68 results on '"Mutlu, Gokhan"'
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2. Anoctamin-1 is induced by TGF-b and contributes to lung myofibroblast differentiation.
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Reed, Eleanor B., Orbeta, Shaina, Miao, Bernadette A., Sitikov, Albert, Chen, Bohao, Levitan, Irena, Solway, Julian, Mutlu, Gokhan M., Yun Fang, Mongin, Alexander A., and Dulin, Nickolai O.
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CHLORIDE channels ,IDIOPATHIC pulmonary fibrosis ,GENE expression ,PULMONARY fibrosis ,MYOFIBROBLASTS ,LUNGS ,SMOOTH muscle - Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive scarring of the lungs and resulting in deterioration in lung function. Transforming growth factor-b (TGF-b) is one of the most established drivers of fibrotic processes. TGF-b promotes the transformation of tissue fibroblasts to myofibroblasts, a key finding in the pathogenesis of pulmonary fibrosis. We report here that TGF-b robustly upregulates the expression of the calcium-activated chloride channel anoctamin-1 (ANO1) in human lung fibroblasts (HLFs) at mRNA and protein levels. ANO1 is readily detected in fibrotic areas of IPF lungs in the same area with smooth muscle a-actin (SMA)-positive myofibroblasts. TGF-b-induced myofibroblast differentiation (determined by the expression of SMA, collagen-1, and fibronectin) is significantly inhibited by a specific ANO1 inhibitor, T16A
inh -A01, or by siRNA mediated ANO1 knockdown. T16Ainh -A01 and ANO1 siRNA attenuate profibrotic TGF-b signaling, including activation of RhoA pathway and AKT, without affecting initial Smad2 phosphorylation. Mechanistically, TGF-b treatment of HLFs results in a significant increase in intracellular chloride levels, which is prevented by T16Ainh -A01 or by ANO1 knockdown. The downstream mechanism involves the chloride-sensing “with-no-lysine (K)” kinase (WNK1). WNK1 siRNA significantly attenuates TGF-b-induced myofibroblast differentiation and signaling (RhoA pathway and AKT), whereas the WNK1 kinase inhibitor WNK463 is largely ineffective. Together, these data demonstrate that 1) ANO1 is a TGF-b-inducible chloride channel that contributes to increased intracellular chloride concentration in response to TGF-b; and 2) ANO1 mediates TGF-b-induced myofibroblast differentiation and fibrotic signaling in a manner dependent on WNK1 protein but independent of WNK1 kinase activity. NEW & NOTEWORTHY This study describes a novel mechanism of differentiation of human lung fibroblasts (HLFs) to myofibroblasts: the key process in the pathogenesis of pulmonary fibrosis. Transforming growth factor-b (TGF-b) drives the expression of calcium-activated chloride channel anoctmin-1 (ANO1) leading to an increase in intracellular levels of chloride. The latter recruits chloride-sensitive with-no-lysine (K) kinase (WNK1) to activate profibrotic RhoA and AKT signaling pathways, possibly through activation of mammalian target of rapamycin complex-2 (mTORC2), altogether promoting myofibroblast differentiation. [ABSTRACT FROM AUTHOR]- Published
- 2024
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3. The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging
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McQuattie-Pimentel, Alexandra C., Ren, Ziyou, Joshi, Nikita, Watanabe, Satoshi, Stoeger, Thomas, Chi, Monica, Lu, Ziyan, Sichizya, Lango, Aillon, Raul Piseaux, Chen, Ching-I, Soberanes, Saul, Chen, Zhangying, Reyfman, Paul A., Walter, James M., Anekalla, Kishore R., Davis, Jennifer M., Helmin, Kathryn A., Runyan, Constance E., Abdala-Valencia, Hiam, Nam, Kiwon, Meliton, Angelo Y., Winter, Deborah R., Morimoto, Richard I., Mutlu, Gokhan M., Bharat, Ankit, Perlman, Harris, Gottardi, Cara J., Ridge, Karen M., Chandel, Navdeep S., Sznajder, Jacob I., Balch, William E., Singer, Benjamin D., Misharin, Alexander V., and Budinger, G.R. Scott
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Lung diseases -- Genetic aspects -- Risk factors ,Age factors in disease -- Genetic aspects ,Macrophages -- Genetic aspects -- Health aspects ,Health care industry - Abstract
Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging., Introduction Advanced age is the most important risk factor for severe disease or death in patients with viral pneumonia, including coronavirus disease 2019 (COVID-19) (1,2). Alveolar macrophages play central roles [...]
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- 2021
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4. Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection
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Peteranderl, Christin, Morales-Nebreda, Luisa, Selvakumar, Balachandar, Lecuona, Emilia, Vadasz, Istvan, Morty, Rory E., Schmoldt, Carole, Bespalowa, Julia, Wolff, Thorsten, Pleschka, Stephan, Mayer, Konstantin, Gattenloehner, Stefan, Fink, Ludger, Lohmeyer, Juergen, Seeger, Werner, Sznajder, Jacob I., Mutlu, Gokhan M., Budinger, G.R. Scott, and Herold, Susanne
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Lung diseases -- Genetic aspects -- Development and progression ,Adenosine triphosphatase -- Properties ,Influenza -- Physiological aspects ,Health care industry - Abstract
Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis-inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury., Introduction Influenza A viruses (IAV) infect cells in the alveolus and induce primary viral pneumonia, which can progress to acute respiratory distress syndrome (ARDS) with high mortality (1). IAV-induced lung [...]
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- 2016
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5. -adrenergic agonists augment air pollution-induced IL-6 release and thrombosis
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Chiarella, Sergio E., Soberanes, Saul, Urich, Daniela, Morales-Nebreda, Luisa, Nigdelioglu, Recep, Green, David, Young, James B., Gonzalez, Angel, Rosario, Carmen, Misharin, Alexander V., Ghio, Andrew J., Wunderink, Richard G., Donnelly, Helen K., Radigan, Kathryn A., Perlman, Harris, Chandel, Navdeep S., Budinger, G.R. Scott, and Mutlu, Gokhan M.
