The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology

Oliveira, Gisele Pinto de; Silva, Johnatas D.; Marques, Patricia; Gonçalves-de-Albuquerque, Cassiano Felippe; Santos, Heloísa L.; Vascocellos, Ana Paula; Takiya, Christina Maeda; Morales, Marcelo M.; Pelosi, Paolo; Mócsai, Attila; Castro‐Faria‐Neto, Hugo C.; Rocco, Patricia R. M.

doi:10.1159/000430325

Cited by 24 publications

(29 citation statements)

References 40 publications

(52 reference statements)

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“…Even though DMSO may result in lung inflammation, pilot studies compared saline with DMSO and found no significant differences in lung mechanics and morphometry or collagen fiber content between groups (Oliveira et al, 2015; Cruz et al, 2016; da Silva et al, 2016). Mice exposed to silica exhibited higher Est,L and ΔP2,L values, which were associated with the presence of silicotic granulomas, alveolar collapse, thickening of alveolar septa, infiltration of inflammatory cells in lung parenchyma, and collagen fiber deposition.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of protein kinases is known to occur in a variety of diseases, including cancer, inflammatory disorders (Summy and Gallick, 2003; Johnson and Gallick, 2007; Hu et al, 2008; Li, 2008; Zarbock and Ley, 2011; Liu et al, 2014; Kong et al, 2015; Ozanne et al, 2015), and fibrotic processes (Chaudhary et al, 2007; Grimminger et al, 2010). Because of its widespread involvement in numerous physiological and pathological processes (Thomas and Brugge, 1997; Dehm and Bonham, 2004; Lemmon and Schlessinger, 2010; Keller and Brummendorf, 2012), it is not surprising that the Src signaling pathway has been successfully targeted by multiple drug-discovery programs (Hopkins and Groom, 2002; Overington et al, 2006) and has been regarded as a promising new therapeutic approach for lung diseases (Richeldi et al, 2011; Oliveira et al, 2015; Cruz et al, 2016; da Silva et al, 2016) due to its anti-inflammatory and anti-fibrotic effects. In this line, nintedanib, an intracellular inhibitor that targets multiple tyrosine kinases, reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis (Richeldi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

et al. 2017

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Silicosis is an occupational lung disease for which no effective therapy exists. We hypothesized that bosutinib, a tyrosine kinase inhibitor, might ameliorate inflammatory responses, attenuate pulmonary fibrosis, and thus improve lung function in experimental silicosis. For this purpose, we investigated the potential efficacy of bosutinib in the treatment of experimental silicosis induced in C57BL/6 mice by intratracheal administration of silica particles. After 15 days, once disease was established, animals were randomly assigned to receive DMSO or bosutinib (1 mg/kg/dose in 0.1 mL 1% DMSO) by oral gavage, twice daily for 14 days. On day 30, lung mechanics and morphometry, total and differential cell count in alveolar septa and granuloma, levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, transforming growth factor (TGF)-β, and vascular endothelial growth factor in lung homogenate, M1 and M2 macrophages, total leukocytes, and T cells in BALF, lymph nodes, and thymus, and collagen fiber content in alveolar septa and granuloma were analyzed. In a separate in vitro experiment, RAW264.7 macrophages were exposed to silica particles in the presence or absence of bosutinib. After 24 h, gene expressions of arginase-1, IL-10, IL-12, inducible nitric oxide synthase (iNOS), metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, and caspase-3 were evaluated. In vivo, in silicotic animals, bosutinib, compared to DMSO, decreased: (1) fraction area of collapsed alveoli, (2) size and number of granulomas, and mononuclear cell granuloma infiltration; (3) IL-1β, TNF-α, IFN-γ, and TGF-β levels in lung homogenates, (4) collagen fiber content in lung parenchyma, and (5) viscoelastic pressure and static lung elastance. Bosutinib also reduced M1 cell counts while increasing M2 macrophage population in both lung parenchyma and granulomas. Total leukocyte, regulatory T, CD4+, and CD8+ cell counts in the lung-draining lymph nodes also decreased with bosutinib therapy without affecting thymus cellularity. In vitro, bosutinib led to a decrease in IL-12 and iNOS and increase in IL-10, arginase-1, MMP-9, and TIMP-1. In conclusion, in the current model of silicosis, bosutinib therapy yielded beneficial effects on lung inflammation and remodeling, therefore resulting in lung mechanics improvement. Bosutinib may hold promise for silicosis; however, further studies are required.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

et al. 2017

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“…Pathophysiological, histological, and morphological differences found in pulmonary and extra-pulmonary ARDS may influence the response to pharmacological agents, mechanical ventilation, and positioning. Some studies have reported a modulation of the inflammatory process in ARDS in response to pharmacological therapies such as dasatinib (Oliveira et al, 2015) and corticosteroids (Leite-Junior et al, 2008) independent of the etiology. Clinical studies have evaluated ARDS treatments according to the underlying etiology.…”

