Pharmacological sphingosine-1 phosphate receptor 1 targeting in cigarette smoke-induced emphysema in mice

dc.contributor.authorGoel, Khushboo
dc.contributor.authorSchweitzer, Kelly S.
dc.contributor.authorSerban, Karina A.
dc.contributor.authorBittman, Robert
dc.contributor.authorPetrache, Irina
dc.contributor.departmentMedicine, School of Medicine
dc.date.accessioned2024-05-16T13:14:58Z
dc.date.available2024-05-16T13:14:58Z
dc.date.issued2022
dc.description.abstractPrimarily caused by chronic cigarette smoking (CS), emphysema is characterized by loss of alveolar cells comprising lung units involved in gas exchange and inflammation that culminate in airspace enlargement. Dysregulation of sphingolipid metabolism with increases of ceramide relative to sphingosine-1 phosphate (S1P) signaling has been shown to cause lung cell apoptosis and is emerging as a potential therapeutic target in emphysema. We sought to determine the impact of augmenting S1P signaling via S1P receptor 1 (S1P1) in a mouse model of CS-induced emphysema. DBA2 mice were exposed to CS for 4 or 6 mo and treated with pharmacological agonists of S1P1: phosphonated FTY720 (FTY720-1S and 2S analogs; 0.01–1.0 mg/kg) or GSK183303A (10 mg/kg). Pharmacological S1P1 agonists ameliorated CS-induced lung parenchymal apoptosis and airspace enlargement as well as loss of body weight. S1P1 agonists had modest inhibitory effects on CS-induced airspace inflammation and lung functional changes measured by Flexivent, improving lung tissue resistance. S1P1 abundance was reduced in chronic CS-conditions and remained decreased after CS-cessation or treatment with FTY720-1S. These results support an important role for S1P-S1P1 axis in maintaining the structural integrity of alveoli during chronic CS exposure and suggest that increasing both S1P1 signaling and abundance may be beneficial to counteract the effects of chronic CS exposure.
dc.identifier.citationGoel K, Schweitzer KS, Serban KA, Bittman R, Petrache I. Pharmacological sphingosine-1 phosphate receptor 1 targeting in cigarette smoke-induced emphysema in mice. Am J Physiol Lung Cell Mol Physiol. 2022;322(6):L794-L803. doi:10.1152/ajplung.00017.2022
dc.identifier.urihttps://hdl.handle.net/1805/40797
dc.language.isoen_US
dc.publisherAmerican Physiological Society
dc.relation.isversionof10.1152/ajplung.00017.2022
dc.relation.journalAmerican Journal of Physiology: Lung Cellular and Molecular Physiology
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectChronic obstructive pulmonary disease
dc.subjectEmphysema
dc.subjectMouse
dc.subjectSphingolipids
dc.subjectSphingosine-1 phosphate receptor 1
dc.titlePharmacological sphingosine-1 phosphate receptor 1 targeting in cigarette smoke-induced emphysema in mice
dc.typeArticle
ul.alternative.fulltexthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9109793/
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