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Interleukin-6 -- Properties ,Physiological research ,Immune response -- Research ,Particles -- Properties ,Catecholamines -- Identification and classification ,Health care industry - Abstract
Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the [β.sub.2]-adrenergic receptor ([β.sub.2]AR) on murine alveolar macrophages and augment the release of IL-6. In mice, [β.sub.2]AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a [β.sub.2]AR agonist augmented IL-6 release, while the addition of a beta blocker inhibited PM-induced IL-6 release. Genetic loss or pharmacologic inhibition of the [β.sub.2]AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous [β.sub.2]AR agonist therapy further augmented these responses in alveolar macrophages through generation of mitochondrial ROS and subsequent increase of adenylyl cyclase activity. Together, these results link the activation of the sympathetic nervous system by [β.sub.2]AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events., Introduction Based on air pollution exposure estimates in the US from the late 1970s to the early 2000s, Pope et al. projected that a 10 µg/[m.sup.3] fall in the mean [...]
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- 2014
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6. Lung-Specific Loss of α3 Laminin Worsens Bleomycin-Induced Pulmonary Fibrosis
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Morales-Nebreda, Luisa I., Rogel, Micah R., Eisenberg, Jessica L., Hamill, Kevin J., Soberanes, Saul, Nigdelioglu, Recep, Chi, Monica, Cho, Takugo, Radigan, Kathryn A., Ridge, Karen M., Misharin, Alexander V., Woychek, Alex, Hopkinson, Susan, Perlman, Harris, Mutlu, Gokhan M., Pardo, Annie, Selman, Moises, Jones, Jonathan C.R., and Budinger, Scott G.R.
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- 2015
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7. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
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Weinberg, Frank, Hamanaka, Robert, Wheaton, William W., Weinberg, Samuel, Joseph, Joy, Lopez, Marcos, Kalyanaraman, Balaraman, Mutlu, Gokhan M., Budinger, G.R. Scott, and Chandel, Navdeep S.
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Carcinogenesis -- Physiological aspects ,Carcinogenesis -- Genetic aspects ,Carcinogenesis -- Research ,Cell metabolism -- Physiological aspects ,Cell metabolism -- Genetic aspects ,Mitochondria -- Physiological aspects ,Mitochondria -- Genetic aspects ,Reactive oxygen species -- Physiological aspects ,Reactive oxygen species -- Research ,Science and technology - Abstract
Otto Warburg's theory on the origins of cancer postulates that tumor cells have defects in mitochondrial oxidative phosphorylation and therefore rely on high levels of aerobic glycolysis as the major source of ATP to fuel cellular proliferation (the Warburg effect). This is in contrast to normal cells, which primarily utilize oxidative phosphorylation for growth and survival. Here we report that the major function of glucose metabolism for Kras-induced anchorage-independent growth, a hallmark of transformed cells, is to support the pentose phosphate pathway. The major function of glycolytic ATP is to support growth under hypoxic conclitions. Glutamine conversion into the tricarboxylic acid cycle intermediate alpha-ketoglutarate through glutaminase and alanine aminotransferase is essential for Kras-induced anchorage-independent growth. Mitochondrial metabolism allows for the generation of reactive oxygen species (ROS) which are required for Kras-induced anchorage-independent growth through regulation of the ERK MAPK signaling pathway. We show that the major source of ROS generation required for anchorage-independent growth is the Qo site of mitochondrial complex III. Furthermore, disruption of mitochondrial function by Ioss of the mitochondrial transcription factor A (TFAM) gene reduced tumorigenesis in an oncogenic Kras-driven mouse model of lung cancer. These results demonstrate that mitochondrial metabolism and mitochondrial ROS generation are essential for Kras-induced cell proliferation and tumorigenesis. Warburg Effect | glutamine | glycolysis | lung cancer | complex III doi/10.1073/pnas.1003428107
- Published
- 2010
8. Ambient particulate matter accelerates coagulation via an IL-6-dependent pathway
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Mutlu, Gokhan M., Green, David, Bellmeyer, Amy, Baker Christina M., Burgess, Zach, Rajamannan, Nalini, Christman, John W., Foiles, Nancy, Kamp, David W., Ghio, Andrew J., Chandel, Navdeep S., Dean, David A., Sznajder, Jacob I., and Budinger, G.R. Scott
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Cardiovascular diseases -- Risk factors ,Cardiovascular diseases -- Research ,Particles -- Complications and side effects ,Particles -- Genetic aspects ,Particles -- Research - Abstract
The mechanisms by which exposure to particulate matter increases the risk of cardiovascular events are not known. Recent human and animal data suggest that particulate matter may induce alterations in [...]
- Published
- 2007
9. Proapoptotic Bid is required for pulmonary fibrosis
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Budinger, G.R. Scott, Mutlu, Gokhan M., Eisenbart, James, Fuller, Alyson C., Bellmeyer, Amy A., Baker, Christina M., Wilson, Mindy, Ridge, Karen, Barrett, Terrence A., Lee, Vivian Y., and Chandel, Navdeep S.
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Apoptosis -- Research ,Bleomycin -- Dosage and administration ,Pulmonary fibrosis -- Care and treatment ,Pulmonary fibrosis -- Research ,Rats -- Research ,Rattus -- Research ,Science and technology - Abstract
The molecular mechanisms of pulmonary fibrosis are poorly understood. Previous reports indicate that activation of TGF-[beta]1 is essential for the development of pulmonary fibrosis. Here, we report that the proapoptotic Bcl-2 family member Bid is required for the development of pulmonary fibrosis after the intratracheal instillation of bleomycin. Mice lacking Bid exhibited significantly less pulmonary fibrosis in response to bleomycin compared with WT mice. The attenuation in pulmonary fibrosis was observed despite similar levels of inflammation, lung injury, and active TGF-[beta]1 in bronchoalveolar lavage fluid 5 days after the administration of bleomycin in mice lacking Bid and in WT controls. Bleomycin induced similar levels cell death in vitro in alveolar epithelial cells isolated from WT and [bid.sup.-/-] mice. By contrast, alveolar epithelial cells from [bid.sup.-/-] mice were resistant to TGF-[beta]1-induced cell death. These results indicate that Bcl-2 family members are critical regulators for the development of pulmonary fibrosis downstream of TGF-[beta]1 activation. apoptosis | Bcl-2 | TGF-[beta]
- Published
- 2006
10. Mechanisms of pulmonary edema clearance
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Mutlu, Gokhan M. and Sznajder, Jacob I.
