Time course of metabolic activity and cellular infiltration in a murine model of acid-induced lung injury

Zambelli, Vanessa; Grigoli, Giuseppe Di; Scanziani, Margherita; Valtorta, Silvia; Amigoni, Maria; Belloli, Sara; Messa, Cristina; Pesenti, Antonio; Fazio, Ferruccio; Bellani, Giacomo; Moresco, Rosa María

doi:10.1007/s00134-011-2456-1

Cited by 22 publications

(19 citation statements)

References 41 publications

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“…We used eight healthy mice as naïve controls as they did not receive any instillation into the main right bronchus, but they were ventilated and treated as the HCl instilled mice. Five mice only received "vehicle" (NaCl 0.9%) into the right main bronchus and they were killed 24 h after the instillation, as previous studies showed that this was the peak time of lung injury (8,39). Therefore the study included six groups of lungs: (1) injured (I) right lung; (2) contralateral noninjured (NI) left lung; (3) naïve control right lung; (4) naïve control left lung; (5) NaCl control right lung; (6) NaCl control left lung.…”

Section: Methodsmentioning

confidence: 99%

Pulmonary surfactant synthesis after unilateral lung injury in mice

Lamonica

Amigoni

Vedovelli

et al. 2014

Journal of Applied Physiology

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Aspiration pneumonitis can lead to alveolar surfactant dysfunction. We employed a murine model of unilateral aspiration to compare surfactant synthesis in the injured (I) and noninjured (NI) contralateral lung. Mice were instilled with hydrochloric acid in the right bronchus and, after 18 h, an intraperitoneal dose of deuterated water was administered as precursor of disaturated phosphatidylcholine (DSPC)-palmitate. Selected bronchoalveolar lavage fluid (BALF) was collected at scheduled time points and lungs were removed. We measured DSPC-palmitate synthesis in lung tissue and secretion in BALF by gas chromatography-isotope ratio mass spectrometry, together with total proteins and myeloperoxidase activity (MPO) by spectrophotometry. BALF total proteins and MPO were significantly increased in the I lungs compared with NI and naïve control lungs. The DSPC pool size was significantly lower in the BALF of the I lungs compared with naïve controls. DSPC synthesis was accelerated in the I and NI lungs. DSPC secretion of the I lungs was similar to their respective naïve controls, and it was markedly lower compared with their respective NI contralateral lungs. DSPC synthesis and secretion were faster, especially in the NI lungs, compared with naïve control lungs, as a possible compensatory mechanism due to a cross-talk between the lungs triggered by inflammation, hyperventilation, and/or undetermined type II cell reaction to the injury.

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Section: Methodsmentioning

confidence: 99%

Pulmonary surfactant synthesis after unilateral lung injury in mice

Lamonica

Amigoni

Vedovelli

et al. 2014

Journal of Applied Physiology

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“…Another recent study demonstrated massive recruitment of neutrophils and macrophages into the lung that was associated with fibrotic evolution in a murine, HCl-induced lung injury model but the mechanisms involved were not investigated [28]. The present in vitro model mimics the in vivo conditions, and provides mechanistic insights demonstrating that the interaction of monocytes with the injured lung epithelial cells after HCl challenge accelerates the lung remodeling process.…”

Section: Discussionmentioning

confidence: 92%

Monocyte interaction accelerates HCl-induced lung epithelial remodeling

et al. 2014

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BackgroundAcute respiratory distress syndrome (ARDS) is characterized by overwhelming inflammatory responses and lung remodeling. We hypothesized that leukocyte infiltration during the inflammatory response modulates epithelial remodeling through a mechanism of epithelial-mesenchymal transition (EMT).MethodsHuman lung epithelial cells were treated for 30 min with hydrochloric acid (HCl). Human monocytes were then cocultured with the epithelial cells for up to 48 h, in the presence or absence of blocking peptides against lymphocyte function-associated antigen-1 (LFA-1), or tyrphostin A9, a specific inhibitor for platelet-derived growth factor (PDGF) receptor tyrosine kinase.ResultsExposure of lung epithelial cells to HCl resulted in increased expression of intercellular adhesion molecule-1 (ICAM-1) and production of interleukin (IL)-8 at 24 h. The expression of the epithelial markers E-cadherin decreased while the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) increased at 24 h and remained high at 48 h. The addition of monocytes augmented the profiles of lower expression of epithelial markers and higher mesenchymal markers accompanied by increased collagen deposition. This EMT profile was associated with an enhanced production of IL-8 and PDGF. Treatment of the lung epithelial cells with the LAF-1 blocking peptides CD11a237–246 or/and CD18112–122 suppressed monocyte adhesion, production of IL-8, PDGF and hydroxyproline as well as EMT markers. Treatment with tyrphostin A9 prevented the EMT profile shift induced by HCl stimulation.ConclusionsThe interaction between epithelial cells and monocytes enhanced epithelial remodelling after initial injury through EMT signalling that is associated with the release of soluble mediators, including IL-8 and PDGF.

