miR-155 deficiency alleviates AAI by diminishing Th2 priming capacity and ATP-/P2R-induced activation of DCs in mice, suggesting this miRNA as a potential therapeutic target of AAI.
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
Recently, ceramide-1-phosphate (C1P) has been shown to modulate acute inflammatory events. Acute lung injury (Arnalich et al. 2000. Infect. Immun. 68: 1942–1945) is characterized by rapid alveolar injury, lung inflammation, induced cytokine production, neutrophil accumulation, and vascular leakage leading to lung edema. The aim of this study was to investigate the role of C1P during LPS-induced acute lung injury in mice. To evaluate the effect of C1P, we used a prophylactic and therapeutic LPS-induced ALI model in C57BL/6 male mice. Our studies revealed that intrapulmonary application of C1P before (prophylactic) or 24 h after (therapeutic) LPS instillation decreased neutrophil trafficking to the lung, proinflammatory cytokine levels in bronchoalveolar lavage, and alveolar capillary leakage. Mechanistically, C1P inhibited the LPS-triggered NF-κB levels in lung tissue in vivo. In addition, ex vivo experiments revealed that C1P also attenuates LPS-induced NF-κB phosphorylation and IL-8 production in human neutrophils. These results indicate C1P playing a role in dampening LPS-induced acute lung inflammation and suggest that C1P could be a valuable candidate for treatment of ALI.
Background Extracellular ATP is known to accumulate in the lung, following allergen challenge, and contributes via activation of purinergic receptors on dendritic cells (DC), to the development of allergic airway inflammation (AAI). Extracellular ATP-levels in the airways are normally tightly regulated by CD39. This ectonucleotidase is highly expressed by DC purified from skin (Langerhans cells) and bone marrow, and has been shown to modulate DC adaptive/haptenic immune responses. In this study, we have evaluated the impact of Cd39 deletion and associated perturbation of purinergic signaling in AAI. Methods Standard OVA-alum and house dust mite (HDM) bone marrow derived DC (BMDC) dependent models of AAI were used to study effects of Cd39. Migration assays, time lapse microscopy and T-cell priming assays were further used to determine functional relevance of Cd39 expression on BMDC in the setting of immune and Th2-mediated responses in these models. Results Cd39−/− mice exhibited marked increases in BALF ATP-levels but paradoxically exhibited limited AAI in both OVA-alum and HDM models. These pathophysiological abnormalities were associated with decreased myeloid DC activation and chemotaxis towards ATP, and were linked to purinergic receptor desensitization responses. Further, Cd39−/− DCs exhibited limited capacity to both prime Th2-responses and form stable immune synaptic interactions with OVA-transgenic naïve T-cells. Conclusions Cd39-deficient DCs exhibit limited capacity to induce Th2 immunity in a DC-driven model of AAI in vivo. Our data demonstrate a role of CD39 and perturbed purinergic signaling in models of AAI,
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.