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Pulmonary edema -- Care and treatment ,Pulmonary edema -- Physiological aspects ,Biological sciences - Abstract
The mechanisms of pulmonary edema resolution are different from those regulating edema formation. Absorption of excess alveolar fluid is an active process that involves vectorial transport of [Na.sup.+] out of alveolar air spaces with water following the [Na.sup.+] osmotic gradient. Active [Na.sup.+] transport across the alveolar epithelium is regulated via apical [Na.sup.+] and chloride channels and basolateral Na-K-ATPase in normal and injured lungs. During lung injury, mechanisms regulating alveolar fluid reabsorption are inhibited by yet unclear pathways and can be upregulated by pharmacological means. Better understanding of the mechanisms that regulate edema clearance may lead to therapeutic interventions to improve the ability of lungs to clear fluid, which is of clinical significance. acute lung injury; acute respiratory distress syndrome; alveolar epithelium; alveoli lung
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- 2005
11. Role of vasopressin in the management of septic shock
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Mutlu, Gokhan M. and Factor, Phillip
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Septic shock -- Drug therapy ,Vasopressin -- Dosage and administration ,Health care industry - Abstract
Byline: Gokhan M. Mutlu (1), Phillip Factor (2) Keywords: Vasopressin; Sepsis; Septic shock; Catecholamine; Norepinephrine Abstract: Vasopressin is a potent vasopressor for improving organ perfusion during septic shock. The rationale for the use of vasopressin is its relative deficiency of plasma levels and hypersensitivity to its vasopressor effects during septic shock. Growing evidence suggests that low-dose ( Author Affiliation: (1) Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Tarry 14--707, Chicago, IL 60611, USA (2) Pulmonary, Allergy and Critical Care Medicine, Columbia University College of Physicians and Surgeons, Room P&S 10-502, 630 W. 168th Street, New York, NY 10032, USA Article History: Registration Date: 12/03/2004 Online Date: 21/04/2004 Article note: This work was supported by the American Heart Association, HL-66211, and the Evanston Northwestern Healthcare Research Institute.
- Published
- 2004
12. Alveolar Epithelial β2-Adrenergic Receptors
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Mutlu, Gokhan M. and Factor, Phillip
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- 2008
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13. Incidence and Outcomes of Acute Lung Injury
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Mutlu, Gokhan M. and Budinger, G.R. Scott
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- 2006
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14. Splenic and Mediastinal Calcifications in Histoplasmosis
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Topin, Jeremy and Mutlu, Gokhan M.
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- 2006
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15. Pulmonary adverse events of anti-tumor necrosis factor-[alpha] antibody therapy
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Mutlu, Gokhan M., Mutlu, Ece A., Bellmeyer, Amy, and Rubinstein, Israel
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Rheumatoid arthritis -- Drug therapy ,Crohn's disease -- Drug therapy ,Tumor necrosis factor -- Research ,Tumor necrosis factor -- Health aspects ,Tuberculosis -- Development and progression ,Health ,Health care industry - Abstract
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjmed.2006.01.015 Byline: Gokhan M. Mutlu (a), Ece A. Mutlu (b), Amy Bellmeyer (a), Israel Rubinstein (c) Keywords: Rheumatoid arthritis; Crohn's disease; Sarcoidosis; Tuberculosis; Fungi Abstract: It is well established that anti-tumor necrosis factor-[alpha] (TNF[alpha]) antibody is an efficacious disease-modifying drug for rheumatoid arthritis and Crohn's disease. Unfortunately, its long-term use can be associated with ominous pulmonary adverse events, most notably mycobacterial and fungal lung infections. To this end, reactivation of latent tuberculosis infection represents a serious concern of anti-TNF[alpha] antibody therapy. Given the anticipated increase in the approved indications for these drugs, community-based physicians should be made aware of these events for implementation of better patient selection for anti-TNF[alpha] antibody therapy and initiation of appropriate measures once these adverse events are observed. This review will address this issue by outlining: 1) the role of TNF[alpha] in host inflammatory response to injury, particularly during mycobacterial and fungal infections; 2) the salutary effects of anti-TNF[alpha] antibody therapy in human diseases; and 3) the ominous pulmonary adverse events associated with these drugs. Author Affiliation: (a) Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill (b) Departments of Gastroenterology and Nutrition, Rush University Medical College, Chicago, Ill (c) Pulmonary, Critical Care and Sleep Medicine, University of Illinois at Chicago and Jesse Brown Veterans Administration Medical Center, Chicago, Ill Article Note: (footnote) This work was supported in part by the American Lung Association, and the American Lung Association of Metropolitan Chicago (G.M.M.), National Institute of Diabetes & Digestive & Kidney Diseases (E.A.M.), National Institute on Aging and Veterans Administration (I.R.).
- Published
- 2006
16. A 41-year-old man with altered mental status and acute flaccid paralysis *
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Mutlu, Gokhan M., Kuzniar, Tomasz, and Factor, Phillip
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West Nile fever -- Diagnosis -- Care and treatment -- Risk factors ,Paralysis -- Risk factors -- Care and treatment -- Diagnosis ,Health ,Diagnosis ,Care and treatment ,Risk factors - Abstract
A41-year-old man with a history of thymoma resection was admitted to the hospital with a 3-week history of generalized body aches and fever during late summer. He also reported severe [...]
- Published
- 2005
17. Risk assessment for inpatient survival in the long-term acute care setting after prolonged critical illness *
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D'Amico, Jane E. Dematte, Donnelly, Helen K., Mutlu, Gokhan M., Feinglass, Joseph, Jovanovic, Borko D., and Ndukwu, Ikeadi Maurice
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Outcome and process assessment (Health Care) -- Evaluation ,Long-term care of the sick -- Evaluation ,Statistics ,Health risk assessment -- Evaluation ,Health ,Evaluation - Abstract
Objective: The past decade has witnessed growth in the long-term acute care (LTAC) hospital industry. There are no reliable risk assessment models that can adjust outcomes across such facilities with [...]
