EFFECT OF COMBINATION THERAPY FOR ACUTE RESPIRATORY DISTRESS SYNDROME THROUGH INHIBITING INFLAMMATION AND FIBROSIS IN HUMAN LUNG EPITHELIAL A549 CELLS

AbstractAcute 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.

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Regeneration of lung epithelial cells by Fullerene C60 nanoformulation: A possible treatment strategy for acute respiratory distress syndrome (ARDS)

10.1101/2020.09.08.287680 ◽

2020 ◽

Author(s):

Nabodita Sinha ◽

Ashwani Kumar Thakur

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Epithelial Cells ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

Respiratory Infections ◽

Fullerene C60 ◽

Lung Epithelial Cells ◽

Proof Of Concept ◽

Lung Epithelial

Acute respiratory distress syndrome (ARDS) involves death of lung epithelial cells. ARDS is a leading reason behind mortality in respiratory infections. Here we show a proof-of-concept that a Fullerene nanoformulation can be used for the regeneration of cells treated with apoptosis-inducing molecules, suggeting its potential for ARDS therapy.

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Pseudomonas Aeruginosa Induced Cell Death in Acute Lung Injury and Acute Respiratory Distress Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms21155356 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5356

Author(s):

Rushikesh Deshpande ◽

Chunbin Zou

Keyword(s):

Pseudomonas Aeruginosa ◽

Cell Death ◽

Acute Respiratory Distress Syndrome ◽

Acute Lung Injury ◽

Lung Injury ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

Lung Epithelial ◽

Epithelial Cell Death

Pseudomonas aeruginosa is an important opportunistic pathogen responsible for the cause of acute lung injury and acute respiratory distress syndrome. P. aeruginosa isthe leading species isolated from patients with nosocomial infection and is detected in almost all the patients with long term ventilation in critical care units. P. aeruginosa infection is also the leading cause of deleterious chronic lung infections in patients suffering from cystic fibrosis as well as the major reason for morbidity in people with chronic obstructive pulmonary disease. P. aeruginosa infections are linked to diseases with high mortality rates and are challenging for treatment, for which no effective remedies have been developed. Massive lung epithelial cell death is a hallmark of severe acute lung injury and acute respiratory distress syndrome caused by P. aeruginosa infection. Lung epithelial cell death poses serious challenges to air barrier and structural integrity that may lead to edema, cytokine secretion, inflammatory infiltration, and hypoxia. Here we review different types of cell death caused by P. aeruginosa serving as a starting point for the diseases it is responsible for causing. We also review the different mechanisms of cell death and potential therapeutics in countering the serious challenges presented by this deadly bacterium.

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Proteolytic Shedding of the Lung Epithelial Glycocalyx Is a Prominent Feature of Human Acute Respiratory Distress Syndrome (ARDS) That Is Associated with Airspace Inflammation

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a5243 ◽

2020 ◽

Author(s):

L. Habegger ◽

J.B. McNeil ◽

N.E. Wickersham ◽

B. Sullivan ◽

E. Weddle ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Distress Syndrome ◽

Prominent Feature ◽

Lung Epithelial ◽

Proteolytic Shedding

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Combination Therapy With Polydeoxyribonucleotide and Pirfenidone Alleviates Symptoms of Acute Respiratory Distress Syndrome in Human Lung Epithelial A549 Cells

International Neurourology Journal ◽

10.5213/inj.2040152.076 ◽

2020 ◽

Vol 24 (Suppl 1) ◽

pp. S56-64 ◽

Cited By ~ 2

Author(s):

Jae-Joon Hwang ◽

Il-Gyu Ko ◽

Jun-Jang Jin ◽

Lakkyong Hwang ◽

Sang-Hoon Kim ◽

...

Keyword(s):

Growth Factor ◽

Combination Therapy ◽

Distress Syndrome ◽

Collagen Type ◽

Human Lung ◽

A549 Cells ◽

Collagen Type I ◽

Type I ◽

Tnf Α ◽

Lung Epithelial

Purpose: Acute respiratory distress syndrome (ARDS) is characterized by its acute onset of symptoms such as bilateral pulmonary infiltrates, severe hypoxemia, and pulmonary edema. Many patients with ARDS survive in the acute phase, but then die from significant lung fibrosis.Methods: The effect of combination therapy with polydeoxyribonucleotide (PDRN) and pirfenidone on ARDS was investigated using human lung epithelial A549 cells. ARDS environment was induced by treatment with lipopolysaccharide and transforming growth factor (TGF)-β. Enzyme-linked immunoassay for connective tissue growth factor (CTGF) and hydroxyproline were conducted. Western blot for collagen type I, fibroblast growth factor (FGF), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 was performed.Results: In this study, 8-μg/mL PDRN enhanced cell viability. Combination therapy with PDRN and pirfenidone and pirfenidone monotherapy suppressed expressions of CTGF and hydroxyproline and inhibited expressions of collagen type I and FGF. Combination therapy with PDRN and pirfenidone and PDRN monotherapy suppressed expression of TNF-α and IL-1β.Conclusions: The combination therapy with PDRN and pirfenidone exerted stronger therapeutic effect against lipopolysaccharide and TGF-β-induced ARDS environment compared to the PDRN monotherapy or pirfenidone monotherapy. The excellent therapeutic effect of combination therapy with PDRN and pirfenidone on ARDS was shown by promoting the rapid anti-inflammatory effect and inhibiting the fibrotic processes.

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