Early and late pulmonary effects of nebulized LPS in mice: An acute lung injury model

Costa, Natália; Júnior, Gabriel Ribeiro; Alemany, Adair Aparecida dos Santos; Belotti, Luciano; Zati, Douglas Hidalgo; Cavalcante, Marcela Frota; Veras, Mariana Matera; Ribeiro, Susan Pereira; Kallás, Esper G.; Saldiva, Paulo Hilário Nascimento; Dolhnikoff, Marisa; Silva, Luiz Fernando Ferraz da

doi:10.1371/journal.pone.0185474

Cited by 75 publications

(53 citation statements)

References 41 publications

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“…Robust neutrophil recruitment into the lungs and BAL fluid was evident 3 h post LPS-exposure, presumably due to the rapid production of pro-neutrophilic/pro-inflammatory chemokines and cytokines observed 3 h following LPS exposure. These findings are consistent with prior studies using aerosolized or intra-nasal LPS administration [ 37 , 41 – 45 ]. The current analysis found no evidence of PAS staining in the lungs, suggesting that mucus hypersecretion was not a feature of the acute response to LPS.…”

Section: Discussionsupporting

confidence: 93%

“…There was also no evidence of LPS-induced airway remodelling. This is consistent with the acute nature of the model, but, as reported elsewhere, may occur at later times post-exposure [ 45 ]. LPS-induced AHR was transient, with marked increases in MCh-induced reactivity observed 3 h following LPS exposure, being largely resolved at 24 h. This result was slightly unexpected as the rapid accumulation of neutrophils into the BAL fluid at 3 h was maintained at both 6 and 24 h post-LPS exposure.…”

Section: Discussionsupporting

confidence: 90%

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A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation

George

Chakraborty

Giembycz

et al. 2018

Allergy Asthma Clin Immunol

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BackgroundAsthma exacerbations are associated with the recruitment of neutrophils to the lungs. These cells release proteases and mediators, many of which act at G protein-coupled receptors (GPCRs) that couple via Gq to promote bronchoconstriction and inflammation. Common asthma therapeutics up-regulate expression of the regulator of G protein signalling (RGS), RGS2. As RGS2 reduces signaling from Gq-coupled GPCRs, we have defined role(s) for this GTPase-activating protein in an acute neutrophilic model of lung inflammation.MethodsWild type and Rgs2−/− C57Bl6 mice were exposed to nebulized lipopolysaccharide (LPS). Lung function (respiratory system resistance and compliance) was measured using a SCIREQ flexivent small animal ventilator. Lung inflammation was assessed by histochemistry, cell counting and by cytokine and chemokine expression in bronchoalveolar lavage (BAL) fluid.ResultsLipopolysaccharide inhalation induced transient airways hyperreactivity (AHR) and neutrophilic lung inflammation. While AHR and inflammation was greatest 3 h post-LPS exposure, BAL neutrophils persisted for 24 h. At 3 h post-LPS inhalation, multiple inflammatory cytokines (CSF2, CSF3, IL6, TNF) and chemokines (CCL3, CCL4, CXCL1, CXCL2) were highly expressed in the BAL fluid, prior to declining by 24 h. Compared to wild type counterparts, Rgs2−/− mice developed significantly greater airflow resistance in response to inhaled methacholine (MCh) at 3 h post-LPS exposure. At 24 h post-LPS exposure, when lung function was recovering in the wild type animals, MCh-induced resistance was increased, and compliance decreased, in Rgs2−/− mice. Thus, Rgs2−/− mice show AHR and stiffer lungs 24 h post-LPS exposure. Histological markers of inflammation, total and differential cell counts, and major cytokine and chemokine expression in BAL fluid were similar between wild type and Rgs2−/− mice. However, 3 and 24 h post-LPS exposure, IL12B expression was significantly elevated in BAL fluid from Rgs2−/− mice compared to wild type animals.ConclusionsWhile Rgs2 is bronchoprotective in acute neutrophilic inflammation, no clear anti-inflammatory effect was apparent. Nevertheless, elevated IL12B expression in Rgs2−/− animals raises the possibility that RGS2 could dampen Th1 responses. These findings indicate that up-regulation of RGS2, as occurs in response to inhaled corticosteroids and long-acting β2-adrenoceptor agonists, may be beneficial in acute neutrophilic exacerbations of airway disease, including asthma.Electronic supplementary materialThe online version of this article (10.1186/s13223-018-0266-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 90%