- Published
- 2003
18. An unresponsive biochemistry professor in the bathtub *. (pulmonary and critical care pearls)
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Mutlu, Gokhan M., Leikin, Jerrold B., Oh, Kyong, and Factor, Phillip
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Self-poisoning -- Care and treatment -- Physiological aspects ,Health ,Care and treatment ,Physiological aspects - Abstract
An 83-year-old retired biochemistry professor was found by his wife unresponsive in his bathtub approximately 60 min after their last conversation. She found him lying upright in the empty bathtub, [...]
- Published
- 2002
19. Acute-onset quadriplegia, respiratory failure, and ventricular tachycardia in a 21-year-old man following a soccer match *. (pulmonary and critical care pearls)
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Mutlu, Gokhan M. and Factor, Phillip
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Respiratory insufficiency -- Causes of -- Diagnosis ,Quadriplegia -- Causes of -- Diagnosis ,Familial periodic paralysis -- Diagnosis ,Ventricular tachycardia -- Causes of -- Diagnosis ,Health ,Diagnosis ,Causes of - Abstract
A 21-year old man was brought to the emergency department (ED) with complaints of acute, progressive generalized weakness and deteriorating mental status. The patient was well until 4 h prior [...]
- Published
- 2002
20. Current management strategies: New vasodilators and genetic therapies are being investigated
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Mutlu, Gokhan M. and Rubinstein, Israel
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Pulmonary hypertension -- Care and treatment ,Health ,Care and treatment - Abstract
ABSTRACT: Management of pulmonary hypertension (PH) includes not only treatment of PH itself but also specific therapy for any underlying cause. An empiric trial with a vasodilator, such as nitric [...]
- Published
- 2001
21. Laryngospasm and Paradoxical Bronchoconstriction After Repeated Doses of β2-Agonists Containing Edetate Disodium
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Mutlu, Gokhan M., Moonjelly, Elizabeth, Chan, Lingtak, and Olopade, Christopher O.
- Published
- 2000
22. Cerebrospinal fluid leak and meningitis associated with nasal continuous positive airway pressure therapy *
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Kuzniar, Tomasz J., Gruber, Benjamin, and Mutlu, Gokhan M.
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Sleep apnea syndromes -- Risk factors ,Sleep apnea syndromes -- Care and treatment ,Sleep apnea syndromes -- Case studies ,Cerebrospinal fluid -- Research ,Health - Abstract
Clear rhinorrhea is a common symptom in patients with obstructive sleep apnea (OSA) and may worsen with continuous positive airway pressure therapy. Clear rhinorrhea can also be the presenting symptom [...]
- Published
- 2005
23. A man with cough and dyspnea
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Breault, Daniel J., Mutlu, Gokhan M., Vescio, Thomas M., and Kuzniar, Tomasz J.
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Bacterial pneumonia -- Complications and side effects -- Case studies -- Care and treatment -- Diagnosis -- Risk factors -- Drug therapy ,Pneumonia -- Complications and side effects -- Case studies -- Care and treatment -- Diagnosis -- Risk factors -- Drug therapy ,Blastomycosis -- Drug therapy -- Complications and side effects -- Diagnosis -- Risk factors -- Case studies -- Care and treatment ,Antibiotics -- Dosage and administration -- Case studies -- Complications and side effects ,Acute respiratory distress syndrome -- Risk factors -- Diagnosis -- Care and treatment -- Case studies -- Drug therapy -- Complications and side effects ,Health - Abstract
The case presented here illustrates the diagnostic challenges and potential severity of a fungal infection. The case A 53-year-old man with a history of hypercholesterolemia presented to the hospital with [...]
- Published
- 2008
24. Pulmonary hypertension, part 1: The diagnostic workup
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MUTLU, GOKHAN M. and RUBINSTEIN, ISRAEL
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Pulmonary hypertension -- Diagnosis ,Health ,Diagnosis - Abstract
ABSTRACT: Pulmonary hypertension (PH) can be idiopathic, but most cases are secondary to pulmonary and cardiac diseases and triggers, such as toxins. The most common presenting symptom is dyspnea during [...]
- Published
- 2001
25. GI Complications in Patients Receiving Mechanical Ventilation(*)
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Mutlu, Gokhan M., Mutlu, Ece A., and Factor, Phillip
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Ventilators ,Gastrointestinal diseases -- Risk factors -- Complications and side effects ,Health ,Complications and side effects ,Risk factors - Abstract
Mechanical ventilation (MV) can be lifesaving by maintaining gas exchange until the underlying disorders are corrected, but it is associated with numerous organ-system complications, which can significantly affect the outcome [...]
- Published
- 2001
26. The Saga of obstructive sleep apnea syndrome and daytime hypercapnia: work in progress
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Mutlu, Gokhan M. and Rubinstein, Israel
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Hypercapnia -- Risk factors -- Diagnosis -- Care and treatment ,Sleep apnea syndromes -- Risk factors -- Diagnosis -- Care and treatment ,Health ,Diagnosis ,Care and treatment ,Risk factors - Abstract
The current body of clinical evidence suggests that the majority of patients with obstructive sleep apnea syndrome (OSAS) are eucapnic during wakefulness, and that detection of daytime hypercapnia attests to [...]
- Published
- 2005
27. Exhaled breath condensate: current knowledge and potential applications. (Clinical Consultation)
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Mutlu, Gokhan M. and Rubinstein, Israel
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Respiratory tract diseases -- Diagnosis ,Breath tests -- Usage ,Health ,Diagnosis ,Usage - Abstract
A number of reports suggest that the analysis of exhaled breath condensate provides information about the lower respiratory tract. Do you expect this to be clinically useful? If so, in [...]
