Role of sphingosine kinase 1 in allergen-induced pulmonary vascular remodeling and hyperresponsiveness

Background

Immunologic processes might contribute to the pathogenesis of pulmonary arterial hypertension (PAH), a fatal condition characterized by progressive pulmonary arterial remodeling, increased pulmonary vascular resistance, and right ventricular failure. Experimental allergen-driven lung inflammation evoked morphologic and functional vascular changes that resembled those observed in patients with PAH. Sphingosine kinase 1 (SphK1) is the main pulmonary contributor to sphingosine-1-phosphate (S1P) synthesis, a modulator of immune and vascular functions.

Objective

We sought to investigate the role of SphK1 in allergen-induced lung inflammation.

Methods

SphK1-deficient mice and C57Bl/6 littermates (wild-type [WT] animals) were subjected to acute or chronic allergen exposure.

Results

After 4 weeks of systemic ovalbumin sensitization and local airway challenge, airway responsiveness increased less in SphK1^−/− compared with WT mice, whereas pulmonary vascular responsiveness was greatly increased and did not differ between strains. Acute lung inflammation led to an increase in eosinophils and mRNA expression for S1P phosphatase 2 and S1P lyase in lungs of WT but not SphK1^−/− mice.

After repetitive allergen exposure for 8 weeks, airway responsiveness was not augmented in SphK1^−/− or WT mice, but pulmonary vascular responsiveness was increased in both strains, with significantly higher vascular responsiveness in SphK1^−/− mice compared with that seen in WT mice. Increased vascular responsiveness was accompanied by remodeling of the small and intra-acinar arteries.

Conclusion:

The data support a role for SphK1 and S1P in allergen-induced airway inflammation. However, SphK1 deficiency increased pulmonary vascular hyperresponsiveness, which is a component of PAH pathobiology. Moreover, we show for the first time the dissociation between inflammation-induced remodeling of the airways and pulmonary vasculature.

Key words: Pulmonary arterial hypertension, allergen-induced lung inflammation, vascular remodeling, perfused mouse lung, sphingosine kinase, sphingosine 1-phosphate

Abbreviations used: BAL, Bronchoalveolar lavage, CT, Threshold cycle, G-CSF, Granulocyte colony-stimulating factor, HPRT, Hypoxanthine guanine phosphoribosyl transferase, MCh, Methacholine, OVA, Ovalbumin, PAH, Pulmonary arterial hypertension, Ppa, Pulmonary arterial pressure, S1P, Sphingosine-1-phospate, S1P1, Sphingosine-1-phospate receptor subtype 1, S1Ply, Sphingosine-1-phosphate lyase, S1PP, Sphingosine-1-phosphate phosphatase, SphK1, Sphingosine kinase 1, WT, Wild-type