23 results on '"Mutlu, Gokhan"'
Search Results
2. Mitochondrial One-Carbon Metabolism is Required for TGF-β-Induced Glycine Synthesis and Collagen Protein Production
- Author
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Meliton, Angelo Y, primary, Cetin-Atalay, Rengul, additional, Tian, Yufeng, additional, Szafran, Jennifer CH, additional, Shin, Kun Woo D, additional, Cho, Takugo, additional, Sun, Kaitlyn A, additional, Woods, Parker S, additional, Shamaa, Obada R, additional, Chen, Bohao, additional, Muir, Alexander, additional, Mutlu, Gokhan M, additional, and Hamanaka, Robert B, additional
- Published
- 2023
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3. Anoctamin-1 is induced by TGF-b and contributes to lung myofibroblast differentiation.
- Author
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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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4. The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging
- Author
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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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5. 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
- Subjects
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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6. Intermittent Hypoxia Attenuates and Reverses Epinephrine‐Induced Changes in Gene Expression in Endothelial Cells
- Author
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Cetin‐Atalay, Rengul, primary, Meliton, Angelo Y., additional, Sun, Kaitlyn A., additional, Woods, Parker S., additional, Peng, Ying‐Jie, additional, Fang, Yun, additional, Hamanaka, Robert B., additional, Prabhakar, Nanduri R., additional, and Mutlu, Gokhan M., additional
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- 2022
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7. 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.
- Published
- 2015
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8. P311 Promotes Lung Fibrosis via Stimulation of Transforming Growth Factor-β1, -β2, and -β3 Translation
- Author
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Duan, Fang-Fang, primary, Barron, Gabriel, additional, Meliton, Angelo, additional, Mutlu, Gokhan M., additional, Dulin, Nickolai O., additional, and Schuger, Lucia, additional
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- 2019
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9. Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1
- Author
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Radigan, Kathryn A., primary, Nicholson, Trevor T., additional, Welch, Lynn C., additional, Chi, Monica, additional, Amarelle, Luciano, additional, Angulo, Martín, additional, Shigemura, Masahiko, additional, Shigemura, Atsuko, additional, Runyan, Constance E., additional, Morales-Nebreda, Luisa, additional, Perlman, Harris, additional, Ceco, Ermelinda, additional, Lecuona, Emilia, additional, Dada, Laura A., additional, Misharin, Alexander V., additional, Mutlu, Gokhan M., additional, Sznajder, Jacob I., additional, and Budinger, G. R. Scott, additional
- Published
- 2019
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10. HIF-1α knockdown under disturbed flow in human aortic endothelial cells
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Wu, David, Huang, Ru-Ting, Hamanaka, Robert, Krause, Matthew, Kuo, Chen-Hsiang, Nigdelioglu, Recep, Meliton, Angelo, Witt, Leah, Dai, Guohao, Civelek, Mete, Prabhakar, Nanduri, Fang, Yun, and Mutlu, Gokhan
- Subjects
HIF-1 alpha ,metabolism ,endothelial cells ,mechanotransduction - Abstract
RNAseq data of human aortic endothelial cells treated with either siRNA targeted toward HIF-1alpha or control for 24 hours, followed by 48 hours of disturbed flow
- Published
- 2017
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11. Flow transcriptome of human aortic endothelial cells
- Author
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Wu, David, Huang, Ru-Ting, Hamanaka, Robert, Krause, Matthew, Kuo, Chen-Hsiang, Nigdelioglu, Recep, Meliton, Angelo, Witt, Leah, Dai, Guohao, Civelek, Mete, Prabhakar, Nanduri, Fang, Yun, and Mutlu, Gokhan
- Subjects
mechanotansduction ,vascular biology ,RNAseq ,endothelial cells - Abstract
Human aortic endothelial cells which were subjected to unidirectional or disturbed flow for 24 hours followed by total RNA sequencing
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- 2017
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12. African-American race and mortality in interstitial lung disease: a multicentre propensity-matched analysis
- Author
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Adegunsoye, Ayodeji, primary, Oldham, Justin M., additional, Bellam, Shashi K., additional, Chung, Jonathan H., additional, Chung, Paul A., additional, Biblowitz, Kathleen M., additional, Montner, Steven, additional, Lee, Cathryn, additional, Hsu, Scully, additional, Husain, Aliya N., additional, Vij, Rekha, additional, Mutlu, Gokhan, additional, Noth, Imre, additional, Churpek, Matthew M., additional, and Strek, Mary E., additional
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- 2018
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13. Targeting dys‐regulated mechano‐transduction mechanisms in treating arterial and pulmonary vascular diseases by nanomedicine
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Fang, Yun, primary, Huang, Ru‐Ting, additional, Wu, David, additional, Oh, Myung‐Jin, additional, Leon, Lorraine, additional, Mutlu, Gokhan, additional, and Tirrell, Matthew, additional
- Published
- 2017
- Full Text
- View/download PDF
14. Oxidized phospholipids protect against lung injury and endothelial barrier dysfunction caused by heat-inactivated Staphylococcus aureus
- Author
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Meliton, Angelo Y., primary, Meng, Fanyong, additional, Tian, Yufeng, additional, Sarich, Nicolene, additional, Mutlu, Gokhan M., additional, Birukova, Anna A., additional, and Birukov, Konstantin G., additional
- Published
- 2015
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15. Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction
- Author
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Meng, Fanyong, primary, Meliton, Angelo, additional, Moldobaeva, Nurgul, additional, Mutlu, Gokhan, additional, Kawasaki, Yoshihiro, additional, Akiyama, Tetsu, additional, and Birukova, Anna A., additional
- Published
- 2015
- Full Text
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16. Abstract 17261: Inhibition of Fibrinolysis Attenuates Influenza A-induced Lung Injury
- Author
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Morales-Nebreda, Luisa, primary, Eren, Mesut, additional, Soberanes, Saul, additional, Nigdelioglu, Recep, additional, Rogel, Micah, additional, Chi, Monica, additional, Cho, Takugo, additional, Hamanaka, Robert, additional, Vaughan, Douglas E, additional, Budinger, GR Scott, additional, and Mutlu, Gokhan M, additional
- Published
- 2014
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17. 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.
