Abstract
BackgroundThe 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.ObjectiveThe present study explored the potential of S-NACH in blocking allergic asthma and examined the potential mechanism by which it exerts its effects.MethodsAcute 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.ResultsSulfated-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.ConclusionsOur 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.
Highlights
The efficacy of heparins and low-MW-heparins (LMWH) against human asthma has been known for decades
These protective effects of Sulfated-non-anticoagulant heparin (S-NACH) may be attributed to modulation of the IL-4/JAK1 signal transduction pathway through an inhibition of signal transducer and activator of transcription 6 (STAT6) phosphorylation and a subsequent inhibition of GATA-3 and inducible NO synthase expression
Our study demonstrates that S-NACH constitutes an opportunity to benefit from the well-known antiasthma properties of heparins/LMWH while bypassing the risk of bleeding
Summary
The efficacy of heparins and low-MW-heparins (LMWH) against human asthma has been known for decades. Much effort has been put into harnessing the anti-inflammatory properties of LMWH but none have been used as therapy for asthma. Heparin and its low molecular weight derivatives (LMWH) are increasingly regarded to harbor antiinflammatory traits that may be harnessed therapeutically against various inflammatory diseases including asthma [4,5,6]. In a clinical trial conducted almost two decades ago, an inhaled form of the LMWH enoxaparin was shown to prevent exercise-induced bronchoconstriction in asthmatics [7], which opened the possibility for these compounds to be used as therapeutic agents against some asthma traits. Patel et al demonstrated that LMWH and montelukast can be combined into an inhalable particulate system that harbors efficient anti-inflammatory effects against ovalbumin (OVA)-induced asthma in rats [9]. The major obstacle against the viability of LMWHs against asthma and other inflammatory disease is their anticoagulant property and the unacceptable risk for excessive bleeding [4,5,6]
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