Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats

Chen, Chin Ming; Peñuelas, Óscar; Quinn, Kieran L.; Cheng, Kuo Chen; Li, Chien‐Feng; Zhang, Haibo; Slutsky, Arthur S.

doi:10.1097/ccm.0b013e3181a55273

Cited by 12 publications

(9 citation statements)

References 43 publications

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“…However, there is no clear consensus on the mechanisms whereby xanthines might influence inflammation. In contrast to our findings, a protective effect of adenosine A 2 receptor agonist has been observed in a mature rat lung injury model [20]. Li showed that chronic caffeine treatment at low dose and acute caffeine treatment at high dose attenuated lung damage and cytokine response in a mature mouse lung injury model, whereas acute caffeine treatment at low dose enhanced lung damage [21].…”

Section: Discussioncontrasting

confidence: 99%

Anti-Inflammatory Effect of Caffeine Is Associated with Improved Lung Function after Lipopolysaccharide-Induced Amnionitis

et al. 2014

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Background: Although caffeine enhances respiratory control and decreases the need for mechanical ventilation and resultant bronchopulmonary dysplasia, it may also have anti-inflammatory properties in protecting lung function. Objective: We hypothesized that caffeine improves respiratory function via an anti-inflammatory effect in lungs of a lipopolysaccharide (LPS)-induced pro-inflammatory amnionitis rat pup model. Methods: Caffeine was given orally (10 mg/kg/day) from postnatal day (p)1 to p14 to pups exposed to intra-amniotic LPS or normal saline. Expression of IL-1β was assessed in lung homogenates at p8 and p14, and respiratory system resistance (R_rs) and compliance (C_rs) as well as CD68 cell counts and radial alveolar counts were assessed at p8. Results: In LPS-exposed rats, IL-1β and CD68 cell counts both increased at p8 compared to normal saline controls. These increases in pro-inflammatory markers were no longer present in caffeine-treated LPS-exposed pups. R_rs was higher in LPS-exposed pups (4.7 ± 0.9 cm H₂O/ml·s) at p8 versus controls (1.6 ± 0.3 cm H₂O/ml·s, p < 0.01). LPS-exposed pups no longer exhibited a significant increase in R_rs (2.8 ± 0.5 cm H₂O/ml·s) after caffeine. C_rs did not differ significantly between groups, although radial alveolar counts were lower in both groups of LPS-exposed pups. Conclusions: Caffeine promotes anti-inflammatory effects in the immature lung of prenatal LPS-exposed rat pups associated with improvement of R_rs, suggesting a protective effect of caffeine on respiratory function via an anti-inflammatory mechanism.

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Section: Discussioncontrasting

confidence: 99%

Anti-Inflammatory Effect of Caffeine Is Associated with Improved Lung Function after Lipopolysaccharide-Induced Amnionitis

et al. 2014

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“…Generally speaking, mechanical ventilation is a lifesaving therapy as it improves hypoxemia and promotes alveolar opening in patients with acute respiratory failure; although, excessive alveolar distention as volutrauma and the cyclic opening and closing of lung units as atelectrauma may promote VILI [ 7 ]. Previous studies have shown that VILI alone may not cause extensive lung injury in the normal lung, but that VILI can enhance lung inflammation in pre-injured lungs [ 8 , 26 ]. This two-hit injury makes the lung more susceptible to mechanical ventilation injury, as there is increased pulmonary permeability, edema, neutrophil recruitment, and cytokine release into plasma [ 8 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…A “two-hit injury” can be caused by VILI preceded by hemorrhagic shock and followed by reperfusion or acid aspiration, which makes the lung more susceptible to MV injury [ 8 , 9 ]. Although using a low tidal volume improves the clinical outcomes of certain populations of patients with ARDS, the mortality of ARDS patients remains high [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Glutamine Attenuates Acute Lung Injury Caused by Acid Aspiration

