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Wendy Ezegbunam, Robert Foronjy
Acute inflammation in the lungs is a vital protective response, efficiently and swiftly eliminating inciters of tissue injury. However, in respiratory diseases characterized by chronic inflammation, such as chronic obstructive pulmonary disease and asthma, enhanced expression of inflammatory mediators leads to tissue damage and impaired lung function. Although transcription is an essential first step in the induction of proinflammatory genes, tight regulation of inflammation requires more rapid, flexible responses...
January 2018: Wiley Interdisciplinary Reviews. RNA
Jonathan A Kropski, Bradley W Richmond, Christa F Gaskill, Robert F Foronjy, Susan M Majka
Chronic lung disease (CLD), including pulmonary fibrosis (PF) and chronic obstructive pulmonary disease (COPD), is the fourth leading cause of mortality worldwide. Both are debilitating pathologies that impede overall tissue function. A common co-morbidity in CLD is vasculopathy, characterized by deregulated angiogenesis, remodeling, and loss of microvessels. This substantially worsens prognosis and limits survival, with most current therapeutic strategies being largely palliative. The relevance of angiogenesis, both capillary and lymph, to the pathophysiology of CLD has not been resolved as conflicting evidence depicts angiogenesis as both reparative or pathologic...
January 2018: Pulmonary Circulation
Christa F Gaskill, Erica J Carrier, Jonathan A Kropski, Nathaniel C Bloodworth, Swapna Menon, Robert F Foronjy, M Mark Taketo, Charles C Hong, Eric D Austin, James D West, Anna L Means, James E Loyd, W David Merryman, Anna R Hemnes, Stijn De Langhe, Timothy S Blackwell, Dwight J Klemm, Susan M Majka
Pulmonary vascular disease is characterized by remodeling and loss of microvessels and is typically attributed to pathological responses in vascular endothelium or abnormal smooth muscle cell phenotypes. We have challenged this understanding by defining an adult pulmonary mesenchymal progenitor cell (MPC) that regulates both microvascular function and angiogenesis. The current understanding of adult MPCs and their roles in homeostasis versus disease has been limited by a lack of genetic markers with which to lineage label multipotent mesenchyme and trace the differentiation of these MPCs into vascular lineages...
June 1, 2017: Journal of Clinical Investigation
Patrick Geraghty, Eran Hadas, Boe-Hyun Kim, Abdoulaye J Dabo, David J Volsky, Robert Foronjy
Cigarette smoke usage is prevalent in human immunodeficiency virus (HIV)-positive patients, and, despite highly active antiretroviral therapy, these individuals develop an accelerated form of chronic obstructive pulmonary disease (COPD). Studies investigating the mechanisms of COPD development in HIV have been limited by the lack of suitable mouse models. Here we describe a model of HIV-induced COPD in wild-type mice using EcoHIV, a chimeric HIV capable of establishing chronic infection in immunocompetent mice...
April 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
Itsaso Garcia-Arcos, Patrick Geraghty, Nathalie Baumlin, Michael Campos, Abdoulaye Jules Dabo, Bakr Jundi, Neville Cummins, Edward Eden, Astrid Grosche, Matthias Salathe, Robert Foronjy
BACKGROUND: The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells. METHODS: Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months...
December 2016: Thorax
Chien-Huan Weng, Sanjay Gupta, Patrick Geraghty, Robert Foronjy, Alessandra B Pernis
Gene-environment interactions are known to play a key role in the development of rheumatoid arthritis (RA). Exposure to cigarette smoke (CS) is one of the strongest environmental risk factors associated with RA and has been shown to mediate a range of complex immunomodulatory effects from decreased T and B cell activation to depressed phagocytic function. The effects of CS on the function of TH17 cells, one of the key TH effector subsets implicated in RA pathogenesis, are not fully understood. IRF4 is one of the crucial transcription factors involved in TH-17 differentiation and is absolutely required for the production of IL-17 and IL-21 but, interestingly, inhibits the synthesis of IL-22...
