NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension

International audienc

Epidemic of surgical-site infections by a single clone of rapidly growing mycobacteria in Brazil

Aim: Our aim is to investigate if the clusters of postsurgical mycobacterial infections, reported between 2004 and 2008 in seven geographically distant states in Brazil, were caused by a single mycobacterial strain. Materials & methods: Available information from 929 surgical patients was obtained from local health authorities. A total of 152 isolates from surgical patients were identified by PCR restriction enzyme analysis of the hsp65 gene (PRA-hsp65) and sequencing of the rpoB gene. Isolates were typed by pulsed-field gel electrophoresis (PFGE) using two restriction enzymes. Dral and Asel. A total of 15 isolates not related to surgical cases were analyzed for comparison. Results: All isolates were identified as Mycobacterium abscessus ssp. massiliense. Isolates from surgical patients and one sputum isolate grouped in a single PFGE cluster, composed of two closely related patterns, with one band difference. A total of 14 other isolates unrelated to surgical cases showed distinctive PFGE patterns. Conclusion: A particular strain of M. abscessus ssp. massiliense was associated with a prolonged epidemic of postsurgical infections in seven Brazilian states, suggesting that this strain may be distributed in Brazilian territory and better adapted to cause surgical-site infections.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, BR-04023062 São Paulo, BrazilUniv Fed Espirito Santo, Nucleo Doencas Infecciosas, Vitoria, ES, BrazilInst Evandro Chagas, Belem, Para, BrazilUniv Fed Rio de Janeiro, Inst Microbiol, BR-21941 Rio de Janeiro, BrazilFundacao Oswaldo Cruz, Inst Pesquisa Evandro Chagas, Rio de Janeiro, BrazilUniv Fed Goias, Dept Microbiol Imunol Parasitol & Patol, Goiania, Go, BrazilSecretaria Municipal Saude Goiania, Goiania, Go, BrazilSecretaria Estadual Saude Parana, Curitiba, Parana, BrazilLab Cent Saude Publ, Porto Alegre, RS, BrazilCtr Vigilancia Epidemiol Prof Alexandre Vranjac, São Paulo, BrazilInst Adolfo Lutz Registro, Setor Micobacterias, São Paulo, BrazilCtr Referencia Prof Helio Fraga, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, BR-04023062 São Paulo, BrazilFAPESP: 06/1533-9CNPq: 470594/2006-3CNPq: 475238/2008-7Web of Scienc

Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease

Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4 -/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD.status: publishe

Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease

International audiencePulmonary veno-occlusive disease (PVOD) occurs in humans either as heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2), or as a sporadic form at older age (sPVOD). The chemotherapeutic agent Mitomycin C is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular and molecular levels to unravel common altered pathomechanisms. MMC-exposure in rats was primarily associated with arterial and microvessels remodeling and secondarily followed by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there were convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of heme oxygenase 1 (HO-1) and CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), two downstream effectors of GCN2 signaling and endoplasmic reticulum (ER) stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells (PAECs) using pharmacological and siRNA approaches demonstrated that GCN2 loss-of-function negatively regulates BMP-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced PAECs proliferation. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9 as potential therapeutic options for PVOD