Inhaled all-trans retinoic acid in an individual with severe emphysema

Frankenberger, Marion; Heimbeck, Irene; Möller, Winfried; Mamidi, Srinivas; Kaßner, Gudrun; Pukelsheim, Katrin; Neiswirth, Margot; Kroneberg, Philipp; Lomas, David A.; Halsall, DJ; Iadarola, Paolo; Fertl, Andreas; Häußinger, K.; Ziegler-Heitbrock, Löms

doi:10.1183/09031936.00105309

Cited by 21 publications

(17 citation statements)

References 15 publications

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“…Limited reversal of functional parameters and of an aerosol-derived measure of airspace size was seen in a papain-induced model of emphysema in dogs [38]. Likewise, clinical studies reported only limited therapeutic effects in humans [15][16][17][18]. As species-and strainspecific differences may account for these discrepancies, we used the same rat strain and therapeutic regimen as in the study performed by MASSARO and MASSARO [7].…”

Section: Discussionmentioning

confidence: 99%

“…First-strand cDNA was synthesised by introducing equal amounts of RNA (1.5 mg) from each sample in a total reaction volume of 20 mL using an oligo (dT) [12][13][14][15][16][17][18] primer (Invitrogen) and Superscript TM II Reverse Transcriptase kit (Invitrogen).…”

Section: Stimulation Of Epithelial Cells In Vitromentioning

confidence: 99%

“…In addition, several experimental studies in rats and mice suggested that regeneration of lost alveolar septa can be achieved by ATRA in elastase-or cigarette smoke-induced emphysema [6][7][8]. However, a number of studies failed to demonstrate a beneficial effect of ATRA in other emphysema models [9][10][11][12][13][14], and beneficial effects in human patients have been marginal so far [15][16][17][18]. The reason for these discrepancies is still unclear [19].…”

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confidence: 99%

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

Seifart

Muyal

Plagens

et al. 2011

European Respiratory Journal

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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: Discussionmentioning

confidence: 99%

Section: Stimulation Of Epithelial Cells In Vitromentioning

confidence: 99%

mentioning

confidence: 99%

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

Seifart

Muyal

Plagens

et al. 2011

European Respiratory Journal

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“…Successful in vivo administration of atRA by intratracheal instillation resulted in a longer half-life of drug compared to intravenous administration (IV) [204]. Inhaled atRAliposomes were safely administered to a patient with extensive emphysema [205]. Vitamins B and C were successfully spray dried to maintain stability and controlled release in food processing yielding microparticles that would potentially be suitable for inhalation [81], while vitamin E metabolites have also been formulated into many preparations, including liposomes, decreasing mortality in an in vivo lung hypoxia model by half [206].…”

Section: Formulation Experience With Hdt In Clinical and Non-clinicalmentioning

confidence: 99%

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery

O'Connor

Gleeson

Fagan-Murphy

et al. 2016

Advanced Drug Delivery Reviews

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“…Taken together, these studies suggest that the total lung deposition of AAT is approximately 70% of the filling dose, irrespective of the degree of lung function impairment, and that this resulted, in short term treatment, and a clear reduction in signs of airway inflammation in CF patients. The AKITA² APIXNEB® equipment has also been used to aerosolize all-trans retinoic acid in a single case of severe emphysema, with improvement in lung function and inflammatory parameters [24] .…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolised with a highly efficient nebulizer

Luisetti

Kroneberg²,

Suzuki

et al. 2011

Pulmonary Pharmacology & Therapeutics

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Pulmonary alveolar proteinosis (PAP) is a rare condition characterized by the accumulation of lipoproteinaceous material within air spaces. Although whole lung lavage is the current standard of care, recent advances in our understanding of PAP pathophysiology suggest that the disorder may benefit from inhalation of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). The aim of this study was to determine the physical properties and bioactivity of rGM-CSF aerosolized by the highly efficient AKITA² APIXNEB® nebulizer system. The physical properties of aerosolised rGM-CSF were investigated in terms of droplet size, output and output rate by laser diffraction and gravimetrical analysis. Lung deposition was assessed using deposition modeling (ICRP). Molecular mass before and after aerosolisation was determined by SDS-PAGE, while the bioactivity of rGM-CSF was evaluated by measuring the GM-CSF-stimulated increase in pSTAT-5 using mAM-hGM-R cells. Ninety-six % of the rGM-CSF filling dose was aerosolized with the Akita 2 Apixneb® nebulizer system. Particle size was highly reproducible, and the amount deposited within the lung was 80.35% of the delivered dose. The aerosolisation did not alter the molecular structure of rGM-CSF, nor its ability to stimulate the pSTAT-5, which increased by 99.5%, similar to values for rGM-CSF prior to aerosolisation. We conclude that the highly efficient AKITA² APIXNEB® nebulizer system is likely to efficaciously deliver rGM-CSF to the airways of patients with autoimmune PAP.

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Inhaled all-trans retinoic acid in an individual with severe emphysema

Cited by 21 publications

References 15 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

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery

Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolised with a highly efficient nebulizer

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