The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071008
The Journal of Experimental Medicine, Vol. 205, No. 2, 361-372
The Rockefeller University Press, 0022-1007 $30.00
© Daley et al.
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ARTICLE

 Pulmonary arterial remodeling induced by a Th2 immune response

Eleen Daley1, Claire Emson2, Christophe Guignabert3, Rene de Waal Malefyt2, Jennifer Louten2, Viswanath P. Kurup4, Cory Hogaboam5, Laimute Taraseviciene-Stewart6, Norbert F. Voelkel6, Marlene Rabinovitch3, Ekkehard Grunig7, and Gabriele Grunig8

1 St. Luke's Roosevelt Hospital, New York, NY 10019
2 Schering Plough Biopharma, Palo Alto, CA 94304
3 Department of Pediatrics, Stanford University School of Medicine, Stanford CA 94305
4 Allergy Immunology Division, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53295
5 Department of Pathology, University of Michigan, Ann Arbor, MI 48109
6 Division of Pulmonary Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262
7 Department of Medicine, Thoraxclinic at the University Hospital Heidelberg, 69117 Heidelberg, Germany
8 Department of Microbiology, Columbia University, New York, NY 10032

CORRESPONDENCE Gabriele Grunig: gg398{at}columbia.edu

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4+ T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule {alpha}, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH.

Abbreviations used: Asp Ag, Aspergillus fumigatus antigen; BALF, bronchoalveolar lavage fluid; H&E, hematoxylin and eosin; i.n., intranasal; PAH, pulmonary arterial hypertension; PCNA, proliferating cell nuclear antigen; RELM, resistin-like molecule; RVSP, right ventricular systolic pressure.

E. Daley and C. Emson contributed equally to this work.

Norbert F. Voelkel's present address is Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, VA 23284.


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