2014

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Inadequate ventilator settings may cause overwhelming inflammatory responses associated with ventilator-induced lung injury (VILI) in patients with acute respiratory distress syndrome (ARDS). Here, we examined potential benefits of glutamine (GLN) on a two-hit model for VILI after acid aspiration-induced lung injury in rats. Rats were intratracheally challenged with hydrochloric acid as a first hit to induce lung inflammation, then randomly received intravenous GLN or lactated Ringer’s solution (vehicle control) thirty min before different ventilator strategies. Rats were then randomized to receive mechanical ventilation as a second hit with a high tidal volume (TV) of 15 mL/kg and zero positive end-expiratory pressure (PEEP) or a low TV of 6 mL/kg with PEEP of 5 cm H2O. We evaluated lung oxygenation, inflammation, mechanics, and histology. After ventilator use for 4 h, high TV resulted in greater lung injury physiologic and biologic indices. Compared with vehicle treated rats, GLN administration attenuated lung injury, with improved oxygenation and static compliance, and decreased respiratory elastance, lung edema, extended lung destruction (lung injury scores and lung histology), neutrophil recruitment in the lung, and cytokine production. Thus, GLN administration improved the physiologic and biologic profiles of this experimental model of VILI based on the two-hit theory.

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“…CGS-21680 Adenosine A2A receptor agonists 1. Adenosine A2A receptor agonists are reparative and anti-inflammatory in the lung following infection, acid, or mechanical injury [ 50 , 51 ] 5. RAGE Inhibitors RAGE neutralization 1.…”

Section: Therapies In Clinical Trials For Ardsmentioning

confidence: 99%

“…The adenosine A2A receptor agonist GW328267C enhanced alveolar fluid clearance in models of acid instillation, LPS, and live E.coli-induced lung injury [ 50 ]. Another adenosine A2A receptor agonist, CGS-21680, improved lung compliance and reduced neutrophil infiltration and pro-inflammatory cytokine release in a rat VILI model [ 51 ].…”

Section: Therapies In Clinical Trials For Ardsmentioning

confidence: 99%

Emerging pharmacological therapies for ARDS: COVID-19 and beyond

et al. 2020

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ARDS, first described in 1967, is the commonest form of acute severe hypoxemic respiratory failure. Despite considerable advances in our knowledge regarding the pathophysiology of ARDS, insights into the biologic mechanisms of lung injury and repair, and advances in supportive care, particularly ventilatory management, there remains no effective pharmacological therapy for this syndrome. Hospital mortality at 40% remains unacceptably high underlining the need to continue to develop and test therapies for this devastating clinical condition. The purpose of the review is to critically appraise the current status of promising emerging pharmacological therapies for patients with ARDS and potential impact of these and other emerging therapies for COVID-19-induced ARDS. We focus on drugs that: (1) modulate the immune response, both via pleiotropic mechanisms and via specific pathway blockade effects, (2) modify epithelial and channel function, (3) target endothelial and vascular dysfunction, (4) have anticoagulant effects, and (5) enhance ARDS resolution. We also critically assess drugs that demonstrate potential in emerging reports from clinical studies in patients with COVID-19-induced ARDS. Several therapies show promise in earlier and later phase clinical testing, while a growing pipeline of therapies is in preclinical testing. The history of unsuccessful clinical trials of promising therapies underlines the challenges to successful translation. Given this, attention has been focused on the potential to identify biologically homogenous subtypes within ARDS, to enable us to target more specific therapies ‘precision medicines.’ It is hoped that the substantial number of studies globally investigating potential therapies for COVID-19 will lead to the rapid identification of effective therapies to reduce the mortality and morbidity of this devastating form of ARDS.

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Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats

Cited by 12 publications

References 43 publications

Anti-Inflammatory Effect of Caffeine Is Associated with Improved Lung Function after Lipopolysaccharide-Induced Amnionitis

Anti-Inflammatory Effect of Caffeine Is Associated with Improved Lung Function after Lipopolysaccharide-Induced Amnionitis

Glutamine Attenuates Acute Lung Injury Caused by Acid Aspiration

Emerging pharmacological therapies for ARDS: COVID-19 and beyond

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