Sulfated non-anticoagulant heparin blocks Th2-induced asthma by modulating the IL-4/signal transducer and activator of transcription 6/Janus kinase 1 pathway

Autor: Ilyes Benslimane, Mohamed A. Ghonim, A. Hamid Boulares, Hanh H Luu, Shaker A. Mousa, Jeffrey Wang, Salome V. Ibba, Kusma Pyakurel
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
S-NACH
Allergy
Anti-Inflammatory Agents
lcsh:Medicine
Cell Separation
Pharmacology
Immunoglobulin E
Mice
0302 clinical medicine
Medicine
STAT6
biology
Janus kinase 1
General Medicine
Heparin
respiratory system
Flow Cytometry
3. Good health
030220 oncology & carcinogenesis
Low-MW-heparins (LMWH)
Th2 inflammation
Signal transduction
Signal Transduction
medicine.drug
Ovalbumin
Hemorrhage
General Biochemistry
Genetics and Molecular Biology
Cell Line
Animal models of asthma
03 medical and health sciences
Th2 Cells
Hypersensitivity
Animals
Humans
Interleukin 4
business.industry
Research
lcsh:R
Anticoagulants
Janus Kinase 1
Asthma
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
A549 Cells
biology.protein
STAT protein
Protein expression
Interleukin-4
STAT6 Transcription Factor
business
Therapeutic potential
Spleen
Zdroj: Journal of Translational Medicine, Vol 16, Iss 1, Pp 1-12 (2018)
Journal of Translational Medicine
ISSN: 1479-5876
Popis: Background The efficacy of heparins and low-MW-heparins (LMWH) against human asthma has been known for decades. However, the clinical utility of these compounds has been hampered by their anticoagulant properties. Much effort has been put into harnessing the anti-inflammatory properties of LMWH but none have been used as therapy for asthma. Sulfated-non-anticoagulant heparin (S-NACH) is an ultra-LMWH with no systemic anticoagulant effects. Objective The present study explored the potential of S-NACH in blocking allergic asthma and examined the potential mechanism by which it exerts its effects. Methods Acute and chronic ovalbumin-based mouse models of asthma, splenocytes, and a lung epithelial cell line were used. Mice were challenged with aerosolized ovalbumin and administered S-NACH or saline 30 min after each ovalbumin challenge. Results Sulfated-non-anticoagulant heparin administration in mice promoted a robust reduction in airway eosinophilia, mucus production, and airway hyperresponsiveness even after chronic repeated challenges with ovalbumin. Such effects were linked to suppression of Th2 cytokines IL-4/IL-5/IL-13/GM-CSF and ovalbumin-specific IgE without any effect on IFN-γ. S-NACH also reduced lung fibrosis in mice that were chronically-exposed to ovalbumin. These protective effects of S-NACH may be attributed to modulation of the IL-4/JAK1 signal transduction pathway through an inhibition of STAT6 phosphorylation and a subsequent inhibition of GATA-3 and inducible NO synthase expression. The effect of the drug on STAT6 phosphorylation coincided with a reduction in JAK1 phosphorylation upon IL-4 treatment. The protective effects of S-NACH treatment was associated with reduction of the basal expression of the two isoforms of arginase ARG1 and ARG2 in lung epithelial cells. Conclusions Our study demonstrates that S-NACH constitutes an opportunity to benefit from the well-known anti-asthma properties of heparins/LMWH while bypassing the risk of bleeding. Our results show, for the first time, that such anti-asthma effects may be associated with reduction of the IL-4/JAK1/STAT6 pathway.
Databáze: OpenAIRE
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