Can Retinoic Acid Ameliorate the Physiologic and Morphologic Effects of Elastase Instillation in the Rat?

Tepper, Jeffrey S.; Pfeiffer, Juergen; Aldrich, Melinda C.; Tumas, Daniel B.; Kern, Jeffrey A.; Hoffman, Eric A.; McLennan, Geoffrey; Hyde, Dallas M.

doi:10.1378/chest.117.5_suppl_1.242s

Cited by 68 publications

(53 citation statements)

References 4 publications

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“…Analysis of lung function indicated uneven distribution of ventilation consistent with distortion of alveolar geometry and/or altered small airway function induced by ATRA after right-sided pneumonectomy in the dog [42]. These data are supported by the findings of TEPPER et al [43] that 2 weeks of supplementation with ATRA had no effect on compliance, forced flows or diffusing capacity of the lung for carbon monoxide in the rat elastase-model of emphysema, although there was a slight, albeit insignificant increase in computed tomography scan lung tissue density. Notably, ATRA-supplementation had no effect on lung function, alveolar structure, or septal ultrastructure after left-sided pneumonectomy in dogs, which suggests that ATRA does not induce compensatory lung growth in the absence of existing cellular growth activities initiated by other primary signals [44].…”

Section: Discussionsupporting

confidence: 77%

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

et al. 2011

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All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs).Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 mg?kg -1 body weight)versus olive oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA-or vehicle-treatment, respectively. ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by alveolar epithelial cells type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1 + :ED2 + macrophages. Bronchoalveolar lavage (BAL) cells exhibited a proinflammatory state and high expression of interleukin-1b, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-a, nuclear factor-kB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP-2 and TIMP-1 activity in BAL fluid of emphysematous lungs. ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs.

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Section: Discussionsupporting

confidence: 77%

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

et al. 2011

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“…This potential dissociation between alveolar number and function is exemplified in the use of supplemental all-trans-retinoic acid to enhance postnatal alveolar septation. In rats treated with retinoic acid compared with placebo-treated control animals, the alveoli are smaller with more subdivisions, but surface area estimated under light microscopy is unchanged [48] and physiological lung diffusing capacity is not improved [49]. Alveolar capillary growth is associated with increased capillary blood volume, endothelial cell volume as well as surface area, and morphological evidence of capillary formation and/ or subdivision.…”

Section: Markers Of Alveolar Growthmentioning

confidence: 95%

Quantitative morphology of compensatory lung growth

Hsia¹

2006

Eur Respir Rev

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Compensatory lung growth is defined by the absolute increases in the quantity of functioning lung tissue in response to injury and/or disease, leading to a positive impact on functional outcome. The pneumonectomy model is used as an example to illustrate the salient features of compensatory growth and the specific considerations in its morphological quantification, including techniques of sampling and analysis, resolution of ultrastructural details, selection of markers for measurement, and interpretation of results in the context of organ architecture and physiology. The potential for structure-function dissociation is described in the present article. The current paper will discuss the application of high-resolution computed tomography to noninvasively quantify regional anatomy as well as temporal evolution of lung growth.

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“…However, subsequent studies on RA-induced alveolar regeneration have not confirmed these striking results. Some have shown only a partial rescue of alveolar SA in elastase-treated rats [6,7], and others have reported no effect of RA at all [8,9]. In the work reported here, a mouse model for regeneration studies using Dex, which inhibits alveologenesis, administered during the period of alveologenesis is described.…”

mentioning

confidence: 85%

Retinoic acid induces alveolar regeneration in the adult mouse lung

Hind¹,

Maden²

2003

Eur Respir J

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Retinoic acid induces alveolar regeneration in the adult mouse lung. M. Hind, M. Maden. #ERS Journals Ltd 2004. ABSTRACT: Recent data suggests that exogenous retinoic acid (RA) can induce alveolar regeneration in a mouse and a rat model of experimental emphysema and disrupted alveolar development. This may be because RA is required during normal alveolar development and the subsequent provision of RA reawakens the gene cascades used during development.Here, additional evidence that RA is required during alveologenesis in the mouse is provided by showing that disulphiram disrupts this process. A further model of disrupted alveolar development using dexamethasone administered postnatally is then described, and it is further shown that RA administered to these adult mice restores the lung architecture to normal.Alveolar regeneration with retinoic acid may therefore be an important novel therapeutic approach to the treatment of respiratory diseases characterised by a reduced gas-exchanging surface area, such as bronchopulmonary dysplasia and emphysema.

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Can Retinoic Acid Ameliorate the Physiologic and Morphologic Effects of Elastase Instillation in the Rat?

Cited by 68 publications

References 4 publications

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages

Quantitative morphology of compensatory lung growth

Retinoic acid induces alveolar regeneration in the adult mouse lung

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