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.
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.
Authors: Danny Jonigk; Heiko Golpon; Clemens L Bockmeyer; Lavinia Maegel; Marius M Hoeper; Jens Gottlieb; Nils Nickel; Kais Hussein; Ulrich Maus; Ulrich Lehmann; Sabina Janciauskiene; Tobias Welte; Axel Haverich; Johanna Rische; Hans Kreipe; Florian Laenger Journal: Am J Pathol Date: 2011-05-11 Impact factor: 4.307
Authors: Romy B Christmann; Everett Hayes; Sarah Pendergrass; Cristina Padilla; Giuseppina Farina; Alsya J Affandi; Michael L Whitfield; Harrison W Farber; Robert Lafyatis Journal: Arthritis Rheum Date: 2011-06
Authors: Jacob J Chabon; Liya Gebreab; Rahul Kumar; Elias Debella; Takeshi Tanaka; Dan Koyanagi; Alexandra Rodriguez Garcia; Linda Sanders; Mario Perez; Rubin M Tuder; Brian B Graham Journal: Pulm Circ Date: 2014-06 Impact factor: 3.017
Authors: Won-Kyung Cho; Chang-Min Lee; Min-Jong Kang; Yan Huang; Frank J Giordano; Patty J Lee; Terence K Trow; Robert J Homer; William C Sessa; Jack A Elias; Chun Geun Lee Journal: Am J Physiol Lung Cell Mol Physiol Date: 2012-11-02 Impact factor: 5.464