Ceramide-1-phosphate inhibits cigarette smoke-induced airway inflammation

Abstract

Sphingolipids are involved in the pathogenesis of inflammatory diseases. The central molecule is ceramide, which can be converted into ceramide-1-phosphate (C1P). Although C1P can exert anti-and pro-inflammatory effects, its influence on cigarette smoke (CS)-induced lung inflammation is unknown. We aimed to clarify the role of C1P in the pathogenesis of CS-triggered pulmonary inflammation and emphysema in humans and mice.The effects of C1P were addressed on CS-induced lung inflammation in C57BL/6 mice, CS extracttriggered activation of human airway epithelial cells (AECs) and neutrophils from patients with chronic obstructive pulmonary disease. Differential cell counts in bronchoalveolar lavage fluid were determined by flow cytometry and pro-inflammatory cytokines were measured by ELISA. Expression and DNA binding of nuclear factor (NF)-κB and neutral sphingomyelinase (nSMase) were quantified by PCR, electrophoretic mobility shift and fluorometric assays.C1P reduced CS-induced acute and chronic lung inflammation and development of emphysema in mice, which was associated with a reduction in nSMase and NF-κB activity in the lungs. nSMase activity in human serum correlated negatively with forced expiratory volume in 1 s % predicted. In human AECs and neutrophils, C1P inhibited CS-induced activation of NF-κB and nSMase, and reduced pro-inflammatory cytokine release.Our results suggest that C1P is a potential target for anti-inflammatory treatment in CS-induced lung inflammation. @ERSpublications Ceramide-1-phosphate, a potential target for anti-inflammatory treatment in cigarette smokeinduced lung inflammation

C1P Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Preventing NF-κB Activation in Neutrophils

“…In our previous study, we already described only an anti-inflammatory effect until a C1P concentration of 10 μM (51), which is in line with the results of Hankins et al (18). Often a proinflammatory effect of C1P (14, 52) is described either with higher C1P concentrations or different solvent (53, 54).…”

Exogenous ceramide-1-phosphate (C1P) and phospho-ceramide analogue-1 (PCERA-1) regulate key macrophage activities via distinct receptors

“…The lab of Gómez-Muñoz has previously demonstrated that C1P prevents apoptosis in macrophages by inhibition of acid SMase activity, resulting in reduced levels of the pro-apoptotic ceramide [9]. A recent report showed that C1P can reduce cigarette smoke-induced lung inflammation, apparently by inhibiting cigarette smoke-induced activation of neutral SMase and NFκB and subsequent pro-inflammatory cytokine release in neutrophils [47]. In relation to these findings, a synthetic C1P analog, named SMA-7, suppressed LPS-stimulated NFκB activation and pro-inflammatory cytokines release from intestinal epithelial cells and from human THP-1 macrophages, by inhibiting LPS-stimulated ceramide production through neutral and acid SMase, respectively [48,49].…”

Ceramide 1-Phosphate: A Mediator of Inflammatory Responses

“…The anti-inflammatory potential of C1P is particularly relevant in the lung where it was shown to inhibit acute and chronic inflammation and development of emphysema. These actions required reduction of pro-inflammatory cytokines and inhibition of SMase and NF-kB activities in inflamed lung tissue (Baudiss et al 2015).…”