- Published
- 2002
28. Enhancement of alveolar epithelial [β.sub.2]-Adrenergic receptor function via gene transfer *
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Factor, Phillip, Azzam, Zaher A., Mutlu, Gokhan M., Sznajder, Jacob I., and Dumasius, Vidas
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Gene therapy -- Research ,Pulmonary edema -- Care and treatment -- Research ,Health ,Care and treatment ,Research - Abstract
Abbreviations: ad[β.sub.2]2AR = first generation recombinant adenovirus that expresses a human [β.sub.2]-adrenergic receptor complementary DNA; adNull = first generation recombinant adenovirus that expresses no complementary DNA; AFC = alveolar fluid [...]
- Published
- 2002
29. Acute lung injury does not impair adenoviral-mediated gene transfer to the alveolar epithelium *
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Dumasius, Vidas, Mendez, Michael, Mutlu, Gokhan M., and Factor, Phillip
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Lungs -- Injuries -- Research ,Genetic transformation -- Research ,Health ,Research ,Injuries - Abstract
Abbreviations: adβ-gal = first-generation human type 5 recombinant adenovirus that expresses an e. coli lac z gene; adnull = first generatoin human type 5 recombinant adenovirus that expresses no cDNA; [...]
- Published
- 2002
30. Oxidized phospholipids protect against lung injury and endothelial barrier dysfunction caused by heat-inactivated Staphylococcus aureus.
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Meliton, Angelo Y., Fanyong Meng, Yufeng Tian, Sarich, Nicolene, Mutlu, Gokhan M., Birukova, Anna A., and Birukov, Konstantin G.
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ENDOTHELIAL cells ,LUNG injuries ,LIPOPOLYSACCHARIDES ,STAPHYLOCOCCUS aureus ,CELL adhesion molecules - Abstract
Increased endothelial cell (EC) permeability and vascular inflammation along with alveolar epithelial damage are key features of acute lung injury (ALI). Products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine oxidation (OxPAPC) showed protective effects against inflammatory signaling and vascular EC barrier dysfunction induced by gram-negative bacterial wall lipopolysaccharide (LPS). We explored the more general protective effects of OxPAPC and investigated whether delayed posttreatment with OxPAPC boosts the recovery of lung inflammatory injury and EC barrier dysfunction triggered by intratracheal injection of heat-killed gram-positive Staphylococcus aureus (HKSA) bacteria. HKSA-induced pulmonary EC permeability, activation of p38 MAP kinase and NF-κB inflammatory cascades, secretion of IL-8 and soluble ICAM1, fibronectin deposition, and expression of adhesion molecules ICAM1 and VCAM1 by activated EC were significantly attenuated by cotreatment as well as posttreatment with OxPAPC up to 16 h after HKSA addition. Remarkably, posttreatment with OxPAPC up to 24 h post-HKSA challenge dramatically accelerated lung recovery by restoring lung barrier properties monitored by Evans blue extravasation and protein content in bronchoalveolar lavage (BAL) fluid and reducing inflammation reflected by decreased MIP-1, KC, TNF-α, IL-13 levels and neutro-phil count in BAL samples. These studies demonstrate potent in vivo and in vitro protective effects of posttreatment with anti-inflammatory oxidized phospholipids in the model of ALI caused by HKSA. These results warrant further investigations into the potential use of OxPAPC compounds combined with antibiotic therapies as a treatment of sepsis and ALI induced by gram-positive bacterial pathogens. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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31. Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction.
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Fanyong Meng, Meliton, Angelo, Moldobaeva, Nurgul, Mutlu, Gokhan, Kawasaki, Yoshihiro, Akiyama, Tetsu, and Birukova, Anna A.
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HEPATOCYTE growth factor ,LIPOPOLYSACCHARIDES ,LUNG injuries ,RESPIRATORY distress syndrome ,GUANINE nucleotide exchange factors ,CELL adhesion - Abstract
Increased vascular endothelial permeability and inflammation are major pathological mechanisms of pulmonary edema and its life-threatening complication, the acute respiratory distress syndrome (ARDS). We have previously described potent protective effects of hepatocyte growth factor (HGF) against thrombin-induced hyperpermeability and identified the Rac pathway as a key mechanism of HGF-mediated endothelial barrier protection. However, anti-inflammatory effects of HGF are less understood. This study examined effects of HGF on the pulmonary endothelial cell (EC) inflammatory activation and barrier dysfunction caused by the gram-negative bacterial pathogen lipopolysaccharide (LPS). We tested involvement of the novel Rac-specific guanine nucleotide exchange factor Asef in the HGF anti-inflammatory effects. HGF protected the pulmonary EC monolayer against LPS-induced hyperpermeability, disruption of monolayer integrity, activation of NF-kB signaling, expression of adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and production of IL-8. These effects were critically dependent on Asef. Small-interfering RNA-induced downregulation of Asef attenuated HGF protective effects against LPS-induced EC barrier failure. Protective effects of HGF against LPS-induced lung inflammation and vascular leak were also diminished in Asef knockout mice. Taken together, these results demonstrate potent anti-inflammatory effects by HGF and delineate a key role of Asef in the mediation of the HGF barrier protective and anti-inflammatory effects. Modulation of Asef activity may have important implications in therapeutic strategies aimed at the treatment of sepsis and acute lung injury/ARDS-induced gram-negative bacterial pathogens. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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32. Reply to Dunser et al
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Mutlu, Gokhan M. and Factor, Phillip
- Subjects
Health care industry - Abstract
Byline: Gokhan M. Mutlu (1), Phillip Factor (2) Author Affiliation: (1) Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, 240 E. Huron, Chicago, IL, 60614, USA (2) Pulmonary, Allergy, and Critical Care Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA Article History: Registration Date: 09/07/2004 Accepted Date: 08/07/2004 Online Date: 23/07/2004
- Published
- 2004
33. How to minimize GI events in mechanically ventilated patients. (In Consultation)
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Mutlu, Gokhan M. and Factor, Phillip
- Subjects
Gastrointestinal system -- Injuries ,Ventilators ,Medicine ,Health - Abstract
What are the most common GI complications associated with mechanical ventilation? What prophylactic measures do you recommend? The dynamic interaction between mechanical ventilation and the GI tract is responsible for [...]
