[Show abstract][Hide abstract] ABSTRACT: Anti-acetylcholine receptor (AChR) autoantibodies target muscles in spontaneous human myasthenia gravis (MG) and its induced experimental autoimmune model MG (EAMG). The aim of this study was to identify novel functional mechanisms occurring in the muscle pathology of myasthenia.
A transcriptome analysis performed on muscle tissue from MG patients (compared with healthy controls) and from EAMG rats (compared with control rats) revealed a deregulation of genes associated with the Interleukin-6 (IL-6) and Insulin-Like Growth Factor 1 (IGF-1) pathways in both humans and rats. The expression of IL-6 and its receptor IL-6R transcripts was found to be altered in muscles of EAMG rats and mice compared with control animals. In muscle biopsies from MG patients, IL-6 protein level was higher than in control muscles. Using cultures of human muscle cells, we evaluated the effects of anti-AChR antibodies on IL-6 production and on the phosphorylation of Protein Kinase B (PKB/Akt). Most MG sera and some monoclonal anti-AChR antibodies induced a significant increase in IL-6 production by human muscle cells. Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.
Anti-AChR antibodies alter IL-6 production by muscle cells, suggesting a putative novel functional mechanism of action for the anti-AChR antibodies. IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin). Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.
[Show abstract][Hide abstract] ABSTRACT: Inflammation and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). CD74 is a receptor for the pro-inflammatory cytokine macrophage migration-inhibitory factor (MIF). This ligand/receptor complex initiates survival pathways and cell proliferation, triggers the synthesis/secretion of major pro-inflammatory factors and cell adhesion molecules.
We hypothesized that MIF/CD74 signaling pathway is over-expressed in idiopathic PAH (iPAH) and contributes to a pro-inflammatory endothelial cell (EC) phenotype.
In human lung tissues, ICAM-1, VCAM-1, and E-selectin expressions are markedly up-regulated in endothelium of distal iPAH pulmonary arteries. Circulating MIF levels are increased in serum of PAH patients as compared to controls and T-cell lymphocytes represent a source of this overabundance. In addition, CD74 is highly expressed in the endothelium of muscularized pulmonary arterioles and in cultured pulmonary ECs from iPAH, contributing to an exaggerated recruitment of peripheral blood mononuclear cells (PBMCs) to pulmonary iPAH ECs. Finally, we found that curative treatments with the MIF antagonist ISO-1 or anti-CD74 neutralizing antibodies partially reverse development of pulmonary hypertension in rats and substantially reduced inflammatory cell infiltration.
We report here that CD74 and MIF are markedly increased and activated in iPAH patients, contributing to the abnormal pro-inflammatory phenotype of pulmonary ECs in iPAH.
American Journal of Respiratory and Critical Care Medicine 07/2015; DOI:10.1164/rccm.201402-0322OC · 11.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fig 1. Preoperative computed tomography scan. Thin arrow, Superior vena cava (SVC) stent. Thick arrow, Pseudoaneurysm arising from the junction of the innominate artery and aorta.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-α (PFT, an inhibitor of p53 activity).
PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 μM PFT.
Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis.
PLoS ONE 06/2015; 10(6):e0131940. DOI:10.1371/journal.pone.0131940 · 3.23 Impact Factor
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 05/2015; DOI:10.1016/j.jvs.2015.02.030 · 2.98 Impact Factor