March 2016: Molecular Immunology
R F Foronjy, P O Ochieng, M A Salathe, A J Dabo, E Eden, N Baumlin, N Cummins, S Barik, M Campos, E B Thorp, P Geraghty
Protein tyrosine phosphatase 1B (PTP1B) has anti-inflammatory potential but PTP1B responses are desensitized in the lung by prolonged cigarette smoke exposure. Here we investigate whether PTP1B expression affects lung disease severity during respiratory syncytial viral (RSV) exacerbations of chronic obstructive pulmonary disease (COPD). Ptp1b(-/-) mice infected with RSV exhibit exaggerated immune cell infiltration, damaged epithelial cell barriers, cytokine production, and increased apoptosis. Elevated expression of S100A9, a damage-associated molecular pattern molecule, was observed in the lungs of Ptp1b(-/-) mice during RSV infection...
September 2016: Mucosal Immunology
Seungyeul Yoo, Sachiko Takikawa, Patrick Geraghty, Carmen Argmann, Joshua Campbell, Luan Lin, Tao Huang, Zhidong Tu, Robert F Foronjy, Robert Feronjy, Avrum Spira, Eric E Schadt, Charles A Powell, Jun Zhu
Chronic Obstructive Pulmonary Disease (COPD) is a complex disease. Genetic, epigenetic, and environmental factors are known to contribute to COPD risk and disease progression. Therefore we developed a systematic approach to identify key regulators of COPD that integrates genome-wide DNA methylation, gene expression, and phenotype data in lung tissue from COPD and control samples. Our integrative analysis identified 126 key regulators of COPD. We identified EPAS1 as the only key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity...
January 2015: PLoS Genetics
Patrick Geraghty, Edward Eden, Manju Pillai, Michael Campos, Noel G McElvaney, Robert F Foronjy
RATIONALE: α1-Antitrypsin (A1AT) was identified as a plasma protease inhibitor; however, it is now recognized as a multifunctional protein that modulates immunity, inflammation, proteostasis, apoptosis, and cellular senescence. Like A1AT, protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, regulates similar biologic processes and plays a key role in chronic obstructive pulmonary disease. OBJECTIVES: Given their common effects, this study investigated whether A1AT acts via PP2A to alter tumor necrosis factor (TNF) signaling, inflammation, and proteolytic responses in this disease...
December 1, 2014: American Journal of Respiratory and Critical Care Medicine
Robert F Foronjy, Abdoulaye J Dabo, Neville Cummins, Patrick Geraghty
BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-β (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR...
2014: BMC Immunology
Gema Flores, Keyvan Dastmalchi, Sturlainny Paulino, Kathleen Whalen, Abdoulaye J Dabo, Kurt A Reynertson, Robert F Foronjy, Jeanine M D'Armiento, Edward J Kennelly
Nine anthocyanins (1-9) from the edible fruits of Eugenia brasiliensis were identified by HPLC-PDA and LC-MS, and seven of these are described for the first time in this Brazilian fruit. Two of the major anthocyanins, delphinidin (8) and cyanidin (9), were studied for their inhibitory activity against chemokine interleukin-8 (IL-8) production before and after cigarette smoke extract (CSE) treatment of cells. In non-treated cells the amount of IL-8 was unchanged following treatment with cyanidin and delphinidin in concentrations 0...
October 1, 2012: Food Chemistry
R F Foronjy, C C Taggart, A J Dabo, S Weldon, N Cummins, P Geraghty
The role of proteases in viral infection of the lung is poorly understood. Thus, we examined matrix metalloproteinases (MMPs) and cathepsin proteases in respiratory syncytial virus (RSV)-infected mouse lungs. RSV-induced gene expression for MMPs -2, -3, -7, -8, -9, -10, -12, -13, -14, -16, -17, -19, -20, -25, -27, and -28 and cathepsins B, C, E, G, H, K, L1, S, W, and Z in the airways of Friend leukemia virus B sensitive strain mice. Increased proteases were present in the bronchoalveolar lavage fluid (BALF) and lung tissue during infection...
January 2015: Mucosal Immunology
Robert F Foronjy, Abdoulaye J Dabo, Clifford C Taggart, Sinead Weldon, Patrick Geraghty
Respiratory syncytial viral (RSV) infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice...