- Published
- 2002
34. Intermittent Hypoxia Attenuates and Reverses Epinephrine‐Induced Changes in Gene Expression in Endothelial Cells.
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Cetin‐Atalay, Rengul, Meliton, Angelo Y., Sun, Kaitlyn A., Woods, Parker S., Peng, Ying‐Jie, Fang, Yun, Hamanaka, Robert B., Prabhakar, Nanduri R., and Mutlu, Gokhan M.
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- 2022
- Full Text
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35. Fatal Acute Cor Pulmonale From Primary Peritoneal Tumor Microemboli
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McNamara, David, Smith, Sean, Bertsch, Elizabeth, and Mutlu, Gokhan
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- 2013
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36. S1785 Exposure to Ambient Particulate Matter Causes Oxidant-Mediated Increase in Gut Permeability in Mice
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Mutlu, Ece, Engen, Phillip, Soberanes, Saul, Urich, Daniela, Gonzalez, Angel R., Nigdelioglu, Recep, Chiarella, Sergio E., Forsyth, Christopher B., Scott Budinger, GR, and Mutlu, Gokhan M.
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- 2010
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37. EFFECT OF AMBIENT PARTICULATE MATTER IN ALVEOLAR EPITHELIAL TIGHT JUNCTIONS AND LUNG INFLAMMATION
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Caraballo, Juan C., Westphal, Whitney, Yshii, Cecilia, Urich, Daniela, Soberanes, S, Mutlu, Gokhan M., Budinger, G R, and Comellas, Alejandro P.
- Published
- 2009
- Full Text
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38. Laryngospasm and Paradoxical Bronchoconstriction After Repeated Doses of β 2- Agonists Containing Edetate Disodium
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Mutlu, Gokhan M., Moonjelly, Elizabeth, Chan, Lingtak, and Olopade, Christopher O.
- Published
- 2000
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39. AIRBORNE PARTICLES ALTER THE ALVEOLAR EPITHELIAL BARRIER VIA A DECREASE IN THE TIGHT JUNCTION PROTEIN OCCLUDIN
- Author
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Yshii, Cecilia H., Butti, Maria L., Urich, Daniela, Mutlu, Gokhan, Budinger, GR S., and Comellas, Alejandro P.
- Published
- 2007
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- View/download PDF
40. Increased alveolar adenosine levels downregulate pulmonary edema clearance during hyperoxic acute lung injury
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Mutlu, Gokhan M., Martino, Janice M., Balagani, Rajesh, Dumasius, Vidas, Albazi, Sargon J., and Factor, Phillip
- Published
- 2004
- Full Text
- View/download PDF
41. INCREASED INTERLEUKIN-15 PRODUCING CELLS IN HUMAN LUNG ALLOGRAFT REJECTION.
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Jaffe, H. Ari, Mutlu, Gokhan M., Sekosan, Marin, Yoder, Mark A., Steinhiser, Sally A., Chan, Lingtak N., Geha, Alexander S., and Massad, Malik
- Published
- 2000
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42. Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1.
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Radigan, Kathryn A., Nicholson, Trevor T., Welch, Lynn C., Chi, Monica, Masahiko Shigemura, Atsuko Shigemura, Runyan, Constance E., Morales-Nebreda, Luisa, Perlman, Harris, Ceco, Ermelinda, Lecuona, Emilia, Dada, Laura A., Misharin, Alexander V., Sznajder, Jacob I., Budinger, G. R. Scott, Amarelle, Luciano, Angulo, Martín, and Mutlu, Gokhan M.
- Abstract
Muscle dysfunction is common in patients with adult respiratory distress syndrome and is associated with morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary for the development of muscle dysfunction. Treatment with a Food and Drug Administration-approved Ab antagonist to the IL-6R (tocilizumab) attenuated the severity of influenza A-induced muscle dysfunction. In cultured myotubes, IL-6 promoted muscle degradation via JAK/STAT, FOXO3a, and atrogin-1 upregulation. Consistent with these findings, atrogin-1+/- and atrogin-1-/- mice had attenuated muscle dysfunction following influenza infection. Our data suggest that inflammatory endocrine signals originating from the injured lung activate signaling pathways in the muscle that induce dysfunction. Inhibiting these pathways may limit morbidity in patients with influenza A pneumonia and adult respiratory distress syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
43. Mitochondrial Reactive Oxygen Species Regulate Transforming Growth Factor-β Signaling.
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Jain, Manu, Rivera, Stephanie, Monclus, Elena A., Synenki, Lauren, Zirk, Aaron, Eisenbart, James, Feghali-Bostwick, Carol, Mutlu, Gokhan M., Budinger, G. R. Scott, and Chandel, Navdeep S.
- Subjects
- *
MITOCHONDRIA , *REACTIVE oxygen species , *TRANSFORMING growth factors , *NADPH oxidase , *GENE expression , *FIBROBLASTS - Abstract
TGF-β signaling is required for normal tissue repair; however, excessive TGF-β signaling can lead to robust profibrotic gene expression in fibroblasts, resulting in tissue fibrosis. TGF-βbindsto cell-surface receptors, resulting inthephosphorylation of the Smad family of transcription factors to initiate gene expression. TGF-β also initiates Smad-independent pathways, which augment gene expression. Here, we report that mitochondrial reactive oxygen species (ROS) generated at complex III are required for TGF-β-induced gene expression in primary normal human lung fibroblasts. TGF-β-induced ROS could be detected in both the mitochondrial matrix and cytosol. Mitochondrially targeted antioxidants markedly attenuated TGF-β-induced gene expression without affecting Smad phosphorylation or nuclear translocation. Genetically disrupting mitochondrial complex III-generated ROS production attenuated TGF-β-induced profibrotic gene expression. Furthermore, inhibiting mitochondrial ROS generation attenuated NOX4 (NADPH oxidase 4) expression, which is required for TGF-β induced myofibroblast differentiation. Lung fibroblasts from patients with pulmonary fibrosis generated more mitochondrial ROS than normal human lung fibroblasts, and mitochondrially targeted antioxidants attenuated profibrotic gene expression in both normal and fibrotic lung fibroblasts. Collectively, our results indicate that mitochondrial ROS are essential for normal TGF-β-mediated gene expression and that targeting mitochondrial ROS might be beneficial in diseases associated with excessive fibrosis. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
