P ulmonary arterial hypertension (PAH) is a rare disorder, with a prevalence of 15 to 50 patients per million in the population. It is characterized by remodeling of the precapillary pulmonary arteries, with endothelial cell dysfunction contributing to endothelial and pulmonary artery smooth muscle cell proliferation. This remodeling increases pulmonary vascular resistance and pulmonary arterial pressure (mean pulmonary arterial pressure ≥25 mm Hg and a pulmonary capillary wedge Background-The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly the accumulation of α-smooth muscle actin-expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those α-smooth muscle actin-expressing cells. Methods and Results-In situ evidence of EndoMT in human PAH was obtained by using confocal microscopy of multiple fluorescent stainings at the arterial level, and by using transmission electron microscopy and correlative light and electron microscopy at the ultrastructural level. Findings were confirmed by in vitro analyses of human PAH and control cultured pulmonary artery endothelial cells. In addition, the mRNA and protein signature of EndoMT was recognized at the arterial and lung level by quantitative real-time polymerase chain reaction and Western blot analyses. We confirmed our human observations in established animal models of pulmonary hypertension (monocrotaline and SuHx). After establishing the first genetically modified rat model linked to BMPR2 mutations (BMPR2 Δ140Ex1/+ rats), we demonstrated that EndoMT is linked to alterations in signaling of BMPR2, a gene that is mutated in 70% of cases of familial PAH and in 10% to 40% of cases of idiopathic PAH. We identified molecular actors of this pathological transition, including twist overexpression and vimentin phosphorylation. We demonstrated that rapamycin partially reversed the protein expression patterns of EndoMT, improved experimental PAH, and decreased the migration of human pulmonary artery endothelial cells, providing the proof of concept that EndoMT is druggable. Conclusions-EndoMT is linked to alterations in BPMR2 signaling and is involved in the occlusive vas cular remodeling of PAH, findings that may have therapeutic implications.

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

Inflammation in pulmonary arterial hypertension. P. Dorfmüller, F. Perros, K. Balabanian, M. Humbert. #ERS Journals Ltd 2003. ABSTRACT: Inflammatory mechanisms appear to play a significant role in some types of pulmonary hypertension (PH), including monocrotaline-induced PH in rats and pulmonary arterial hypertension of various origins in humans, such as connective tissue diseases (scleroderma, systemic lupus erythematosus, mixed connective disease), human immunodeficiency virus infection, or plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal (M) protein and skin changes (POEMS) syndrome.Interestingly, some patients with severe pulmonary arterial hypertension associated with systemic lupus erythematosus have experienced significant improvements with immunosuppressive therapy, emphasising the relevance of inflammation in a subset of patients presenting with PH. Patients with primary PH (PPH) also have some immunological disturbances, suggesting a possible role for inflammation in the pathophysiology of this disease. A subset of PPH patients have been shown to have circulating autoantibodies, including antinuclear antibodies, as well as elevated circulating levels of the pro-infammatory cytokines, interleukins -1 and -6. Lung histology has also revealed inflammatory infiltrates in the range of plexiform lesions in patients displaying severe PPH, as well as an increased expression of the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and fractalkine.Further analysis of the role of inflammatory mechanisms is necessary to understand whether this component of the disease is relevant to its pathophysiology. Pulmonary arterial hypertension (PAH) is characterised by an elevated mean pulmonary artery pressure o25 mmHg at rest, with a normal pulmonary artery wedge pressure. This severe condition leads to progressive right heart failure and ultimately death [1]. The Evian Classification reflects recent advances in the understanding of pulmonary hypertensive diseases, and recognises the similarity between "unexplained" pulmonary hypertension (PH) (primary PH (PPH)) and PAH of certain known aetiologies, such as collagen vascular diseases, human immunodeficiency virus (HIV) infection, portal hypertension, congenital systemic-to-pulmonary shunts and anorexigen exposure [2].PAH results from chronic obstruction of small pulmonary arteries, which is due, at least in part, to endothelial and vascular smooth muscle cell dysfunction and proliferation [3]. The recent discovery that a significant proportion of patients with familial, as well as sporadic, PPH have germline mutations of genes encoding receptor members of the transforming growth factor (TGF)-b family (bone morphogenetic protein receptor-II and activin receptor-like kinase-1), suggests that dysfunctional TGF-b signalling could lead to an abnormal proliferation of pulmonary vascular cells [4,5]. Although these major advances have improved the understanding of PAH, more information is needed to evaluate th...

We highlight the main features of lymphoid neogenesis specifically in the lungs of patients with IPAH, providing new evidence of immunological mechanisms in this severe condition.

In IPAH, c-kit(+) cells infiltrate pulmonary arterial lesions and may participate to vascular remodeling. Therefore, c-kit may represent a potential target for innovative PAH therapy.

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Haematopoietic c-kit+ progenitor cells may contribute to pulmonary vascular remodelling and pulmonary hypertension (PH). Stromal derived factor-1 (SDF-1/CXCL12) and its receptors CXCR4 and CXCR7 have been shown to be critical for homing and mobilisation of haematopoietic c-kit+ progenitor cells in the perivascular niche.We administered AMD3100, a CXCR4 antagonist, and CCX771, a CXCR7 antagonist, to chronic hypoxia exposed mice in order to study the role of c-kit+ progenitor cells in PH. CXCL12, CXCR4 and CXCR7 protein expression, haemodynamic parameters, right ventricular mass, extent of vascular remodelling and perivascular progenitor cell accumulation were studied.Chronic hypoxia-exposed mice showed increased total lung tissue expression of CXCR4, CXCR7 and CXCL12 after development of PH. This was associated with significantly increased right ventricular systolic pressure and evidence of right ventricular hypertrophy, vascular remodelling and perivascular c-kit+/sca-1+ progenitor cell accumulation. CCX771 administration did not abrogate these effects. In contrast, administration of AMD3100, whether alone or combined with CCX771, prevented vascular remodelling, PH and perivascular accumulation of c-kit+/sca-1+ progenitor cells, with a synergistic effect of these agents.This study offers important pathophysiological insights into the role of haematopoietic c-kit+ progenitors in hypoxia-induced vascular remodelling and may have therapeutic implications for PH.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.