Caffeine administration modulates TGF-β signaling but does not attenuate blunted alveolarization in a hyperoxia-based mouse model of bronchopulmonary dysplasia

Rath, Philipp; Nardiello, Claudio; Solaligue, David E. Surate; Agius, Ronald; Mižíková, Ivana; Mayer, Konstantin; Vadász, István; Herold, Susanne; Runkel, Frank; Seeger, Werner; Morty, Rory E.

doi:10.1038/pr.2017.21

Cited by 38 publications

(47 citation statements)

References 38 publications

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“…6 and Table 1). Confirming previous reports [15,36,37], exposure of newborn wildtype mice to 85% O 2 for the first 2 weeks of postnatal life caused alveolar simplification, which was evident by fewer alveoli, which were of a larger size ( Fig. 6B) in comparison to the alveolar structure noted in 21% O 2 -exposed wild-type mice (Fig.…”

Section: Tgm2 Does Not Mediate the Effects Of Hyperoxia On Lung Alveosupporting

confidence: 92%

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

et al. 2018

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The generation, maturation and remodelling of the extracellular matrix (ECM) are essential for the formation of alveoli during lung development. Alveoli formation is disturbed in preterm infants that develop bronchopulmonary dysplasia (BPD), where collagen fibres are malformed, and perturbations to lung ECM structures may underlie BPD pathogenesis. Malformed ECM structures might result from abnormal protein cross-linking, in part attributable to the increased expression and activity of transglutaminase 2 (TGM2) that have been noted in affected patient lungs, as well as in hyperoxia-based BPD animal models. The objective of the present study was to assess whether TGM2 plays a causal role in normal and aberrant lung alveolarization. Targeted deletion of Tgm2 in C57BL/6J mice increased septal thickness and reduced gas-exchange surface area in otherwise normally developing lungs. During aberrant lung alveolarization that occurred under hyperoxic conditions, collagen structures in Tgm2 mice were partially protected from the impact of hyperoxia, where normal dihydroxylysinonorleucine and hydroxylysylpiridinoline collagen cross-link abundance was restored; however, the lung alveolar architecture remained abnormal. Inhibition of transglutaminases (including TGM2) with cysteamine appreciably reduced transglutaminase activity in vivo, as assessed by N -(γ-l-glutamyl)-l-lysine abundance and TGM catalytic activity, and restored normal dihydroxylysinonorleucine and hydroxylysylpiridinoline collagen cross-link abundance under pathological conditions. Furthermore, a moderate improvement in alveoli size and gas-exchange surface density was noted in cysteamine-treated mouse lungs in which BPD was modelled. These data indicate that TGM2 plays a role in normal lung alveolarization, and contributes to the formation of aberrant ECM structures during disordered lung alveolarization.

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Section: Tgm2 Does Not Mediate the Effects Of Hyperoxia On Lung Alveosupporting

confidence: 92%

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

et al. 2018

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“…; Rath et al. ). Mouse lungs were fixed through intratracheal installation of a mixture of 1.5% (w/v) paraformaldehyde (Sigma, Darmstadt, Germany; P6148) and 1.5% (w/v) glutaraldehyde (Serva, Heidelberg, Germany, 23116.02) in 150 m m HEPES (Sigma; H0887) dissolved in phosphate‐buffered saline (PBS; Sigma; D8537), pH 7.4.…”

Section: Methodsmentioning

confidence: 98%

“…; Rath et al. ). Specific to the present study, the arithmetic mean septal thickness, τ (sep), was assessed by two different approaches using the individual lung lobes.…”

Section: Methodsmentioning

confidence: 98%

“…All methods employed for the analysis of lung structure were based on American Thoracic Society/European Respiratory Society recommendations for quantitative assessment of lung structure (Hsia et al 2010). The protocol employed for the design-based stereological analysis of neonatal mouse lungs has been described in detail previously (Nardiello et al 2017b;Pozarska et al 2017;Rath et al 2017). Mouse lungs were fixed through intratracheal installation of a mixture of 1.5% (w/v) paraformaldehyde (Sigma, Darmstadt, Germany; P6148) and 1.5% (w/v) glutaraldehyde (Serva, Heidelberg, Germany, 23116.02) in 150 mM HEPES (Sigma; H0887) dissolved in phosphate-buffered saline (PBS; Sigma; D8537), pH 7.4.…”

