Ression of ICAM-1 has been observed in rats with monocrotaline injection [26]- and chronic hypoxia exposure [27?8]-induced PH. Moreover, increased flow pulsatility has been shown to induce endothelial expression of inflammatoryInflammation and HO-1 in Right Ventricular FailureFigure 2. Morphometry on smallest pulmonary arterioles (,75 micrometers) obtained in Sham and Shunt piglets and labeled by the method of von Gieson-orcein. At least 50 resistive arterioles have been measured per animal. The medial thickness (MT) has been reported in vessel diameter following the formula MT = [(26 MT)/ED]6100 where ED is the external diameter of arterioles measured. MT in pulmonary arteries under 75 micrometers correlated to lung tissue relative IL-19 mRNA content. Values expressed as mean6SEM. doi:10.1371/journal.pone.0069470.ggenes, including ICAM-1 [29], suggesting that prolonged shuntinduced overcirculation could contribute to the development of an inflammatory phenotype in the lungs of the present experimental model. In accordance with the present results showing a tight BIBS39 relation between pulmonary ICAM-1 expression and the PVR, the severity of the pulmonary hypertensive disease has been tightly correlated to serum level of soluble ICAM-1 in patients with congenital heart disease and PH [2]. In the present experimental model of PAH, IL-33 was overexpressed in the lungs, while expression of its ST2 receptor remained unchanged. Recently described member of the IL-1 cytokine family, IL-33 is a strong inducer of T helper 2 (Th2) immune responses [30] and contributes to the early events in endothelial activation, promoting endothelial expression of adhesion molecules (e.a. ICAM-1 and VCAM-1) and pro-inflammatory chemokines (e.a. monocyte chemoattractant protein-1) [31]. IL-33 could therefore contribute to the endothelial activation and subsequent pulmonary arterial remodeling in PAH. Normally released by necrotic cells as an “alarming factor” alerting the immune system to tissue damage or stress, mechanical strain hasalso been shown to induce the secretion of IL-33 in fibroblasts in the absence of cellular necrosis [32]. Via its 548-04-9 web binding to the ST2 receptor, IL-33 also strongly induces Th2 cytokine production (e.a. IL-4, -13 and -19) from these cells and can promote the pathogenesis of Th2-related disease, such as pulmonary arterial remodeling [33]. Six-month systemic-to-pulmonary shunting increased pulmonary expression of IL-19, while STAT3 expression did not change. This could be seen as a Th2-related cytokine production. In vascular smooth muscle cells, IL-19 rapidly evokes the activation and the translocation of STAT3 transcription factor [34] which has been recently incriminated in the development of idiopathic PAH [35] and experimental monocrotaline injection-induced PH [36]. IL-19 also induces the expression of the potent inflammatory modulator HO-1 1317923 and decreases the production of reactive oxygen species in human vascular smooth muscle cells [17]. IL-19 has been shown to decrease dose-dependently the proliferation of vascular smooth muscle cells [15,34,37?8], whereas, in endothelial cell, HO-1 induction increases cell cycle progression [39]. Increased pulmonary IL-19 expression could be therefore partlyInflammation and HO-1 in Right Ventricular FailureFigure 3. Panel A: Relative lung tissue mRNA content for the heme-oxygenase(HO)-1 and -2 tumor necrosis factor(TNF)-a, intercellular adhesion molecule(ICAM)-1 and -2, vascular cell adhesion mol.Ression of ICAM-1 has been observed in rats with monocrotaline injection [26]- and chronic hypoxia exposure [27?8]-induced PH. Moreover, increased flow pulsatility has been shown to induce endothelial expression of inflammatoryInflammation and HO-1 in Right Ventricular FailureFigure 2. Morphometry on smallest pulmonary arterioles (,75 micrometers) obtained in Sham and Shunt piglets and labeled by the method of von Gieson-orcein. At least 50 resistive arterioles have been measured per animal. The medial thickness (MT) has been reported in vessel diameter following the formula MT = [(26 MT)/ED]6100 where ED is the external diameter of arterioles measured. MT in pulmonary arteries under 75 micrometers correlated to lung tissue relative IL-19 mRNA content. Values expressed as mean6SEM. doi:10.1371/journal.pone.0069470.ggenes, including ICAM-1 [29], suggesting that prolonged shuntinduced overcirculation could contribute to the development of an inflammatory phenotype in the lungs of the present experimental model. In accordance with the present results showing a tight relation between pulmonary ICAM-1 expression and the PVR, the severity of the pulmonary hypertensive disease has been tightly correlated to serum level of soluble ICAM-1 in patients with congenital heart disease and PH [2]. In the present experimental model of PAH, IL-33 was overexpressed in the lungs, while expression of its ST2 receptor remained unchanged. Recently described member of the IL-1 cytokine family, IL-33 is a strong inducer of T helper 2 (Th2) immune responses [30] and contributes to the early events in endothelial activation, promoting endothelial expression of adhesion molecules (e.a. ICAM-1 and VCAM-1) and pro-inflammatory chemokines (e.a. monocyte chemoattractant protein-1) [31]. IL-33 could therefore contribute to the endothelial activation and subsequent pulmonary arterial remodeling in PAH. Normally released by necrotic cells as an “alarming factor” alerting the immune system to tissue damage or stress, mechanical strain hasalso been shown to induce the secretion of IL-33 in fibroblasts in the absence of cellular necrosis [32]. Via its binding to the ST2 receptor, IL-33 also strongly induces Th2 cytokine production (e.a. IL-4, -13 and -19) from these cells and can promote the pathogenesis of Th2-related disease, such as pulmonary arterial remodeling [33]. Six-month systemic-to-pulmonary shunting increased pulmonary expression of IL-19, while STAT3 expression did not change. This could be seen as a Th2-related cytokine production. In vascular smooth muscle cells, IL-19 rapidly evokes the activation and the translocation of STAT3 transcription factor [34] which has been recently incriminated in the development of idiopathic PAH [35] and experimental monocrotaline injection-induced PH [36]. IL-19 also induces the expression of the potent inflammatory modulator HO-1 1317923 and decreases the production of reactive oxygen species in human vascular smooth muscle cells [17]. IL-19 has been shown to decrease dose-dependently the proliferation of vascular smooth muscle cells [15,34,37?8], whereas, in endothelial cell, HO-1 induction increases cell cycle progression [39]. Increased pulmonary IL-19 expression could be therefore partlyInflammation and HO-1 in Right Ventricular FailureFigure 3. Panel A: Relative lung tissue mRNA content for the heme-oxygenase(HO)-1 and -2 tumor necrosis factor(TNF)-a, intercellular adhesion molecule(ICAM)-1 and -2, vascular cell adhesion mol.