Heterogeneity in ventilation during positive end-expiratory pressure

Tripathi, Mukesh; Pandey, Mamta

doi:10.1186/cc9212

Cited by 3 publications

(4 citation statements)

References 6 publications

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“…While investigating whether or not the A 2A receptor would be a relevant therapeutic target in silicosis, we studied the effect of the interventional intraperitoneal treatment with the selective A 2A agonist CGS 21680 (0.5 or 1 mg/kg) on AHR triggered by silica particle intranasal instillation in mice. As illustrated in Figure 2 , values of airway resistance and lung elastance following aerosolized methacholine (3–27 mg/mL) were elevated 28 days after silica instillation, compared to negative control mice challenged with saline (silica particle vehicle), pointing out a state of airway hyper-reactivity (AHR) in line with previous studies ( Tripathi and Pandey, 2010 ). CGS 21680 treatment completely reversed silica-induced AHR regarding both airway resistance ( Figure 2A ) and lung elastance changes ( Figure 2B ) at dose of 1 mg/kg, being partially effective at 0.5 mg/kg.…”

Section: Resultssupporting

confidence: 87%

“…Using invasive whole-body plethysmography in mice exposed to silica particles, we noted that the LASSBio-897 treatment significantly reduced the elevated levels of lung resistance and elastance, also inhibiting the state of airway hyper-reactivity to the bronchoconstrictor methacholine as compared to non-treated silicotic controls. Similarly to the granuloma and fibrotic responses, also the bronchial hyper-reactivity noted in animal models of silicosis has been associated in a causative manner to inflammatory mediators generated locally ( Tripathi and Pandey, 2010 ; Ferreira et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…In attempt to further clarify the mechanism that underpins the protective effect of LASSBio-897 in this model, we found first that the treatment reduced the levels of inflammatory agents such as TNF-α, IL-6, and MIP-2/CXCL-2. These mediators are largely implicated in the recruitment and activation of macrophages and fibroblasts, which play a central role in the genesis of silica particle-induced tissue injury in the respiratory tract ( Driscoll, 2000 ; Tripathi and Pandey, 2010 ; Fazzi et al, 2014 ). This is relevant since the granulomatous inflammation induced by silica particles consists predominantly of macrophages ( Hamilton et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

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LASSBio-897 Reduces Lung Injury Induced by Silica Particles in Mice: Potential Interaction with the A2A Receptor

et al. 2017

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Silicosis is a lethal fibro-granulomatous pulmonary disease highly prevalent in developing countries, for which no proper therapy is available. Among a small series of N-acylhydrazones, the safrole-derived compound LASSBio-897 (3-thienylidene-3, 4-methylenedioxybenzoylhydrazide) raised interest due to its ability to bind to the adenosine A2A receptor. Here, we evaluated the anti-inflammatory and anti-fibrotic potential of LASSBio-897, exploring translation to a mouse model of silicosis and the A2A receptor as a site of action. Pulmonary mechanics, inflammatory, and fibrotic changes were assessed 28 days after intranasal instillation of silica particles in Swiss–Webster mice. Glosensor cAMP HEK293G cells, CHO cells stably expressing human adenosine receptors and ligand binding assay were used to evaluate the pharmacological properties of LASSBio-897 in vitro. Molecular docking studies of LASSBio-897 were performed using the genetic algorithm software GOLD 5.2. We found that the interventional treatment with the A2A receptor agonist CGS 21680 reversed silica particle-induced airway hyper-reactivity as revealed by increased responses of airway resistance and lung elastance following aerosolized methacholine. LASSBio-897 (2 and 5 mg/kg, oral) similarly reversed pivotal lung pathological features of silicosis in this model, reducing levels of airway resistance and lung elastance, granuloma formation and collagen deposition. In competition assays, LASSBio-897 decreased the binding of the selective A2A receptor agonist [3H]-CGS21680 (IC50 = 9.3 μM). LASSBio-897 (50 μM) induced modest cAMP production in HEK293G cells, but it clearly synergized the cAMP production by adenosine in a mechanism sensitive to the A2A antagonist SCH 58261. This synergism was also seen in CHO cells expressing the A2A, but not those expressing A2B, A1 or A3 receptors. Based on the evidence that LASSBio-897 binds to A2A receptor, molecular docking studies were performed using the A2A receptor crystal structure and revealed possible binding modes of LASSBio-897 at the orthosteric and allosteric sites. These findings highlight LASSBio-897 as a lead compound in drug development for silicosis, emphasizing the role of the A2A receptor as its putative site of action.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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LASSBio-897 Reduces Lung Injury Induced by Silica Particles in Mice: Potential Interaction with the A2A Receptor

et al. 2017

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“…Finally, previous reports stated that patients with silicosis exhibit a respiratory deficit and airway hyper-reactivity (48), and in more severe cases increased airways resistance and residual volume were reported (6,49,50). By means of whole-body invasive plethysmography, it became evident that flunisolide decreased silica-induced state of airway hyper-reactivity, as attested by the reduction in lung resistance and elastance following methacholine aerosolization.…”