Section: Design-based Stereologymentioning

confidence: 99%

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Stereological analysis of individual lung lobes during normal and aberrant mouse lung alveolarisation

et al. 2018

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The quantitative assessment of the lung architecture forms the foundation of many studies on lung development and lung diseases, where parameters such as alveoli number, alveolar size, and septal thickness are quantitatively influenced by developmental or pathological processes. Given the pressing need for robust data that describe the lung structure, there is currently much enthusiasm for the development and refinement of methodological approaches for the unbiased assessment of lung structure with improved precision. The advent of stereological methods highlights one such approach. However, design-based stereology is both expensive and time-demanding. The objective of this study was to examine whether 'limited' stereological analysis, such as the stereological analysis of a single mouse lung lobe, may serve as a surrogate for studies on whole, intact mouse lungs; both in healthy lungs and in diseased lungs, using an experimental animal model of bronchopulmonary dysplasia (BPD). This served the dual-function of exploring BPD pathobiology, asking whether there are regional (lobar) differences in the responses of developing mouse lungs to oxygen injury, by examining each mouse lung lobe separately in the BPD model. Hyperoxia exposure resulted in decreased alveolar density, alveoli number, and gas-exchange surface area in all five mouse lung lobes, and increased the arithmetic mean septal thickness in all mouse lung lobes except the lobus cardialis. The data presented here suggest that - in healthy developing mice - a single mouse lung lobe might serve as a surrogate for studies on whole, intact mouse lungs. This is not the case for oxygen-injured developing mouse lungs, where a single lobe would not be suitable as a surrogate for the whole, intact lung. Furthermore, as the total number of alveoli can only be determined by an analysis of the entire lung, and given regional differences in lung structure, particularly under pathological conditions, the stereological assessment of the whole, intact lung remains desirable.

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“…Using the hyperoxia model of experimental BPD, caffeine could protect against alveolar simplification and inflammation in rats (82, 83) and rabbits (84), but not in mice (85, 86). Potential mechanisms include its abilities to amplify glucocorticoid-mediated SP-B expression in alveolar type 2 cells (87, 88), to modulate connective tissue growth factor (CTGF) expression (89) and TGFβ pathway members (85), and to attenuate endoplasmic reticulum (ER) stress (82). Conflictingly, both up- and downregulation of alveolar apoptosis has been reported (82, 86).…”

Section: Bpd In 2017mentioning

confidence: 99%

The Future of Bronchopulmonary Dysplasia: Emerging Pathophysiological Concepts and Potential New Avenues of Treatment

Collins¹,

Tibboel²,

Kleer³

et al. 2017

Front. Med.

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Yearly more than 15 million babies are born premature (<37 weeks gestational age), accounting for more than 1 in 10 births worldwide. Lung injury caused by maternal chorioamnionitis or preeclampsia, postnatal ventilation, hyperoxia, or inflammation can lead to the development of bronchopulmonary dysplasia (BPD), one of the most common adverse outcomes in these preterm neonates. BPD patients have an arrest in alveolar and microvascular development and more frequently develop asthma and early-onset emphysema as they age. Understanding how the alveoli develop, and repair, and regenerate after injury is critical for the development of therapies, as unfortunately there is still no cure for BPD. In this review, we aim to provide an overview of emerging new concepts in the understanding of perinatal lung development and injury from a molecular and cellular point of view and how this is paving the way for new therapeutic options to prevent or treat BPD, as well as a reflection on current treatment procedures.

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Caffeine administration modulates TGF-β signaling but does not attenuate blunted alveolarization in a hyperoxia-based mouse model of bronchopulmonary dysplasia

Abstract: Caffeine modulated TGF-β signaling in vitro and in vivo. Caffeine administration was well-tolerated by newborn mice, but did not influence the course of blunted postnatal lung maturation in a hyperoxia-based experimental mouse model of BPD.

Cited by 38 publications

References 38 publications

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

Stereological analysis of individual lung lobes during normal and aberrant mouse lung alveolarisation

The Future of Bronchopulmonary Dysplasia: Emerging Pathophysiological Concepts and Potential New Avenues of Treatment

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