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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents



ID: 559627.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension
Authors: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.
Title of Journal:Am J Respir Crit Care Med
Volume:182
Issue / Number:6
Start Page:805
End Page:18
Audience:Not Specified
Abstract / Description: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-13Ralpha1, and IL-13Ralpha2 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-13Ralpha2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Ralpha1 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.
Free Keywords:Adolescent; Adult; Animals; Disease Models, Animal; Female; Flow Cytometry; Humans; Hypertension, Pulmonary/*etiology; Immunohistochemistry; Interleukin-13/*metabolism; Interleukin-13 Receptor alpha1 Subunit/metabolism; Interleukin-13 Receptor alpha2 Subunit/metabolism; Lung/metabolism; Male; Mice; Middle Aged; Muscle, Smooth, Vascular/metabolism; Myocytes, Smooth Muscle/metabolism; Pulmonary Artery/metabolism; Rats; Receptors, Interleukin-13/*physiology; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation/*physiology; Young Adult
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Department of Internal Medicine (Pulmonology), University of Giessen Lung Center, Justus Liebig University, Giessen, Germany.
Identifiers:ISSN:1535-4970 (Electronic) 1073-449X (Linking)
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=..
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