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Combined Pulmonary Fibrosis and Emphysema: An Experimental and Clinically Relevant Phenotype

The article by Lundblad and colleagues (1) elegantly showed that tumor necrosis factor- (TNF-) overexpression driven by the surfactant protein C promoter in transgenic mice induces pathologic changes consistent with both emphysema and pulmonary fibrosis. The authors state that this phenotype is not representative of any single human disease. We do not agree and consider that their research may provide keys to understanding the syndrome of combined pulmonary fibrosis and emphysema (CPFE).

This underrecognized syndrome, mentioned in case reports or short series (2), may indeed be encountered in smokers with usually severe dyspnea on exertion. In a homogenous group of 61 patients, we characterized CPFE by emphysema with upper zone predominance and frequent paraseptal emphysema, imaging changes consistent with fibrosis of the lower lobes, preserved lung volumes, strongly impaired diffusing capacity, hypoxemia at exercise, high prevalence of pulmonary arterial hypertension, and a poor prognosis (3). Although CPFE in humans might result from the coincidental occurrence of interstitial lung disease and smoking-related emphysema, it could also be related to a common genetic susceptibility factor and (or) environmental trigger, as suggested by the animal model of Lundblad and coworkers (1).

The effect of tobacco smoking on the TNF- pathways is unclear. Nicotine induces the release of TNF- in endothelial cells (4), and plasma soluble TNF-–receptor-1 levels are elevated in smokers (5). However, exposure to cigarette smoke extracts suppresses the production of TNF- by monocytes and macrophages (6). Cytokine promoter gene polymorphisms might determine individual susceptibility to CPFE induced by exogenous agents, such as tobacco smoking.

Thus the experimental model described by Lundblad and colleagues in TNF- overexpressing mice is of major interest for clinicians as it reinforces the concept that CPFE is a distinct entity. Investigating the effect of tobacco smoking in TNF-–transgenic mice might further help in understanding CPFE pathogenesis.

Vincent Cottin and Jean-François Cordier

Center for Orphan Lung Diseases Lyon, France

FOOTNOTES

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Lundblad LK, Thompson-Figueroa J, Leclair T, Sullivan MJ, Poynter ME, Irvin CG, Bates JH. Tumor necrosis factor-alpha overexpression in lung disease: a single cause behind a complex phenotype. Am J Respir Crit Care Med 2005;171:1363–1370.
2. Wiggins J, Strickland B, Turner-Warwick M. Combined cryptogenic fibrosing alveolitis and emphysema: the value of high resolution computed tomography in assessment. Respir Med 1990;84:365–369.
3. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G, Tillie-Leblond I, Israel-Biet D, Court-Fortune I, Valeyre D, Cordier JF, and the Groupe d'Etude et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P). Combined pulmonary fibrosis and emphysema: a distinct underrecognized entity. Eur Respir 2005;26:586–593.
4. Albaugh G, Kann B, Strande L, Vemulapalli P, Hewitt C, Alexander JB. Nicotine induces endothelial TNF-alpha expression, which mediates growth retardation in vitro. J Surg Res 2001;99:381–384.
5. Zoppini G, Faccini G, Muggeo M, Zenari L, Falezza G, Targher G. Elevated plasma levels of soluble receptors of TNF-alpha and their association with smoking and microvascular complications in young adults with type 1 diabetes. J Clin Endocrinol Metab 2001;86:3805–3808.
6. McCrea KA, Ensor JE, Nall K, Bleecker ER, Hasday JD. Altered cytokine regulation in the lungs of cigarette smokers. Am J Respir Crit Care Med 1994;150:696–703.

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