title: Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression.
abstract: The enforcement of sphingosine-1-phosphate (S1P) signaling network protects from radiation-induced pneumonitis. We now demonstrate that, in contrast to early postirradiation period, late postirradiation sphingosine kinase-1 (SphK1) and sphingoid base-1-phosphates are associated with radiation-induced pulmonary fibrosis (RIF). Using the mouse model, we demonstrate that RIF is characterized by a marked upregulation of S1P and dihydrosphingosine-1-phosphate (DHS1P) levels in the lung tissue and in circulation accompanied by increased lung SphK1 expression and activity. Inhibition of sphingolipid de novo biosynthesis by targeting serine palmitoyltransferase (SPT) with myriocin reduced radiation-induced pulmonary inflammation and delayed the onset of RIF as evidenced by increased animal lifespan and decreased expression of markers of fibrogenesis, such as collagen and α-smooth muscle actin (α-SMA), in the lung. Long-term inhibition of SPT also decreased radiation-induced SphK activity in the lung and the levels of S1P-DHS1P in the lung tissue and in circulation. In vitro, inhibition or silencing of serine palmitoyltransferase attenuated transforming growth factor-β1 (TGF-β)-induced upregulation of α-SMA through the negative regulation of SphK1 expression in normal human lung fibroblasts. These data demonstrate a novel role for SPT in regulating TGF-β signaling and fibrogenesis that is linked to the regulation of SphK1 expression and S1P-DHS1P formation.
authors.affiliation: Institute for Personalized Respiratory Medicine, Section of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Gorshkova
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Biji
authors.initials: B
authors.lastname: Mathew
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takekoshi
authors.forename: Palash
authors.initials: P
authors.lastname: Bhattacharya
authors.forename: Brett
authors.initials: B
authors.lastname: Smith
authors.forename: Bulent
authors.initials: B
authors.lastname: Aydogan
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Berdyshev
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D011833:Radiation Injuries, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013909:Thorax / Q000528:radiation effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D000099157:Sphingosine Kinase
chemical_list: D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D017853:Phosphotransferases (Alcohol Group Acceptor); D051102:Serine C-Palmitoyltransferase; D013110:Sphingosine; D016212:Transforming Growth Factor beta; D000099157:Sphingosine Kinase; C060504:dihydrosphingosine 1-phosphate; C001996:thermozymocidin