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Guignabert C, Alvira CM, Alastalo T-P, Sawada H, Hansmann G, Zhao M, Wang L, El-Bizri N, Rabinovitch M. Tie2-mediated loss of peroxisome proliferator-activated receptor-[gamma] in mice causes PDGF receptor-[beta]-dependent pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 297: L1082-L1090, 2009. First published October 2, 2009; doi: 10.1152/ajplung.00199.2009.--Peroxisome proliferator-activated receptor (PPAR)-[gamma] is reduced in pulmonary arteries (PAs) of patients with PA hypertension (PAH), and we reported that deletion of PPAR[gamma] in smooth muscle cells (SMCs) of transgenic mice results in PAH. However, the sequelae of loss of PPAR[gamma] in PA endothelial cells (ECs) are unknown. Therefore, we bred Tie2-Cre mice with PPAR[[gamma].sup.flox/flox] mice to induce EC loss of PPAR[gamma] (Tie2 PPAR[[gamma].sup.-/-]), and we assessed PAH by right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and muscularized distal PAs in room air (RA), after chronic hypoxia (CH), and after 4 wk of recovery in RA (Rec-RA). The Tie2 PPAR[[gamma].sup.-/-] mice developed spontaneous PAH in RA with increased RVSP, RVH, and muscularized PAs vs. wild type (WT); both genotypes exhibited a similar degree of PAH following chronic hypoxia, but Tie2 PPAR[[gamma].sup.-/-] mice had more residual PAH compared with WT mice after Rec-RA. The Tie2 PPAR[[gamma].sup.-/-] vs. WT mice in RA had increased platelet-derived growth factor receptor-[beta] (PDGF-R[beta]) expression and signaling, despite an elevation in the PPAR[gamma] target apolipoprotein E, an inhibitor of PDGF signaling. Inhibition of PDGF-R[beta] signaling with imatinib, however, was sufficient to reverse the PAH observed in the Tie2 PPAR[[gamma.sup.-/-] mice. Thus the disruption of PPAR[gamma] signaling in EC is sufficient to cause mild PAH and to impair recovery from CH-induced PAH. Inhibition of heightened PDGF-R[beta] signaling is sufficient to reverse PAH in this genetic model. endothelial cells; platelet-derived growth factor receptor-[beta]; pulmonary remodeling; smooth muscle cell; platelet-derived growth factor doi: 10.1152/ajplung.00199.2009

This paper explores the economic conditions under which single-model assembly lines are operated in a batch mode (through intermittent manufacture at higher production rates) rather than by the traditional method of continuous production at the demand rate. A model for optimizing the 'cycle time, station number' combination is developed through consideration of five factors: the learning, inventory, setup, balancing and facility costs. Economic justification for operating in a batch mode was found for total demands ranging from 20 to 4000 assembled products which is expected to include a sizable percentage of the total products manufactured in industralised countries each year. Greatest savings occur for total demands in the order of 1000 products. [ABSTRACT FROM AUTHOR]