- Subjects
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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18. Abstract 15597: Temporal Differences in the Cardioprotective Effects of Cardiomyocyte Specific Genetic Ablation of the Mitochondrial Fission Factor Dynamic Related Protein 1
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Piao, Lin, Fang, Yong-Hu, Hamanaka, Robert, Mutlu, Gokhan, Archer, Stephen L, and Sharp, Willard W
- Abstract
Introduction:Increased mitochondrial fission occurs following myocardial ischemia/reperfusion (IR) injury. Acute, in vitro,genetic inhibition of the mitochondrial fission factor, Dynamin related protein 1 (Drp1), as well as pharmacological inhibition of Drp1, results in significant cardio-protection from myocardial IR injury ex vivo. However, evidence of a protective role of in vivoDrp1 ablation in myocardial IR is lacking.Hypothesis:Conditional, acute cardiomyocyte-specific ablation of Drp1 will result in myocardial cardioprotection from IR injury in mice.Methods and Results:Drp1 cardiomyocyte-specific knockout (KO) mice were generated using the Myh6-MerCreMer allele. Tamoxifen (20 mg/Kg for 6 days) was administered at 8 weeks of age resulted in Drp1 KO that was evident within 3 weeks post-tamoxifen. Hearts from Drp1 KO mice were functionally normal at 3 weeks, but developed a dilated cardiomyopathy with lowered left ventricular ejection fraction (control 45.8% vs Drp1 KO 28.3%, P<0.001) at 6 weeks. Three-week Drp1 KO hearts were highly protected from 30-minutes of global myocardial IR injury, as demonstrated by preserved left ventricular end diastolic pressures (Drp1 KO 8?2 vs. Control 35?10 mmHg, P<0.001). Three-week Drp1 KO also reduced IR associated mitochondrial swelling, reactive oxygen species generation, and cytochrome C release while preserving mitochondrial respiration.Conclusion:Brief ablation of Drp1 (3-weeks) results in myocardial protection from IR injury while prolonged Drp1 ablation (6-weeks) has delirious effects on basal cardiac function, culminating in progressive lethal cardiomyopathy. These results demonstrate that targeting Drp1 for cardioprotection is a promising therapy for acute myocardial IR injury; but suggests long-term inhibition of Drp1 may have limited therapeutic use due to its ability to induce cardiomyopathy.
- Published
- 2019
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19. SARS-CoV-2 infection reduces Krüppel-Like Factor 2 in human lung autopsy.
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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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20. 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
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21. 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
22. Oxidized phospholipids protect against lung injury and endothelial barrier dysfunction caused by heat-inactivated Staphylococcus aureus.
- Author
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Meliton AY, Meng F, Tian Y, Sarich N, Mutlu GM, Birukova AA, and Birukov KG
- Subjects
- Acute Lung Injury chemically induced, Acute Lung Injury metabolism, Acute Lung Injury pathology, Animals, Bronchoalveolar Lavage, Cells, Cultured, Cytokines metabolism, Disease Models, Animal, Endothelium, Vascular pathology, Humans, Intercellular Adhesion Molecule-1 metabolism, Male, Mice, Oxidation-Reduction, Phosphatidylcholines metabolism, Vascular Cell Adhesion Molecule-1 metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Acute Lung Injury prevention & control, Capillary Permeability drug effects, Endothelium, Vascular metabolism, Hot Temperature, Phosphatidylcholines pharmacology, Staphylococcus aureus chemistry
- 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 neutrophil 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., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
23. 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
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