2014: PloS One
Anthony Brehm, Patrick Geraghty, Michael Campos, Itsaso Garcia-Arcos, Abdoulaye Jules Dabo, Adam Gaffney, Edward Eden, Xian-Cheng Jiang, Jeanine D'Armiento, Robert Foronjy
Phospholipid transfer protein (PLTP) regulates phospholipid transport in the circulation and is highly expressed within the lung epithelium, where it is secreted into the alveolar space. Since PLTP expression is increased in chronic obstructive pulmonary disease (COPD), this study aimed to determine how PLTP affects lung signaling and inflammation. Despite its increased expression, PLTP activity decreased by 80% in COPD bronchoalveolar lavage fluid (BALF) due to serine protease cleavage, primarily by cathepsin G...
May 2014: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Patrick Geraghty, Andrew Hardigan, Robert F Foronjy
The diagnosis of chronic obstructive pulmonary disease (COPD) confers a 2-fold increased lung cancer risk even after adjusting for cigarette smoking, suggesting that common pathways are operative in both diseases. Although the role of the tyrosine kinase c-Src is established in lung cancer, less is known about its impact in other lung diseases, such as COPD. This study examined whether c-Src activation by cigarette smoke contributes to the pathogenesis of COPD. Cigarette smoke increased c-Src activity in human small airway epithelial (SAE) cells from healthy donors and in the lungs of exposed mice...
March 2014: American Journal of Respiratory Cell and Molecular Biology
Patrick Geraghty, Anne E Wyman, Itsaso Garcia-Arcos, Abdoulaye J Dabo, Sonya Gadhvi, Robert Foronjy
Signal transducer and activator of transcription-3 (STAT3) regulates inflammation, apoptosis, and protease expression, which are critical processes associated with airway injury and lung tissue destruction. However, the precise role of STAT3 in the development of airway diseases such as chronic obstructive pulmonary disease (COPD) has not been established. This study shows that cigarette smoke activates STAT3 in the lungs of mice. Since cigarette smoke activated STAT3 in the lung, we then evaluated how the loss of STAT3 would impact on smoke-mediated lung inflammation, protease expression, and apoptosis...
2013: Frontiers in Physiology
Robert Foronjy, Jeanine D'Armiento
The inhalation of cigarette smoke triggers a marked cellular influx in the lung and this inflammation is believed to play a central role in the development of smoke-related lung diseases such as asthma and COPD. Studies demonstrate that smoke-derived oxidants are a major factor in this inflammatory reaction to cigarette smoke. These oxidants can overwhelm the lung's antioxidant defenses and they can up regulate inflammation by a number of mechanisms. Free radicals directly stimulate the production of chemotactic compounds such as 8-isoprostane...
January 1, 2006: Clinical and Applied Immunology Reviews
Gema Flores, Keyvan Dastmalchi, Shi-Biao Wu, Kathleen Whalen, Abdoulaye J Dabo, Kurt A Reynertson, Robert F Foronjy, Jeanine M D Armiento, Edward J Kennelly
The potential therapeutic effects of Costa Rican guava (Psidium friedrichsthalianum) extracts for chronic obstructive pulmonary disease were examined. The ethyl acetate fraction displayed the highest antioxidant activity, as compared to the hexane, chloroform, and n-butanol fractions, as well as the crude extract. This fraction was evaluated for its anti-inflammatory activity response relationship against interleukin-8 (IL-8) and inhibition of matrix metalloproteinase-1 (MMP-1) expression before and after treatment with cigarette smoke...
November 15, 2013: Food Chemistry
Patrick Geraghty, Robert Foronjy
Increasing protein expression enables researchers to better understand the functional role of that protein in regulating key biological processes(1). In the lung, this has been achieved typically through genetic approaches that utilize transgenic mice(2,3) or viral or non-viral vectors that elevate protein levels via increased gene expression(4). Transgenic mice are costly and time-consuming to generate and the random insertion of a transgene or chronic gene expression can alter normal lung development and thus limit the utility of the model(5)...
2013: Journal of Visualized Experiments: JoVE
Robert F Foronjy, Susan M Majka
Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a potential therapy in patients with such inflammatory lung diseases including, but not limited to, chronic lung disease, pulmonary arterial hypertension (PAH), pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD)/emphysema and asthma...
December 2012: Cells
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