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Efficacy of Optimized Treatment Protocol Using LAU-7b Formulation against Ovalbumin (OVA) and House Dust Mite (HDM) -Induced Allergic Asthma in Atopic Hyperresponsive A/J Mice

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Abstract

Purpose

To assess the efficacy of the novel clinical formulation of fenretinide (LAU-7b) for the treatment of allergic asthma. To study the association between LAU-7b treatment in allergic asthma and the modulation of very long chain ceramides (VLCC).

Methods

We used two allergens (OVA and HDM) to induce asthma in mouse models and we established a treatment protocol with LAU-7b. The severity of allergic asthma reaction was quantified by measuring the airway resistance, quantifying lung inflammatory cell infiltration (Haematoxylin and eosin stain) and mucus production (Periodic acid Schiff satin). IgE levels were measured by ELISA. Immunophenotyping of T cells was done using Fluorescence-activated cell sorting (FACS) analysis. The analysis of the specific species of lipids and markers of oxidation was performed using mass spectrometry.

Results

Our data demonstrate that 10 mg/kg of LAU-7b was able to protect OVA- and HDM-challenged mice against increase in airway hyperresponsiveness, influx of inflammatory cells into the airways, and mucus production without affecting IgE levels. Treatment with LAU-7b significantly increased percentage of regulatory T cells and CD4+ IL-10-producing T cells and significantly decreased percentage of CD4+ IL-4-producing T cells. Our data also demonstrate a strong association between the improvement in the lung physiology and histology parameters and the drug-induced normalization of the aberrant distribution of ceramides in allergic mice.

Conclusion

9 days of 10 mg/kg of LAU-7b daily treatment protects the mice against allergen-induced asthma and restores VLCC levels in the lungs and plasma.

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Abbreviations

AA:

Arachidonic acid

AHR:

Airway hyperresponsiveness

ANOVA:

Analysis of variance

C1P:

Ceramide-1-phosphate

DHA:

Docosahexaenoic acid

ELISA:

Enzyme-linked immunosorbent assay

FEN:

Fenretinide

H&E:

Haematoxylin and eosin

HDM:

House dust mite

i.n.:

Intranasal

i.p.:

Intraperitoneal

LCC:

Long chain ceramides

MDA:

Malondialdehyde

MCh:

Methacholine

NT:

Nitrotyrosine

OVA:

Ovalbumin

p.o.:

per os

PAS:

Periodic acid Schiff

S1P:

Sphingosine-1-phosphate

VLCC:

Very long chain ceramides

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Authors and Affiliations

  1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

    Mina Youssef, Cynthia Kanagaratham & Danuta Radzioch

  2. Program in Infectious Diseases and Immunity in Global Health, McGill University Health Center, 1001 Decarie Boulevard, Room EM3-3211, Montreal, Quebec, H4A 3J1, Canada

    Mina Youssef, Cynthia Kanagaratham, Shao Tao, Eisha Ahmed & Danuta Radzioch

  3. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

    Juan B. De Sanctis

  4. Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Cynthia Kanagaratham

  5. Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada

    Shao Tao, Eisha Ahmed & Danuta Radzioch

Authors
  1. Mina Youssef
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  2. Juan B. De Sanctis
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  3. Cynthia Kanagaratham
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  4. Shao Tao
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Correspondence to Danuta Radzioch.

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Youssef, M., De Sanctis, J.B., Kanagaratham, C. et al. Efficacy of Optimized Treatment Protocol Using LAU-7b Formulation against Ovalbumin (OVA) and House Dust Mite (HDM) -Induced Allergic Asthma in Atopic Hyperresponsive A/J Mice. Pharm Res 37, 31 (2020). https://doi.org/10.1007/s11095-019-2743-z

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