title: Pulmonary arterial remodeling induced by a Th2 immune response.
abstract: 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.
authors.affiliation: St. Luke's Roosevelt Hospital, New York, NY 10019, USA.
authors.forename: Eleen
authors.initials: E
authors.lastname: Daley
authors.forename: Claire
authors.initials: C
authors.lastname: Emson
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.forename: Rene
authors.initials: R
authors.lastname: de Waal Malefyt
authors.forename: Jennifer
authors.initials: J
authors.lastname: Louten
authors.forename: Viswanath P
authors.initials: VP
authors.lastname: Kurup
authors.forename: Cory
authors.initials: C
authors.lastname: Hogaboam
authors.forename: Laimute
authors.initials: L
authors.lastname: Taraseviciene-Stewart
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grunig
authors.forename: Gabriele
authors.initials: G
authors.lastname: Grunig
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology; D001794:Blood Pressure; D006352:Heart Ventricles / Q000503:physiopathology; D007114:Immunization; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011651:Pulmonary Artery / Q000276:immunology* / Q000473:pathology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000946:Antigens, Fungal; D018793:Interleukin-13; D015847:Interleukin-4; D010047:Ovalbumin