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Hecker, M.* ; Zaslona, Z.* ; Kwapiszewska, G.* ; Niess, G.* ; Zakrzewicz, A.* ; Hergenreider, E.* ; Wilhelm, J.* ; Marsh, L.M.* ; Sedding, D.* ; Klepetko, W.* ; Lohmeyer, J.* ; Dimmeler, S.* ; Seeger, W.* ; Weissmann, N.* ; Schermuly, R.T.* ; Kneidinger, N.* ; Eickelberg, O. ; Morty, R.E.*

Dysregulation of the IL-13 receptor system: A novel pathomechanism in pulmonary arterial hypertension.

Am. J. Respir. Crit. Care Med. 182, 805-818 (2010)
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy due to pulmonary artery smooth muscle cell (paSMC) hyperplasia. Inflammation is proposed to play a role in vessel remodeling associated with IPAH. IL-13 is emerging as a regulator of tissue remodeling; however, the contribution of the IL-13 system to IPAH has not been assessed. OBJECTIVES: The objective of this study was to assess the possible contribution of the IL-13 system to IPAH. METHODS: Expression and localization of IL-13, and IL-13 receptors IL-4R, IL-13Rα1, and IL-13Rα2 were assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and flow cytometry in lung tissue, paSMC, and microdissected vascular lesions from patients with IPAH, and in lung tissue from rodents with hypoxia- or monocrotaline-induced pulmonary hypertension. A whole-genome microarray analysis was used to study IL-13-regulated genes in paSMC. MEASUREMENTS AND MAIN RESULTS: Pulmonary expression of the IL-13 decoy receptor IL-13Rα2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Rα1 in patients with IPAH and in two animal models of IPAH. IL-13, signaling via STAT3 and STAT6, suppressed proliferation of paSMC by promoting G(0)/G(1) arrest. Whole-genome microarrays revealed that IL-13 suppressed endothelin-1 production by paSMC, suggesting that IL-13 controlled paSMC growth by regulating endothelin production. Ectopic expression of the il13ra2 gene resulted in partial loss of paSMC growth control by IL-13 and blunted IL-13 suppression of endothelin-1 production by paSMC, whereas small-interfering RNA knockdown of il13ra2 gene expression had the opposite effects. CONCLUSIONS: The IL-13 system is a novel regulator of paSMC growth. Dysregulation of IL-13 receptor expression in IPAH may partially underlie smooth muscle hypertrophy associated with pathological vascular remodeling in IPAH.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter smooth muscle; endothelin; interleukin; pulmonary arterial hypertension
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Quellenangaben Band: 182, Heft: 6, Seiten: 805-818 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Begutachtungsstatus Peer reviewed