A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation

George

Chakraborty

Giembycz

et al. 2018

Allergy Asthma Clin Immunol

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“…Serum inflammatory cytokines TNF-α and IL-6 increased with time. LPS injection is a known experimental model causing lung inflammation [30,31]; in the current study we confirmed the detrimental effects up to 6 hours after LPS injection.…”

Section: Discussionsupporting

confidence: 84%

Salvia miltiorrhiza Injection Alleviates LPS‐Induced Acute Lung Injury by Adjusting the Balance of MMPs/TIMPs Ratio

Chen

Zhu

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Salvia miltiorrhiza injection (SMI) is a classical traditional Chinese medicine, which plays an active role in the treatment of many diseases such as promoting blood circulation, removing blood stasis, reducing inflammatory reaction, and improving acute lung injury (ALI). Previous studies have shown that matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in the pathophysiological process of ALI. However, the relationship between SMI and MMPs/TIMPs remains unclear. In this study, Wistar rats were randomly divided into control group (NC), Salvia miltiorrhiza group (SM), lipopolysaccharide group (LPS), and Salvia miltiorrhiza treatment group (Tsm). The four groups were subdivided into four time points (2, 6, 12, and 24 hours), and specimens were collected after animal sacrifice at each time point. Serum TNF-α and IL-6 levels were detected by ELISA. The degree of lung injury was determined by lung tissue hematoxylin-eosin staining, lung wet/dry weight (W/D) ratio, and lung permeability index. The changes in lung MMPs/TIMPs protein and mRNA were detected by Western blot and real-time quantitative PCR. The results showed that rats injected with LPS experience acute lung injury, and the ratio of MMPs/TIMPs in lung tissues increased gradually with time. In the Tsm group, the ratio of MMPs/TIMPs decreased gradually, and likewise, the balance was gradually restored, while indicators related to lung injury were gradually declined. These data suggest that SMI alleviates LPS-induced acute lung injury; this protective effect may be related to regulation of the balance of MMPs/TIMPs ratio.

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“…Costa et al developed an experimental model of ARDS, induced by nebulized LPS, and they found that, 24 h after LPS, the animals showed increased pro-inflammatory cytokine levels, increased total septal volume, and a thickening associated with reduced surface density of the alveolar septa. However, after five weeks, the animals showed an increased total lung volume and accentuated collagen deposition, particularly collagen subtype I, associated with reduced MMP-2 protein expression [188]. This model could contribute to a better understanding of the remodeling process in ARDS, and the development of preventive or therapeutic strategies, to counteract lung remodeling in ARDS.…”

Section: Extracellular Matrix Remodeling In Ardsmentioning

confidence: 99%

“…* ALI induced by Escherichia coli LPS intratracheal or intraperitoneal administration [174]. ALI induced by LPS intranasal [187] or intratracheal administration [191] or LPS nebulization [188].…”

Section: Figurementioning

confidence: 99%

Extracellular Matrix Component Remodeling in Respiratory Diseases: What Has Been Found in Clinical and Experimental Studies?

Ito

Lourenço

Righetti

et al. 2019

Cells

125

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Changes in extracellular matrix (ECM) components in the lungs are associated with the progression of respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). Experimental and clinical studies have revealed that structural changes in ECM components occur under chronic inflammatory conditions, and these changes are associated with impaired lung function. In bronchial asthma, elastic and collagen fiber remodeling, mostly in the airway walls, is associated with an increase in mucus secretion, leading to airway hyperreactivity. In COPD, changes in collagen subtypes I and III and elastin, interfere with the mechanical properties of the lungs, and are believed to play a pivotal role in decreased lung elasticity, during emphysema progression. In ARDS, interstitial edema is often accompanied by excessive deposition of fibronectin and collagen subtypes I and III, which can lead to respiratory failure in the intensive care unit. This review uses experimental models and human studies to describe how inflammatory conditions and ECM remodeling contribute to the loss of lung function in these respiratory diseases.

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Early and late pulmonary effects of nebulized LPS in mice: An acute lung injury model

Cited by 75 publications

References 41 publications

A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation

A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation

Salvia miltiorrhiza Injection Alleviates LPS‐Induced Acute Lung Injury by Adjusting the Balance of MMPs/TIMPs Ratio

Extracellular Matrix Component Remodeling in Respiratory Diseases: What Has Been Found in Clinical and Experimental Studies?

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