Although the incidence of pulmonary hypertension is higher in female patients, numerous experimental studies have demonstrated better outcome in female animals, exacerbation of the disease after ovariectomy, and a strong protective effect of estrogen: a phenomenon known as the "estrogen paradox" of pulmonary hypertension. On the other hand, some clinical studies have indirectly linked estrogen to increased risk of portopulmonary hypertension, whereas others implicate increased estrogen metabolism and high levels of certain estrogen metabolites in promoting pulmonary vascular remodeling in familial pulmonary arterial hypertension. In this review we investigate the estrogen paradox through highlighting the differential receptor-mediated effects of estrogen. Although estrogen and estrogen receptor-based therapies have shown promise in rescuing preexisting pulmonary hypertension in animals, their role is yet to be defined in humans. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary hypertension (PH) is a progressive disease with unclear etiology. The significance of autophagy in PH remains unknown.Objectives: To determine the mechanisms by which autophagic proteins regulate tissue responses during PH.Methods: Lungs from patients with PH, lungs from mice exposed to chronic hypoxia, and human pulmonary vascular cells were examined for autophagy using electron microscopy and Western analysis. Mice deficient in microtubule-associated protein-1 light chain-3B (LC3B(-/-)), or early growth response-1 (Egr-1(-/-)), were evaluated for vascular morphology and hemodynamics.Measurements and Main Results: Human PH lungs displayed elevated lipid-conjugated LC3B, and autophagosomes relative to normal lungs. These autophagic markers increased in hypoxic mice, and in human pulmonary vascular cells exposed to hypoxia. Egr-1, which regulates LC3B expression, was elevated in PH, and increased by hypoxia in vivo and in vitro. LC3B(-/-) or Egr-1(-/-), but not Beclin 1(+/-), mice displayed exaggerated PH during hypoxia. In vitro, LC3B knockdown increased reactive oxygen species production, hypoxia-inducible factor-1α stabilization, and hypoxic cell proliferation. LC3B and Egr-1 localized to caveolae, associated with caveolin-1, and trafficked to the cytosol during hypoxia.Conclusions: The results demonstrate elevated LC3B in the lungs of humans with PH, and of mice with hypoxic PH. The increased susceptibility of LC3B(-/-) and Egr-1(-/-) mice to hypoxia-induced PH and increased hypoxic proliferation of LC3B knockdown cells suggest adaptive functions of these proteins during hypoxic vascular remodeling. The results suggest that autophagic protein LC3B exerts a protective function during the pathogenesis of PH, through the regulation of hypoxic cell proliferation. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor (PPAR)-γ is reduced in pulmonary arteries (PAs) of patients with PA hypertension (PAH), and we reported that deletion of PPAR-y in smooth muscle cells (SMCs) of transgenic mice results in PAH. However, the sequelae of loss of PPAR-γ in PA endothelial cells (ECs) are unknown. Therefore, we bred Tie2-Cre mice with PPARγflox/flox mice to induce EC loss of PPARγ (Tie2 PPAR-γ-/-), and we assessed PAH by right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and muscularized distal PAs in room air (RA), after chronic hypoxia (CH), and after 4 wk of recovery in RA (Rec-RA). The Tie2 PPARγ-/- mice developed spontaneous PAH in RA with increased RVSP, RVH, and muscularized PAs vs. wild type (WT); both genotypes exhibited a similar degree of PAH following chronic hypoxia, but Tie2 PPARγ-/- mice had more residual PAH compared with WT mice after Rec-RA. The Tie2 PPARγ-/- vs. WT mice in RA had increased platelet-derived growth factor receptor-β (PDGF-Rβ) expression and signaling, despite an elevation in the PPARγ target apolipoprotein E, an inhibitor of PDGF signaling. Inhibition of PDGF-Rγ signaling with imatinib, however, was sufficient to reverse the PAH observed in the Tie2 PPARγ-/- mice. Thus the disruption of PPARγ signaling in EC is sufficient to cause mild PAH and to impair recovery from CH-induced PAH. Inhibition of heightened PDGF-Rβ signaling is sufficient to reverse PAH in this genetic model. [ABSTRACT FROM AUTHOR]

Rationale: Injurious agents often cause less severe injury in neonates as compared with adults.Objective: We hypothesized that maturational differences in lung inflammation induced by lipopolysaccharide (LPS) may be related to the nature of the nuclear factor (NF)-kappaB complex activated, and the profile of target genes expressed.Methods: Neonatal and adult mice were injected with intraperitoneal LPS. Lung inflammation was assessed by histology, and apoptosis was determined by TUNEL (terminal deoxynucleotidyl transferase UTP nick-end labeling). The expression of candidate inflammatory and apoptotic mediators was evaluated by quantitative real-time polymerase chain reaction and Western immunoblot.Results: Neonates demonstrated reduced inflammation and apoptosis, 24 hours after LPS exposure, as compared with adults. This difference was associated with persistent activation of NF-kappaB p65p50 heterodimers in the neonates in contrast to early, transient activation of p65p50 followed by sustained activation of p50p50 in the adults. Adults had increased expression of a panel of inflammatory and proapoptotic genes, and repression of antiapoptotic targets, whereas no significant changes in these mediators were observed in the neonates. Inhibition of NF-kappaB activity in the neonates decreased apoptosis, but heightened inflammation, with increased expression of the same inflammatory genes elevated in the adults. In contrast, inhibition of NF-kappaB in the adults resulted in partial suppression of the inflammatory response.Conclusions: NF-kappaB activation in the neonatal lung is antiinflammatory, protecting against LPS-mediated lung inflammation by repressing similar inflammatory genes induced in the adult. [ABSTRACT FROM AUTHOR]

