Abstract
In asthma, excessive bronchial narrowing associated with thickening of the airway smooth muscle (ASM) causes respiratory distress. Numerous pharmacological agents prevent experimental airway hyperresponsiveness (AHR) when delivered prophylactically. However, most fail to resolve this feature after disease is instated. Although sphingosine analogs are primarily perceived as immune modulators with the ability to prevent experimental asthma, they also influence processes associated with tissue atrophy, supporting the hypothesis that they could interfere with mechanisms sustaining pre-established AHR. We thus assessed the ability of a sphingosine analog (AAL-R) to reverse AHR in a chronic model of asthma. We dissected the pharmacological mechanism of this class of agents using the non-phosphorylatable chiral isomer AAL-S and the pre-phosphorylated form of AAL-R (AFD-R) in vivo and in human ASM cells. We found that a therapeutic course of AAL-R reversed experimental AHR in the methacholine challenge test, which was not replicated by dexamethasone or the non-phosphorylatable isomer AAL-S. AAL-R efficiently interfered with ASM cell proliferation in vitro, supporting the concept that immunomodulation is not necessary to interfere with cellular mechanisms sustaining AHR. Moreover, the sphingosine-1-phosphate lyase inhibitor SM4 and the sphingosine-1-phosphate receptor antagonist VPC23019 failed to inhibit proliferation, indicating that intracellular accumulation of sphingosine-1-phosphate or interference with cell surface S1P1/S1P3 activation, are not sufficient to induce cytostasis. Potent AAL-R-induced cytostasis specifically related to its ability to induce intracellular AFD-R accumulation. Thus, a sphingosine analog that possesses the ability to be phosphorylated in situ interferes with cellular mechanisms that beget AHR.
Highlights
Asthma is a prevalent and complex syndrome (Lotvall et al, 2011)
Using a model where persistent airway smooth muscle (ASM) thickening and airway hyperresponsiveness (AHR) are pre-established using chronic exposure to house dust mite (HDM) (Figure 2), we first evaluated the in vivo potential of AAL-R to reverse AHR, when administered at well-tolerated doses, yet sufficient to induce biological effects
We found that AAL-R (1 mg/kg/day) reversed HDM-induced AHR to a level 70% lower than the vehicle treatment (Figure 3)
Summary
Asthma is a prevalent and complex syndrome (Lotvall et al, 2011). Alarmingly, a significant proportion of asthmatic patients responds poorly to mainstay therapies, some achieving symptom control only with oral prednisone; and others remaining refractory to any pharmacological option currently available (Reddel et al, 2015). Among the multiple factors that interact to elicit AHR, the increased amount of smooth muscle within the airway wall is thought to contribute significantly. This paradigm is fuelled by several observations. Strategies that aim at reducing the amount of ASM should benefit asthmatic patients by reducing their level of airway responsiveness. In this regard, bronchial thermoplasty, an interventional procedure proven to reduce ASM volume (Salem et al, 2016), decreases by nearly 50% the rate of exacerbations in patients with moderate to severe persistent asthma (Wechsler et al, 2013). There is currently no pharmacological treatment that efficiently reverses ASM thickening
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