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“…Lung uptake of 18 F-FDG on PET is well recognized as a hallmark of ALI/ARDS [18,19,22,23]. 18 F-FDG uptake by the lungs and has been shown to correlate with neutrophil influx into the lungs in a variety of experimental pulmonary inflammatory lesions [21,26,27,32,33]. Previously we demonstrated, in a small clinical series, that diffuse lung uptake of 18 F-FDG PET was present 1–3 days prior to the point at which the clinical diagnostic criteria for ARDS were met [22].…”

Section: Discussionmentioning

confidence: 99%

“…However, these methods may be limited by heterogeneity in expression of biomarkers. Previous studies have indicated infiltration of neutrophils may represent the major component of 18 F-FDG uptake in lung parenchyma in ALI [26,27]. The goal of this study was to characterize the time course for pulmonary uptake of 18 F-FDG relative to neutrophil influx and to compare this to development of increased tomographic density (pulmonary edema) in a rat model of endotoxin (LPS)-induced ALI.…”

Section: Introductionmentioning

confidence: 99%

18 F-fluoro-2-deoxyglucose PET informs neutrophil accumulation and activation in lipopolysaccharide-induced acute lung injury

Rodrigues

Bozza

Hanrahan

et al. 2017

Nuclear Medicine and Biology

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Introduction Molecular imaging of the earliest events related to the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) could facilitate therapeutic development and patient management. We previously reported that 18F-fluoro-2-deoxyglucose (18F-FDG) PET identifies ALI/ARDS prior to radiographic abnormalities. The purpose of this study was to establish the time courses of 18F-FDG uptake, edema and neutrophil recruitment in an endotoxin-induced acute lung injury model and to examine molecular events required for 14C-2DG uptake in activated neutrophils. Methods Lung uptake of 18F-FDG was measured by PET in control male Sprague Dawley rats and at 2, 6 and 24 hours following the intraperitoneal injection of 10 mg/kg LPS. Lung edema (attenuation) was measured by microCT. Neutrophil influx into the lungs was measured by myeloperoxidase assay. Control and activated human donor neutrophils were compared for uptake of 14C-2DG, transcription and content of hexokinase and GLUT isoforms and for hexokinase (HK) activity. Results Significant uptake of 18F-FDG occurred by 2h following LPS, and progressively increased to 24h. Lung uptake of 18F-FDG preceded increased CT attenuation (lung edema). Myeloperoxidase activity in the lungs, supporting neutrophil influx, paralleled 18F-FDG uptake. Activation of isolated human neutrophils resulted in increased uptake of 14C-2DG, expression of GLUT 3 and GLUT 4 and expression and increased HK1 activity. Conclusion Systemic endotoxin-induced ALI results in very early and progressive uptake of 18F-FDG, parallels neutrophil accumulation and occurs earlier than lung injury edema. Activated neutrophils show increased uptake of 14C-2DG, expression of specific GLUT3, GLUT4 and HK1 protein and HK activity. Advances in knowledge and implications for patient care 18F-FDG pulmonary uptake is an early biomarker of neutrophil recruitment in ALI and is associated with specific molecular events that mediate 14C-2DG uptake in activated neutrophils. 18F-FDG PET may provide a potential mechanism for early diagnosis and therapeutic assessment of ALI/ARDS.

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Time course of metabolic activity and cellular infiltration in a murine model of acid-induced lung injury

Abstract: This study demonstrated that PET imaging is a valid means of tracking the inflammatory response, also in longitudinal studies. Moreover, a correlation was found between persistence of the inflammatory response and fibrotic evolution of the injury.

Cited by 22 publications

References 41 publications

Pulmonary surfactant synthesis after unilateral lung injury in mice

Pulmonary surfactant synthesis after unilateral lung injury in mice

Monocyte interaction accelerates HCl-induced lung epithelial remodeling

18 F-fluoro-2-deoxyglucose PET informs neutrophil accumulation and activation in lipopolysaccharide-induced acute lung injury

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