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577 results on '"Hla, Timothy"'

2. Report from the 2023 workshop on endothelial permeability, edema and inflammation

Author

Vestweber, Dietmar, Claesson-Welsh, Lena, McDonald, Donald M, Williams, Timothy, Schwartz, Martin A, Scallan, Joshua, Gavins, Felicity NE, van Buul, Jaap, Gamble, Jennifer, Vadas, Matthew, Annex, Brian H, Messe, Steven R, Perretti, Mauro, André, Helder, Ferrara, Napoleone, Hla, Timothy, Nourshargh, Sussan, and Simons, Michael

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Rare Diseases, Cardiovascular
Published
2023

11. Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock

Author

Gazit, Salomé L, Mariko, Boubacar, Thérond, Patrice, Decouture, Benoit, Xiong, Yuquan, Couty, Ludovic, Bonnin, Philippe, Baudrie, Véronique, Le Gall, Sylvain M, Dizier, Blandine, Zoghdani, Nesrine, Ransinan, Jessica, Hamilton, Justin R, Gaussem, Pascale, Tharaux, Pierre-Louis, Chun, Jerold, Coughlin, Shaun R, Bachelot-Loza, Christilla, Hla, Timothy, Ho-Tin-Noé, Benoit, and Camerer, Eric

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Hematology, Cardiovascular, Anaphylaxis, Animals, Blood Platelets, Blood Vessels, Endothelium, Vascular, Erythrocytes, Homeostasis, Human Umbilical Vein Endothelial Cells, Humans, Lysophospholipids, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Sphingosine, anaphylaxis, endothelium, shock, sphingosine-1-phosphate, vascular endothelial function, vascular permeability, vascular tone regulation, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

RationaleSphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The relative importance of S1P sources sustaining these processes remains unclear.ObjectiveTo address the level of redundancy in bioactive S1P provision to the developing and mature vasculature.Methods and resultsS1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, or smooth muscle cells by targeted deletion of genes encoding sphingosine kinases -1 and -2. S1P deficiency impaired aggregation and spreading of washed platelets and profoundly reduced their capacity to promote endothelial barrier function ex vivo. However, and in contrast to recent reports, neither platelets nor any other source of S1P was essential for vascular development, vascular integrity, or hemostasis/thrombosis. Yet rapid and profound depletion of plasma S1P during systemic anaphylaxis rendered both platelet- and erythrocyte-derived S1P essential for survival, with a contribution from blood endothelium observed only in the absence of circulating sources. Recovery was sensitive to aspirin in mice with but not without platelet S1P, suggesting that platelet activation and stimulus-response coupling is needed. S1P deficiency aggravated vasoplegia in this model, arguing a vital role for S1P in maintaining vascular resistance during recovery from circulatory shock. Accordingly, the S1P2 receptor mediated most of the survival benefit of S1P, whereas the endothelial S1P1 receptor was dispensable for survival despite its importance for maintaining vascular integrity.ConclusionsAlthough source redundancy normally secures essential S1P signaling in developing and mature blood vessels, profound depletion of plasma S1P renders both erythrocyte and platelet S1P pools necessary for recovery and high basal plasma S1P levels protective during anaphylactic shock.

Published
2016

29. Augmentation of Endothelial S1PR1 Attenuates Postviral Pulmonary Fibrosis.

Author

Brazee, Patricia L., Cartier, Andreane, Kuo, Andrew, Haring, Alexis M., Trong Nguyen, Hariri, Lida P., Griffith, Jason W., Hla, Timothy, Medoff, Benjamin D., and Knipe, Rachel S.

Subjects
PULMONARY fibrosis, GENETIC overexpression, ADULT respiratory distress syndrome, DISABILITIES, INFLUENZA A virus
Abstract

Respiratory viral infections are frequent causes of acute respiratory distress syndrome (ARDS), a disabling condition with a mortality of up to 46%. The pulmonary endothelium plays an important role in the development of ARDS as well as the pathogenesis of pulmonary fibrosis; however, the therapeutic potential to modulate endothelium-dependent signaling to prevent deleterious consequences has not been well explored. Here, we used a clinically relevant influenza A virus infection model, endothelial cell--specific transgenic gain-of-function and loss-of-function mice as well as pharmacologic approaches and in vitro modeling, to define the mechanism by which S1PR1 expression is dampened during influenza virus infection and determine whether therapeutic augmentation of S1PR1 has the potential to reduce long-term postviral fibrotic complications. We found that the influenza virus--induced inflammatory milieu promoted internalization of S1PR1, which was pharmacologically inhibited with paroxetine, an inhibitor of GRK2. Moreover, genetic overexpression or administration of paroxetine days after influenza virus infection was sufficient to reduce postviral pulmonary fibrosis. Taken together, our data suggest that endothelial S1PR1 signaling provides critical protection against long-term fibrotic complications after pulmonary viral infection. These findings support the development of antifibrotic strategies that augment S1PR1 expression in virus-induced ARDS to improve long-term patient outcomes. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Augmentation of Endothelial S1PR1 Attenuates Post-Viral Pulmonary Fibrosis.

Author

Brazee, Patricia L., Cartier, Andreane, Kuo, Andrew, Haring, Alexis M., Nguyen, Trong, Hariri, Lida P., Griffith, Jason W., Hla, Timothy, Medoff, Benjamin D., and Knipe, Rachel S.

Subjects
PULMONARY fibrosis, GENE expression, MOLECULAR biology, REGULATORY T cells, CYTOLOGY, BOTANICAL nomenclature
Abstract

The article focuses on a model of low-dose influenza A virus (IAV) infection in wild-type (WT) mice, examining factors such as weight retention, survival rates, and viral load in lung homogenates. It mentions the results show significant differences in viral load and protein content in bronchoalveolar lavage fluid (BALF) between naïve mice and those infected with IAV, highlighting the impact of the infection on various physiological parameters.

Published
2024
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50. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

Author

Wagschal, Alexandre, Najafi-Shoushtari, S Hani, Wang, Lifeng, Goedeke, Leigh, Sinha, Sumita, deLemos, Andrew S, Black, Josh C, Ramírez, Cristina M, Li, Yingxia, Tewhey, Ryan, Hatoum, Ida, Shah, Naisha, Lu, Yong, Kristo, Fjoralba, Psychogios, Nikolaos, Vrbanac, Vladimir, Lu, Yi-Chien, Hla, Timothy, de Cabo, Rafael, Tsang, John S, Schadt, Eric, Sabeti, Pardis C, Kathiresan, Sekar, Cohen, David E, Whetstine, Johnathan, Chung, Raymond T, Fernández-Hernando, Carlos, Kaplan, Lee M, Bernards, Andre, Gerszten, Robert E, and Näär, Anders M

Subjects
Physiological aspects, Analysis, Genetic aspects, Research, MicroRNA -- Research, Genome-wide association studies -- Analysis, Cholesterol -- Physiological aspects -- Genetic aspects, Triglycerides -- Physiological aspects -- Genetic aspects
Abstract

Author(s): Alexandre Wagschal [1, 2]; S Hani Najafi-Shoushtari [1, 2]; Lifeng Wang [1, 2]; Leigh Goedeke [3]; Sumita Sinha [4]; Andrew S deLemos [5]; Josh C Black [1, 6]; Cristina [...], Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from [greater than] 188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

Published
2015
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