Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic disease for which novel approaches are urgently required. We reported increased sphingosine kinase 1 (SPHK1) in IPF lungs and that SPHK1 inhibition using genetic and pharmacologic approaches reduces murine bleomycin-induced pulmonary fibrosis. We determined whether PF543, a specific SPHK1 inhibitor post bleomycin or asbestos challenge mitigates lung fibrosis by reducing mitochondrial (mt) DNA damage and pro-fibrotic monocyte recruitment—both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µg/50 µL) or controls was intratracheally instilled in Wild-Type (C57Bl6) mice. PF543 (1 mg/kg) or vehicle was intraperitoneally injected once every two days from day 7−21 following bleomycin and day 14−21 or day 30−60 following asbestos. PF543 reduced bleomycin- and asbestos-induced pulmonary fibrosis at both time points as well as lung expression of profibrotic markers, lung mtDNA damage, and fibrogenic monocyte recruitment. In contrast to human lung fibroblasts, asbestos augmented lung epithelial cell (MLE) mtDNA damage and PF543 was protective. Post-exposure PF543 mitigates pulmonary fibrosis in part by reducing lung epithelial cell mtDNA damage and monocyte recruitment. We reason that SPHK1 signaling may be an innovative therapeutic target for managing patients with IPF and other forms of lung fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive age-related lung disease that affects nearly 120,000 people in the USA and has a median survival of only 3–5 years [1,2]
The pathogenesis of pulmonary fibrosis is incompletely understood but accumulating evidence firmly implicate three important events including: (i) increased levels of bioactive lipid mediators originating from sphingosine kinase 1 (SPHK1) [1,3–5]; (ii) alveolar epithelial cell (AEC) apoptosis resulting from mitochondrial dysfunction and the production of reactive oxygen species (ROS) that can promote mitochondrial DNA damage [1,6–11]; and (iii) recruitment of the profibrotic monocyte-derived alveolar macrophages (Mo-AMs) that are causally implicated in mediating both bleomycin- and asbestos-induced murine lung [12–14]
Our group showed that S1P and S1P lyase (S1PL) are highly expressed in the lung tissues of patients with IPF and bleomycin-challenged mice and, notably, demonstrated that SPHK1 levels negatively correlated with lung function and IPF survival [3,15,20]
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive age-related lung disease that affects nearly 120,000 people in the USA and has a median survival of only 3–5 years [1,2]. SPHK1/S1P signaling activates the Hippo/Yes-associated protein (YAP) pathway and mitochondrial reactive oxygen species (ROS) production in pro-fibrotic lung fibroblasts [21] It is unknown whether administration of SPHK1 specific inhibitor PF543, following exposure to fibrogenic agents can still mitigate pulmonary fibrosis and, if so, whether the SPHK1/S1P pathway impacts AEC mtDNA integrity and recruitment of pro-fibrotic Mo-AMs. The mitochondria are the ATP-generating powerhouse of cells but are crucial for regulating complex intracellular signals that determine whether cells live or die. We reasoned that SPHK1 inhibition by PF543 administered following exposure to a fibrogenic agent will afford substantial protection against lung fibrosis by reducing AEC mtDNA damage and recruitment of Mo-AMs. In this study, we report that PF543 reduces both bleomycin- and asbestos-induced pulmonary fibrosis when administered 7- or 14-days post challenge, and that the protective effects occur in association with diminished lung expression of profibrotic markers, lung. PF5T4o3 iAntvteenstuiagtaetseApsobessstiobsl-eInmdueccehdaSn1isPtiPcropdauthctwioanyasndacmcotDunNtAinDg afmoragthe einpMrootuescetiLvuenegfsfaenctdsMofLEPFC5e4ll3s in ourTomiondveels, tsiegvaetreapl poassthibwleaymsewcheraeneisxtpiclopraedth.wGaivyesnatchceoudnirteinctgasfosorctihaetiopnrobteetcwtieveenepffleacstms aoSf 1PPFl5e4v3els inaonudr mIPoFdmel,orsteavleitryalapnadthawnaimysalwmeroedeexlsploofreldu.ngGsiv[e3n,4,t1h5e,2d0i]reacntdastshoactiaStPioHnKb1etiwneheibnitpiolansmmaitSig1aPtes levbelelsoamnydciInP-FinmdourcteadlitiyncarnedasaensiminalpmlaosdmealsSoIfPlulnevgesl[s3,[41,51]5,,2w0]eaansdsetshsaetdSPwHhKet1hienrhPibFi5ti4o3n ammiteilgioatreastes blepolmasymcainS-i1nPdulecvedelsinwcrheaesnesadinmpinlaissmteareSdIPevleevreylso[t1h5e]r, wdaeyasaste1ssmedg/wkghe[t3h5e,3r6P]F. 5A4s3 sahmoewlinorainteFsipgluarsem6aA, S1cPolmevpealsrewdhtoenveahdimclien-itsrteearteeddecvoenrtyrooltsh,ePrFd5a4y3 apto1smt-egx/kpgos[u35re,3r6e]d. uAcsesdhpolwasnmina SF1igPulreev6eAls,acto2m1pdabreyd~5to0% ve(hSi1cPle-letrveealtse[dpcmoonlt/rmolLs,]:PvFe5h4i3clpeocshta-ellxepnogseu- r1e15re3d±u6c0edvsp.lPaFsm54a3-S514P0le±v2e4l0s;apt
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