Section: Lung Injury Induced By Lipopolysaccharide Challengementioning

confidence: 99%

Molecular Dynamics of Lipopolysaccharide-Induced Lung Injury in Rodents

et al. 2020

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Acute respiratory distress syndrome (ARDS) is a common disease entity in critical care medicine and is still associated with a high mortality. Because of the heterogeneous character of ARDS, animal models are an insturment to study pathology in relatively standardized conditions. Rodent models can bridge the gap from in vitro investigations to large animal and clinical trials by facilitating large sample sizes under physiological conditions at comparatively low costs. One of the most commonly used rodent models of acute lung inflammation and ARDS is administration of lipopolysaccharide (LPS), either into the airways (direct, pulmonary insult) or systemically (indirect, extra-pulmonary insult). This narrative review discusses the dynamics of important pathophysiological pathways contributing to the physiological response to LPS-induced injury. Pathophysiological pathways of LPS-induced lung injury are not only influenced by the type of the primary insult (e.g., pulmonary or extra-pulmonary) and presence of additional stimuli (e.g., mechanical ventilation), but also by time. As such, findings in animal models of LPS-induced lung injury may depend on the time point at which samples are obtained and physiological data are captured. This review summarizes the current evidence and highlights uncertainties on the molecular dynamics of LPS-induced lung injury in rodent models, encouraging researchers to take accurate timing of LPS-induced injury into account when designing experimental trials.

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“…Survivors of EA-TEF often suffer from chronic respiratory tract disease characterized by hoarse cough, repeated pneumonia or bronchiectasis and chronic bronchitis [20][21][22]. Peptic bronchitis, gastro-esophageal reflux or fistula stump account in part for these sequelae, but defects in the airway or lung parenchyme, or lung hypoplasia might also play a role [12,23,24].…”

Section: Discussionmentioning

confidence: 99%

Impaired VEGF Signaling in Lungs with Hypoplastic Esophageal Atresia and Effects on Branching Morphogenesis

Liu

et al. 2016

Cell Physiol Biochem

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Background/Aims: Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often suffer chronic respiratory tract disease. We previously reported that primary lung maldevelopment caused by deficient branching of embryonal airways in experimental EA-TEF was induced by Adriamycin. In this study, we investigated the Vascular endothelial growth factor (VEGF) pathway in the developing lung in an EA-TEF rat model. We further analyzed the effect of recombinant VEGF treatment in vitro on branching morphogenesis of embryo lungs in experimental EA-TEF. Methods: Pregnant rats received either Adriamycin or vehicle on E7, E8 and E9. Lungs were recovered at E15, E18 and E21. Expression of VEGF and receptors (Flk-1 and Flt-1) were assessed by quantitative PCR, immunohistochemistry and immunoblotting. E13 lungs were cultured for 72 hours with 50 ng/mL of recombinant rat VEGF in serum-free medium. The rates of increase in bud count and airway contour were evaluated. Results: Our results showed a significant downregulation of VEGF during pseudoglandular and canalicular stages. In contrast, there were significantly higher levels of the Flt-1 receptor in the canalicular stage, which may represent a compensatory response to decreased VEGF. However, both variables returned to normal levels at the saccular stage. Exogenous VEGF treatment enhanced hypoplastic lung growth, evidenced by the increase in bud count and airway contour. Conclusions: A VEGF signaling defect possibly plays an important role in defective embryonic airway branching. Additionally, VEGF treatment may accelerate lung growth in EA-TEF lungs.

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The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology

Cited by 24 publications

References 40 publications

Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

Molecular Dynamics of Lipopolysaccharide-Induced Lung Injury in Rodents

Impaired VEGF Signaling in Lungs with Hypoplastic Esophageal Atresia and Effects on Branching Morphogenesis

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