Journal article

Publication year: 2010

Pages: 805-818

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 182

Issue number: 6

ISSN: 1073-449X

eISSN: 1535-4970

DOI Link: https://doi.org/10.1164/rccm.200909-1367OC

Publisher: American Thoracic Society

Abstract: 

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-13R alpha 1, and IL-13R alpha 2 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-13R alpha 2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13R alpha 1 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.

Harvard Citation style: Hecker, M., Zaslona, Z., Kwapiszewska, G., Niess, G., Zakrzewicz, A., Hergenreider, E., et al. (2010) Dysregulation of the IL-13 Receptor System A Novel Pathomechanism in Pulmonary Arterial Hypertension, American Journal of Respiratory and Critical Care Medicine, 182(6), pp. 805-818. https://doi.org/10.1164/rccm.200909-1367OC

APA Citation style: Hecker, M., Zaslona, Z., Kwapiszewska, G., Niess, G., Zakrzewicz, A., Hergenreider, E., Wilhelm, J., Marsh, L., Sedding, D., Klepetko, W., Lohmeyer, J., Dimmeler, S., Seeger, W., Weissmann, N., Schermuly, R., Kneidinger, N., Eickelberg, O., & Morty, R. (2010). Dysregulation of the IL-13 Receptor System A Novel Pathomechanism in Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine. 182(6), 805-818. https://doi.org/10.1164/rccm.200909-1367OC