BACKGROUND--The formation of coronary artery neointima experimentally induced in piglets after cardiac transplantation is related to an immune-inflammatory reaction associated with increased expression of T cells and inflammatory mediators (tumour necrosis factor alpha and interleukin 1 beta) and upregulation of fibronectin. In vivo blockade of tumour necrosis factor alpha in rabbits after cardiac transplantation results in reduced neointimal formation. The objective of this study was to investigate the hypothesis that coronary restenosis after atherectomy or percutaneous balloon angioplasty is associated with a similar inflammatory cascade initiated by mechanical injury. METHODS--Specimens taken at coronary atherectomy were analysed from 16 patients. Nine had had the procedure performed twice, firstly, to remove a primary lesion, and secondly, to remove a restenotic lesion. Seven had percutaneous balloon angioplasty after removal of restenotic tissue. Coronary atherectomy specimens were analysed by immunohistochemistry for the presence of T cells, macrophages, major histocompatibility complex II, interleukin 1 beta, tumour necrosis factor alpha, fibronectin, and the receptor for hyaluronan mediated motility. RESULTS--The groups were clinically and angiographically similar with equivalent lumens before and after atherectomy. Restenotic lesions had increased expression of tumour necrosis factor alpha and fibronectin compared with the primary lesions (P < 0.05 for both). There was also a trend towards a greater number of T cells and increased expression of interleukin 1 beta. CONCLUSIONS--Restenosis is associated with increased expression of tumour necrosis factor alpha and fibronectin, suggesting that an immune-inflammatory reaction probably contributes to neointimal formation and may represent a form of wound healing and repair secondary to mechanical injury. [ABSTRACT FROM PUBLISHER]

OBJECTIVE--To describe the demographic and haemodynamic variables of children presenting with primary pulmonary hypertension or pulmonary hypertension appearing or persisting after surgical correction of congenital heart defects and to assess the acute effect of vasodilator drugs on their pulmonary vascular bed. DESIGN--Retrospective review. SETTING--Paediatric cardiology department and intensive care unit of a large tertiary centre. PATIENTS--Fourteen consecutive patients presenting with primary pulmonary hypertension (group 1) or pulmonary hypertension persisting or appearing late after complete surgical repair (group 2). INTERVENTION--Baseline haemodynamic measurements were taken in room air at rest and repeated in 100% oxygen. With constant monitoring of heart rate and pulmonary and systemic arterial pressures, patients were given serial intravenous, sublingual, or oral incremental doses of vasodilators (mean 4.1 trials per patient). The maximum effect of the drug was charted. MAIN OUTCOME MEASURES--A positive response to acute vasodilator tests was defined as a decrease in mean pulmonary or mean systemic arterial pressure > 15% with the mean pulmonary artery pressure not reaching the systemic level and either no change or an increase in mean systemic arterial pressure. Haemodynamic variables between groups (1 v 2, responders v non-responders, patients experiencing or not experiencing adverse effects to vasodilators) were compared by a two tailed unpaired Student's t test, and their survival curves were compared by the log rank statistic. RESULTS--Groups are small and definitive conclusions are difficult to draw, but the baseline haemodynamic assessments were not significantly different between group 1 and 2 or between responders and non-responders to vasodilators. Patients experiencing adverse effects had a higher pulmonary vascular resistance (p = 0.04) and wedge pressure (p = 0.02) than those without adverse effects. Of the vasodilators used, tolazoline, hydralazine, salbutamol, phentolamine, and phenoxybenzamine were ineffective. A positive response was seen in five of 13 patients given oxygen, in one of eight given prostacyclin, four of 12 given nifedipine, four of eight given diltiazem, one of six given captopril, and two of seven given glyceryl trinitrate. Estimates of survival of the population with primary pulmonary hypertension were 37% at one year and 12% at 2.5 years. Survival was significantly shorter in the non-responders than in the responders (p = 0.005). CONCLUSION--Children with primary pulmonary hypertension present to the cardiologist at a young age (five of eight were younger than 7 years) but with advanced pulmonary vascular disease and have a poor prognosis. 64% of group 1 and group 2 patients had a positive response to acute treatment with at least one vasodilator. Calcium channel blockers were the most effective agents. There was a positive response to drugs despite a negative response to acute treatment with oxygen. The survival of non-responders was shorter than that of the responders. [ABSTRACT FROM PUBLISHER]