44. SARS-CoV-2 infection reduces Krüppel-Like Factor 2 in human lung autopsy.
- Author
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Lee TH, Wu D, Guzy R, Schoettler N, Adegunsoye A, Mueller J, Hussein A, Sperling A, Mutlu GM, and Fang Y
- Abstract
Acute respiratory distress syndrome (ARDS) occurred in ~12% of hospitalized COVID-19 patients in a recent New York City cohort. Pulmonary endothelial dysfunction, characterized by increased expression of inflammatory genes and increased monolayer permeability, is a major component of ARDS. Vascular leak results in parenchymal accumulation of leukocytes, protein, and extravascular water, leading to pulmonary edema, ischemia, and activation of coagulation associated with COVID-19. Endothelial inflammation further contributes to uncontrolled cytokine storm in ARDS. We have recently demonstrated that Kruppel-like factor 2 (KLF2), a transcription factor which promotes endothelial quiescence and monolayer integrity, is significantly reduced in experimental models of ARDS. Lung inflammation and high-tidal volume ventilation result in reduced KLF2, leading to pulmonary endothelial dysfunction and acute lung injury. Mechanistically, we found that KLF2 is a potent transcriptional activator of Rap guanine nucleotide exchange factor 3 (RAPGEF3) which orchestrates and maintains vascular integrity. Moreover, KLF2 regulates multiple genome-wide association study (GWAS)-implicated ARDS genes. Whether lung KLF2 is regulated by SARS-CoV-2 infection is unknown. Here we report that endothelial KLF2 is significantly reduced in human lung autopsies from COVID-19 patients, which supports that ARDS due to SARS-CoV-2 is a vascular phenotype possibly attributed to KLF2 down-regulation. We provide additional data demonstrating that KLF2 is down-regulated in SARS-CoV infection in mice.
- Published
- 2021
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- View/download PDF
45. IL6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections.
- Author
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Kimmig LM, Wu D, Gold M, Pettit NN, Pitrak D, Mueller J, Husain AN, Mutlu EA, and Mutlu GM
- Abstract
Background: Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and predispose to secondary infections., Methods: We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution., Results: 111 patients were identified, of which 54 had received tocilizumab while 57 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (48.1% vs. 28.1%, p=0.029 and fungal (5.6% vs. 0%, p=0.112) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (35.2% vs. 19.3%, p=0.020). Seven cases underwent autopsy. In 3 cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the 4 cases that had not been given tocilizumab, 2 showed evidence of aspiration pneumonia and 2 exhibited diffuse alveolar damage., Conclusions: Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, predispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.
- Published
- 2020
- Full Text
- View/download PDF
46. P311 Promotes Lung Fibrosis via Stimulation of Transforming Growth Factor-β1, -β2, and -β3 Translation.
- Author
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Duan FF, Barron G, Meliton A, Mutlu GM, Dulin NO, and Schuger L
- Subjects
- Animals, Bleomycin, Case-Control Studies, Collagen genetics, Collagen metabolism, Disease Models, Animal, Fibroblasts metabolism, Humans, Idiopathic Pulmonary Fibrosis metabolism, Idiopathic Pulmonary Fibrosis pathology, Male, Mice, Inbred C57BL, Mice, Knockout, Protein Biosynthesis, Pulmonary Fibrosis chemically induced, Pulmonary Fibrosis genetics, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Transforming Growth Factor beta2 genetics, Transforming Growth Factor beta2 metabolism, Transforming Growth Factor beta3 genetics, Transforming Growth Factor beta3 metabolism, Fibroblasts pathology, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Oncogene Proteins metabolism, Pulmonary Fibrosis pathology
- Abstract
Interstitial lung fibrosis, a frequently idiopathic and fatal disease, has been linked to the increased expression of profibrotic transforming growth factor (TGF)-βs. P311 is an RNA-binding protein that stimulates TGF-β1, -β2, and -β3 translation in several cell types through its interaction with the eukaryotic translation initiation factor 3b. We report that P311 is switched on in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and in the mouse model of bleomycin (BLM)-induced pulmonary fibrosis. To assess the in vivo role of P311 in lung fibrosis, BLM was instilled into the lungs of P311-knockout mice, in which fibrotic changes were significantly decreased in tandem with a reduction in TGF-β1, -β2, and -β3 concentration/activity compared with BLM-treated wild-type mice. Complementing these findings, forced P311 expression increased TGF-β concentration/activity in mouse and human lung fibroblasts, thereby leading to an activated phenotype with increased collagen production, as seen in IPF. Consistent with a specific effect of P311 on TGF-β translation, TGF-β1-, -β2-, and -β3-neutralizing antibodies downregulated P311-induced collagen production by lung fibroblasts. Furthermore, treatment of BLM-exposed P311 knockouts with recombinant TGF-β1, -β2, and -β3 induced pulmonary fibrosis to a degree similar to that found in BLM-treated wild-type mice. These studies demonstrate the essential function of P311 in TGF-β-mediated lung fibrosis. Targeting P311 could prove efficacious in ameliorating the severity of IPF while circumventing the development of autoimmune complications and toxicities associated with the use of global TGF-β inhibitors.
