5 results on '"Pragi Patel"'
Search Results
2. mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury
- Author
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Hyunwook Lee, Qinqin Fei, Adam Streicher, Wenjuan Zhang, Colleen Isabelle, Pragi Patel, Hilaire C. Lam, Antonio Arciniegas-Rubio, Miguel Pinilla-Vera, Diana P. Amador-Munoz, Diana Barragan-Bradford, Angelica Higuera-Moreno, Rachel K. Putman, Lynette M. Sholl, Elizabeth P. Henske, Christopher M. Bobba, Natalia Higuita-Castro, Emily M. Shalosky, R. Duncan Hite, John W. Christman, Samir N. Ghadiali, Rebecca M. Baron, and Joshua A. Englert
- Subjects
Pulmonology ,Medicine - Abstract
The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.
- Published
- 2021
- Full Text
- View/download PDF
3. Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates injury during mechanical ventilation
- Author
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Carleen R. Spitzer, Robert J. Lee, Rachel K. Putman, Mark D. Wewers, Joshua A. Englert, MuChun Tsai, John W. Christman, Vasudha C. Shukla, Qinqin Fei, Hyunwook Lee, Megan N. Ballinger, Samir N. Ghadiali, Christopher M Bobba, and Pragi Patel
- Subjects
Male ,0301 basic medicine ,THP-1 Cells ,medicine.medical_treatment ,Science ,General Physics and Astronomy ,Lung injury ,Bronchoalveolar Lavage ,Mechanotransduction, Cellular ,Article ,Non-coding RNAs ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Macrophages, Alveolar ,medicine ,Animals ,Humans ,Mechanotransduction ,Inflammation ,Mice, Knockout ,Mechanical ventilation ,Respiratory tract diseases ,Multidisciplinary ,Lung ,medicine.diagnostic_test ,business.industry ,Interleukin-8 ,Gene Transfer Techniques ,Lung Injury ,General Chemistry ,Middle Aged ,respiratory system ,Adoptive Transfer ,Respiration, Artificial ,Up-Regulation ,MicroRNAs ,030104 developmental biology ,Bronchoalveolar lavage ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Breathing ,Cancer research ,Nanoparticles ,Female ,Mechanosensitive channels ,business - Abstract
Mechanical ventilation generates injurious forces that exacerbate lung injury. These forces disrupt lung barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides including microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We use humanized in-vitro systems, mouse models, and biospecimens from patients to elucidate the expression dynamics of miR-146a needed to decrease lung injury during mechanical ventilation. We find that the endogenous increase in miR-146a following injurious ventilation is not sufficient to prevent lung injury. However, when miR-146a is highly overexpressed using a nanoparticle delivery platform it is sufficient to prevent injury. These data indicate that the endogenous increase in microRNA-146a during mechanical ventilation is a compensatory response that partially limits injury and that nanoparticle delivery of miR-146a is an effective strategy for mitigating lung injury during mechanical ventilation., There are no targeted pharmacologic therapies to treat lung injury during mechanical ventilation (MV). Here the authors identify a mechanosensitive microRNA (miR-146a) in alveolar macrophages during MV and increase miR-146a to supraphysiological levels in these cells to mitigate ventilator induced lung injury.
- Published
- 2021
4. Mechanosensitive activation of mTORC1 mediates ventilator induced lung injury during the acute respiratory distress syndrome
- Author
-
Colleen Isabelle, Angelica Higuera, Rebecca M. Baron, R. Duncan Hite, Hilaire C. Lam, Hyunwook Lee, Wenjuan Zhang, Joshua A. Englert, Adam Streicher, Rachel K. Putman, Qinqin Fei, John W. Christman, Natalia Higuita-Castro, Samir N. Ghadiali, Christopher M Bobba, Pragi Patel, Diana Barragan-Bradford, Elizabeth P. Henske, Miguel Pinilla-Vera, and Diana Amador-Munoz
- Subjects
Mechanical ventilation ,0303 health sciences ,ARDS ,Lung ,business.industry ,medicine.medical_treatment ,Inflammation ,mTORC1 ,Lung injury ,respiratory system ,medicine.disease ,respiratory tract diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Respiratory failure ,Cancer research ,medicine ,Mechanosensitive channels ,medicine.symptom ,biological phenomena, cell phenomena, and immunity ,business ,030304 developmental biology - Abstract
Acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation maintains gas exchange in patients with ARDS, but exposes lung cells to physical forces that exacerbate lung injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during mechanical ventilation exacerbates lung injury. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells exacerbates physiologic lung dysfunction during mechanical ventilation. Conversely, treatment with rapamycin at the time mechanical ventilation is initiated prevents physiologic lung injury (i.e. decreased compliance) without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during mechanical ventilation. Our data demonstrate that in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during mechanical ventilation exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator induced lung injury during ARDS.
- Published
- 2020
- Full Text
- View/download PDF
5. Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates lung injury during mechanical ventilation
- Author
-
Carleen R. Spitzer, Mark D. Wewers, Vasudha C. Shukla, Qinqin Fei, John W. Christman, Rachel K. Putman, Samir N. Ghadiali, Megan N. Ballinger, Christopher M Bobba, Pragi Patel, Hyunwook Lee, MuChun Tsai, and Joshua A. Englert
- Subjects
Mechanical ventilation ,0303 health sciences ,Lung ,business.industry ,medicine.medical_treatment ,Endogeny ,respiratory system ,Lung injury ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,microRNA ,medicine ,Cancer research ,Mechanosensitive channels ,Mechanotransduction ,business ,030304 developmental biology - Abstract
During mechanical ventilation, injurious biophysical forces exacerbate lung injury. These forces disrupt alveolar capillary barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides such as microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We used humanized in-vitro systems, mouse models, and biospecimens from mechanically ventilated patients to elucidate the expression dynamics of miR-146a that might be required to decrease lung injury during mechanical ventilation. We found that the endogenous increase in miR-146a following injurious was relatively modest and not sufficient to prevent lung injury. However, when miR-146a was highly overexpressed using a nanoparticle-based delivery platform in vivo, it was sufficient to prevent lung injury. These data indicate that the endogenous increase in microRNA-146a during MV is a compensatory response that only partially limits VILI and that nanoparticle delivery approaches that significantly over-express microRNA-146a in AMs is an effective strategy for mitigating VILI.
- Published
- 2019
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