL fluid HNP profile.7 We found that mean (± SEM) epithelial lining fluid HNP concentrations were significantly higher in subjects with sarcoidosis than in volunteers (400.4 ± 31 vs 37 ± 8 ng/mL, respectively; p = 0.00001) and that subjects with stage 2 and 3 disease had significantly higher epithelial lining fluid HNP levels than subjects with stage 1 disease (453 ± 43 and 432.5 ± 63 ng/mL vs 230 ± 32 ng/mL, respectively; p = 0.01 and 0.01, respectively), although no differences were observed between subjects with active and inactive disease (p = 0.16). Furthermore, alveolar macrophages (AMs) harvested from subjects were used to evaluate tumor necrosis factor (TNF)-α release after exposure to HNP at the concentrations detected in the lower respiratory tract of affected individuals. We found that HNP induced the production of significantly higher concentrations of TNF-α by AMs from subjects with inactive and active sarcoidosis than those from volunteers (subjects with inactive sarcoidosis: 325 pg/mL; 95% confidence interval [CI], 231 to 419 pg/mL; subjects with active sarcoidosis: 612 pg/mL; 95% CI, 317 to 908 pg/mL; and healthy volunteers: 191 pg/mL; 95% CI, −36 to 417 pg/mL) [Fig 1].

Figure Jump LinkFigure 1 Dose-related TNF-α production by AMs from subjects with active sarcoidosis (▾), subjects with inactive sarcoidosis (○), and volunteers (●). AM subjects were incubated for 24 h without (0) and in the presence of increasing HNP concentrations (200, 400, and 1,000 pg/mL). Values are given as the mean and SEM.Grahic Jump Location

Our data support the notion that HNPs might play a role as a marker of disease severity. Furthermore, because of their ability to stimulate the in vitro release of TNF-α, a molecule with a pivotal role during sarcoidosis, HNPs, besides their antibacterial effects, may contribute to sustaining the inflammatory response that is typical of this disorder.

American Thoracic Society Statement on sarcoidosis. Am J Respir Crit Care Med. 1999;160:736-755. [PubMed]
 
Ziegenhagen MW, Benner UK, Zissel G, et al. Sarcoidosis: TNF-α release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med. 1997;156:1586-1592. [PubMed]
 
Ziegenhagen MW, Muller-Quernheim J. The cytokine network in sarcoidosis and its clinical relevance. J Intern Med. 2003;253:18-30. [PubMed] [CrossRef]
 
Inui N, Matsui T, Suda T, et al. Anti-endothelial cell antibodies in patients with sarcoidosis. Chest. 2008;133:955-960. [PubMed]
 
Ageberth B, Grunewald J, Castaños-Velez E, et al. Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Am J Respir Crit Care Med. 1999;160:283-290. [PubMed]
 
Costabel U. Sarcoidosis: clinical update. Eur Respir J. 2001;18:56S-68S
 
Paone G, Wada A, Stevens LA, et al. ADP rybosylation of human neutrophil peptide-1 regulates its biological properties. Proc Natl Acad Sci U S A. 2002;99:8231-8235. [PubMed]
 
American Thoracic Society Statement on sarcoidosis. Am J Respir Crit Care Med. 1999;160:736-755. [PubMed]
 
Ziegenhagen MW, Benner UK, Zissel G, et al. Sarcoidosis: TNF-α release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med. 1997;156:1586-1592. [PubMed]
 
Ziegenhagen MW, Muller-Quernheim J. The cytokine network in sarcoidosis and its clinical relevance. J Intern Med. 2003;253:18-30. [PubMed]
 
Inui N, Matsui T, Suda T, et al. Anti-endothelial cell antibodies in patients with sarcoidosis. Chest. 2008;133:955-960. [PubMed]
 
Ageberth B, Grunewald J, Castaños-Velez E, et al. Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Am J Respir Crit Care Med. 1999;160:283-290. [PubMed]
 
Costabel U. Sarcoidosis: clinical update. Eur Respir J. 2001;18:56S-68S
 
Paone G, Wada A, Stevens LA, et al. ADP rybosylation of human neutrophil peptide-1 regulates its biological properties. Proc Natl Acad Sci U S A. 2002;99:8231-8235. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Dose-related TNF-α production by AMs from subjects with active sarcoidosis (▾), subjects with inactive sarcoidosis (○), and volunteers (●). AM subjects were incubated for 24 h without (0) and in the presence of increasing HNP concentrations (200, 400, and 1,000 pg/mL). Values are given as the mean and SEM.Grahic Jump Location

Tables

References

American Thoracic Society Statement on sarcoidosis. Am J Respir Crit Care Med. 1999;160:736-755. [PubMed]
 
Ziegenhagen MW, Benner UK, Zissel G, et al. Sarcoidosis: TNF-α release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med. 1997;156:1586-1592. [PubMed]
 
Ziegenhagen MW, Muller-Quernheim J. The cytokine network in sarcoidosis and its clinical relevance. J Intern Med. 2003;253:18-30. [PubMed] [CrossRef]
 
Inui N, Matsui T, Suda T, et al. Anti-endothelial cell antibodies in patients with sarcoidosis. Chest. 2008;133:955-960. [PubMed]
 
Ageberth B, Grunewald J, Castaños-Velez E, et al. Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Am J Respir Crit Care Med. 1999;160:283-290. [PubMed]
 
Costabel U. Sarcoidosis: clinical update. Eur Respir J. 2001;18:56S-68S
 
Paone G, Wada A, Stevens LA, et al. ADP rybosylation of human neutrophil peptide-1 regulates its biological properties. Proc Natl Acad Sci U S A. 2002;99:8231-8235. [PubMed]
 
American Thoracic Society Statement on sarcoidosis. Am J Respir Crit Care Med. 1999;160:736-755. [PubMed]
 
Ziegenhagen MW, Benner UK, Zissel G, et al. Sarcoidosis: TNF-α release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med. 1997;156:1586-1592. [PubMed]
 
Ziegenhagen MW, Muller-Quernheim J. The cytokine network in sarcoidosis and its clinical relevance. J Intern Med. 2003;253:18-30. [PubMed]
 
Inui N, Matsui T, Suda T, et al. Anti-endothelial cell antibodies in patients with sarcoidosis. Chest. 2008;133:955-960. [PubMed]
 
Ageberth B, Grunewald J, Castaños-Velez E, et al. Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Am J Respir Crit Care Med. 1999;160:283-290. [PubMed]
 
Costabel U. Sarcoidosis: clinical update. Eur Respir J. 2001;18:56S-68S
 
Paone G, Wada A, Stevens LA, et al. ADP rybosylation of human neutrophil peptide-1 regulates its biological properties. Proc Natl Acad Sci U S A. 2002;99:8231-8235. [PubMed]
 
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