- Published
- 2019
- Full Text
- View/download PDF
47. African-American race and mortality in interstitial lung disease: a multicentre propensity-matched analysis.
- Author
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Adegunsoye A, Oldham JM, Bellam SK, Chung JH, Chung PA, Biblowitz KM, Montner S, Lee C, Hsu S, Husain AN, Vij R, Mutlu G, Noth I, Churpek MM, and Strek ME
- Subjects
- Adult, Aged, Cause of Death, Female, Humans, Logistic Models, Lung Diseases, Interstitial ethnology, Male, Middle Aged, Multivariate Analysis, Propensity Score, Retrospective Studies, United States, Black or African American, Hospitalization statistics & numerical data, Lung Diseases, Interstitial mortality
- Abstract
We studied whether African-American race is associated with younger age and decreased survival time at diagnosis of interstitial lung disease (ILD).We performed a multicentre, propensity score-matched analysis of patients with an ILD diagnosis followed at five US hospitals between 2006 and 2016. African-Americans were matched with patients of other races based on a time-dependent propensity score calculated from multiple patient, physiological, diagnostic and hospital characteristics. Multivariable logistic regression models were used. All-cause mortality and hospitalisations were compared between race-stratified patient cohorts with ILD, and sensitivity analyses were performed.The study included 1640 patients with ILD, 13% of whom were African-American, followed over 5041 person-years. When compared with patients of other races, African-Americans with ILD were younger at diagnosis (56 years versus 67 years), but in the propensity-matched analyses had greater survival (hazard ratio 0.46, 95% CI 0.28-0.77; p=0.003) despite similar risk of respiratory hospitalisations (relative risk 1.04, 95% CI 0.83-1.31; p=0.709), and similar GAP-ILD (gender-age-physiology-ILD) scores at study entry. Sensitivity analyses in a separate cohort of 9503 patients with code-based ILD diagnosis demonstrated a similar association of baseline demographic characteristics with all-cause mortality.We conclude that African-Americans demonstrate a unique phenotype associated with younger age at ILD diagnosis and perhaps longer survival time., Competing Interests: Conflict of interest: R. Vij received a grant from Genentech to study the genomics of autoimmune interstitial lung diseases. Conflict of interest: I. Noth received honoraria for advisory boards from Boehringer Ingelheim, InterMune and Anthera within the last 12 months related to IPF. He has also received speaking honoraria from GSK and consulting fees for Immuneworks. He also has study contracts with the NIH, Stromedix, Sanofi and BI for the conduct of clinical trials in IPF. Conflict of interest: M.M. Churpek is supported by a career development award from the National Heart, Lung, and Blood Institute (K08 HL121080), has received honoraria from Chest for invited speaking engagements and also has a patent pending (ARCD.P0535US.P2) for risk stratification algorithms for hospitalised patients. Conflict of interest: M.E Strek received institutional funding for interstitial lung disease research from Genentech, Gilead and MedImmune, and serves on a data monitoring committee for Boehringer Ingelheim. Conflict of interest: J.M. Oldham received speaking and advisory board fees from Genentech and Boehringer Ingelheim., (Copyright ©ERS 2018.)
- Published
- 2018
- Full Text
- View/download PDF
48. The NIEHS TaRGET II Consortium and environmental epigenomics.
- Author
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Wang T, Pehrsson EC, Purushotham D, Li D, Zhuo X, Zhang B, Lawson HA, Province MA, Krapp C, Lan Y, Coarfa C, Katz TA, Tang WY, Wang Z, Biswal S, Rajagopalan S, Colacino JA, Tsai ZT, Sartor MA, Neier K, Dolinoy DC, Pinto J, Hamanaka RB, Mutlu GM, Patisaul HB, Aylor DL, Crawford GE, Wiltshire T, Chadwick LH, Duncan CG, Garton AE, McAllister KA, Bartolomei MS, Walker CL, and Tyson FL
- Subjects
- Genome drug effects, Humans, National Institute of Environmental Health Sciences (U.S.), United States, Environmental Exposure adverse effects, Epigenomics
- Published
- 2018
- Full Text
- View/download PDF
49. Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction.
- Author
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Meng F, Meliton A, Moldobaeva N, Mutlu G, Kawasaki Y, Akiyama T, and Birukova AA
- Subjects
- Cell Adhesion drug effects, Cell Membrane Permeability drug effects, Cell Movement drug effects, Endothelial Cells drug effects, Endothelial Cells metabolism, Endothelial Cells pathology, Endothelium, Vascular drug effects, Humans, Inflammation pathology, Lipopolysaccharides, Lung drug effects, Lung pathology, Lung physiopathology, Neutrophils cytology, Neutrophils drug effects, Protective Agents pharmacology, Rho Guanine Nucleotide Exchange Factors metabolism, Signal Transduction drug effects, Endothelium, Vascular pathology, Endothelium, Vascular physiopathology, Guanine Nucleotide Exchange Factors metabolism, Hepatocyte Growth Factor pharmacology, Lung Injury pathology, Lung Injury physiopathology
- Abstract
Increased vascular endothelial permeability and inflammation are major pathological mechanisms of pulmonary edema and its life-threatening complication, the acute respiratory distress syndrome (ARDS). We have previously described potent protective effects of hepatocyte growth factor (HGF) against thrombin-induced hyperpermeability and identified the Rac pathway as a key mechanism of HGF-mediated endothelial barrier protection. However, anti-inflammatory effects of HGF are less understood. This study examined effects of HGF on the pulmonary endothelial cell (EC) inflammatory activation and barrier dysfunction caused by the gram-negative bacterial pathogen lipopolysaccharide (LPS). We tested involvement of the novel Rac-specific guanine nucleotide exchange factor Asef in the HGF anti-inflammatory effects. HGF protected the pulmonary EC monolayer against LPS-induced hyperpermeability, disruption of monolayer integrity, activation of NF-kB signaling, expression of adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and production of IL-8. These effects were critically dependent on Asef. Small-interfering RNA-induced downregulation of Asef attenuated HGF protective effects against LPS-induced EC barrier failure. Protective effects of HGF against LPS-induced lung inflammation and vascular leak were also diminished in Asef knockout mice. Taken together, these results demonstrate potent anti-inflammatory effects by HGF and delineate a key role of Asef in the mediation of the HGF barrier protective and anti-inflammatory effects. Modulation of Asef activity may have important implications in therapeutic strategies aimed at the treatment of sepsis and acute lung injury/ARDS-induced gram-negative bacterial pathogens., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
50. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis.
- Author
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Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS, and Chandel NS
- Subjects
- Cell Line, Tumor, Humans, Neoplasms pathology, Carcinogenesis, Electron Transport Complex I drug effects, Metformin pharmacology, Neoplasms enzymology
- Abstract
Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.DOI: http://dx.doi.org/10.7554/eLife.02242.001., (Copyright © 2014, Wheaton et al.)
- Published
- 2014
- Full Text
- View/download PDF
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