Section: Discussionmentioning

confidence: 87%

Intranasal Flunisolide Suppresses Pathological Alterations Caused by Silica Particles in the Lungs of Mice

et al. 2020

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Silicosis is an occupational disease triggered by the inhalation of fine particles of crystalline silica and characterized by inflammation and scarring in the form of nodular lesions in the lungs. In spite of the therapeutic arsenal currently available, there is no specific treatment for the disease. Flunisolide is a potent corticosteroid shown to be effective for controlling chronic lung inflammatory diseases. In this study, the effect of flunisolide on silica-induced lung pathological changes in mice was investigated. Swiss-Webster mice were injected intranasally with silica particles and further treated with flunisolide from day 21 to 27 post-silica challenge. Lung function was assessed by whole body invasive plethysmography. Granuloma formation was evaluated morphometrically, collagen deposition by Picrus sirius staining and quantitated by Sircol. Chemokines and cytokines were evaluated using enzyme-linked immunosorbent assay. The sensitivity of lung fibroblasts was also examined in in vitro assays. Silica challenge led to increased leukocyte numbers (mononuclear cells and neutrophils) as well as production of the chemokine KC/CXCL-1 and the cytokines TNF-α and TGF-β in the bronchoalveolar lavage. These alterations paralleled to progressive granuloma formation, collagen deposition and impairment of lung function. Therapeutic administration of intranasal flunisolide inhibited granuloma and fibrotic responses, noted 28 days after silica challenge. The upregulation of MIP-1α/CCL-3 and MIP-2/CXCL-2 and the cytokines TNF-α and TGF-β, as well as deposition of collagen and airway hyper-reactivity to methacholine were shown to be clearly sensitive to flunisolide, as compared to silica-challenge untreated mice. Additionally, flunisolide effectively suppressed the responses of proliferation and MCP-1/CCL-2 production from IL-13 stimulated lung fibroblasts from silica-or saline-challenged mice. In conclusion, we report that intranasal treatment with the corticosteroid flunisolide showed protective properties on pathological features triggered by silica particles in mice, suggesting that the compound may constitute a promising strategy for the treatment of silicosis.

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Mechanical ventilation decreases tidal volume heterogeneity but increases heterogeneity in end-expiratory volumes

Preissner,

Song,

Trevascus

et al. 2023

Journal of Applied Physiology

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How the heterogeneous distribution of lung volumes changes in response to different mechanical ventilation (MV) strategies is unclear. Using our well-developed four-dimensional computed tomography (4DCT) high resolution imaging technique, we aimed to assess the effect of different MV strategies on the distribution and heterogeneity of regional lung volumes. Healthy adult female BALB/c mice received either 2h of "injurious" MV (n=6, HPZP) with a peak inspiratory pressure (PIP) of 20cmH2O and zero positive end-expiratory pressure (PEEP), or 2h of "protective" MV (n=8, LPP) with PIP=12cmH2O and PEEP=2cmH2O. 4DCT images were obtained at baseline (0h) and after 2h of MV. Tidal volume (Vt) and end-expiratory lung volume (EEV) were measured throughout the whole lung on a voxel-by-voxel basis. Heterogeneity of ventilation was determined by the coefficient of variation (COV) of Vt and EEV. Our data showed that MV had minimal impact on global Vt but decreased EEV in the HPZP group ( p<0.05). Both ventilation modes decreased the COV of Vt (39.4% for HPZP and 9.7% for LPP) but increased the COV in EEV (36.4% for HPZP and 29.2% for LPP). This was consistent with the redistribution index which was significantly higher in the HVZP group than the LPP group ( p<0.001). We concluded that regional assessment of the change in EEV showed different patterns in progression between LPP and HPZP strategies. Both ventilation strategies decreased heterogeneity in Vt after 2h of MV but increased heterogeneity in EEV. Further work is required to determine the link between these effects and ventilator induced lung injury.

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Heterogeneity in ventilation during positive end-expiratory pressure

Cited by 3 publications

References 6 publications

LASSBio-897 Reduces Lung Injury Induced by Silica Particles in Mice: Potential Interaction with the A2A Receptor

LASSBio-897 Reduces Lung Injury Induced by Silica Particles in Mice: Potential Interaction with the A2A Receptor

Intranasal Flunisolide Suppresses Pathological Alterations Caused by Silica Particles in the Lungs of Mice

Mechanical ventilation decreases tidal volume heterogeneity but increases heterogeneity in end-expiratory volumes

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