Acute respiratory distress syndrome (ARDS) refers to the injury of alveolar epithelial cells and capillary endothelial cells due to various injury factors. Research on the pathogenesis of ARDS has made great progress, but the exact pathogenesis of ARDS has not been fully elucidated. Up to now, the prevention and treatment of ARDS is still an important scientific problem that needs to be solved urgently. In this work, we analyzed the effect of uridine on ARDS. An ARDS model was successfully constructed by lipopolysaccharide (LPS) stimulation. Western-blotting, IFA, ELISA, RT-PCT and CLSM were conducted to investigate the effect of uridine on ARDS and insulin resistance, and the results showed that lung histopathological alterations were significantly attenuated by uridine treatment. Further work showed that the levels of proinflammatory cytokines were significantly down-regulated in the lung tissue after treatment with uridine. Additionally, the numbers of total cells and neutrophils in the bronchoalveolar lavage fluid (BALF) were also decreased in the uridine-treated ARDS mice. We further explored the potential mechanism by which uridine could treat ARDS, and the results indicated that NF-κB signaling was down-regulated by uridine treatment. Next, we studied insulin sensitivity in the ARDS mice, and found that insulin signaling was significantly down-regulated, and uridine could enhance insulin sensitivity in the ARDS mice model. Furthermore, we found that the levels of inflammation and oxidative stress were decreased by uridine treatment, which may be the potential mechanism by which uridine could improve insulin sensitivity. Taken together, the current work provides evidence that uridine can serve as a potential drug to treat ARDS and insulin resistance.
Ji M , Chen M , Hong X , Chen T , Zhang N . The effect of diabetes on the risk and mortality of acute lung injury/acute respiratory distress syndrome: a meta-analysis. Medicine (Baltimore) 2019; 98(13): e15095. https://doi.org/10.1097/MD.0000000000015095.
Chen X , Tang J , Shuai W , Meng J , Feng J , Han Z . Macrophage polarization and its role in the pathogenesis of acute lung injury/acute respiratory distress syndrome. Inflamm Res. 2020; 69(9): 883–895. https://doi.org/10.1007/s00011-020-01378-2.
Deshpande R , Zou C . Pseudomonas aeruginosa induced cell death in acute lung injury and acute respiratory distress syndrome. Int J Mol Sci. 2020; 21(15): 5356. https://doi.org/10.3390/ijms21155356.
Lew TW , Kwek TK , Tai D , Earnest A , Loo S , Singh K , et al. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 2003; 290(3): 374–380. https://doi.org/10.1001/jama.290.3.374.
Stapleton RD , Wang BM , Hudson LD , Rubenfeld GD , Caldwell ES , Steinberg KP . Causes and timing of death in patients with ARDS. Chest 2005; 128(2): 525–532. https://doi.org/10.1378/chest.128.2.525.
Wu C , Chen X , Cai Y , Xia Ja , Zhou X , Xu S , et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020; 180(7): 934–943. https://doi.org/10.1001/jamainternmed.2020.0994.
Kong G , Huang X , Wang L , Li Y , Sun T , Han S , et al. Astilbin alleviates LPS-induced ARDS by suppressing MAPK signaling pathway and protecting pulmonary endothelial glycocalyx. Int Immunopharmacol. 2016; 36: 51–58. https://doi.org/10.1016/j.intimp.2016.03.039.
Hetzel M , Bachem M , Anders D , Trischler G , Faehling M . Different effects of growth factors on proliferation and matrix production of normal and fibrotic human lung fibroblasts. Lung 2005; 183(4): 225–237. https://doi.org/10.1007/s00408-004-2534-z.
Liu XY , Xu HX , Li JK , Zhang D , Ma XH , Huang LN , et al. Neferine protects endothelial glycocalyx via mitochondrial ROS in lipopolysaccharide-induced acute respiratory distress syndrome. Front Physiol. 2018; 9: 102. https://doi.org/10.3389/fphys.2018.00102.
Ma X , Liu X , Feng J , Zhang D , Huang L , Li D , et al. Fraxin alleviates LPS-induced ARDS by downregulating inflammatory responses and oxidative damages and reducing pulmonary vascular permeability. Inflammation. 2019; 42(5): 1901–1912. https://doi.org/10.1007/s10753-019-01052-8.
Jeengar MK , Thummuri D , Magnusson M , Naidu VGM , Uppugunduri S . Uridine ameliorates dextran Sulfate Sodium (DSS)-Induced colitis in mice. Sci Rep. 2017; 7(1): 3924. https://doi.org/10.1038/s41598-017-04041-9.
Simon HU , Haj-Yehia A , Levi-Schaffer F . Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 2000; 5(5): 415–418. https://doi.org/10.1023/a:1009616228304.
Pan L , Yao DC , Yu YZ , Li SJ , Chen BJ , Hu GH , et al. Necrostatin-1 protects against oleic acid-induced acute respiratory distress syndrome in rats. Biochem Biophys Res Commun. 2016; 478(4): 1602–1608. https://doi.org/10.1016/j.bbrc.2016.08.163.
Tang PS , Mura M , Seth R , Liu M . Acute lung injury and cell death: how many ways can cells die? Am J Physiol Lung Cell Mol Physiol. 2008; 294(4): L632–L641. https://doi.org/10.1152/ajplung.00262.2007.
Kitamura Y , Hashimoto S , Mizuta N , Kobayashi A , Kooguchi K , Fujiwara I , et al. Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice. Am J Respir Crit Care Med. 2001; 163(3 Pt 1): 762–769. https://doi.org/10.1164/ajrccm.163.3.2003065.
Chen L , Li W , Qi D , Wang D . Lycium barbarum polysaccharide protects against LPS-induced ARDS by inhibiting apoptosis, oxidative stress, and inflammation in pulmonary endothelial cells. Free Radic Res. 2018; 52(4): 480–490. https://doi.org/10.1080/10715762.2018.1447105.
Mironova GD , Khrenov MO , Talanov EY , Glushkova OV , Parfenyuk SB , Novoselova TV , et al. The role of mitochondrial KATP channel in anti-inflammatory effects of uridine in endotoxemic mice. Arch Biochem Biophys. 2018; 654: 70–76. https://doi.org/10.1016/j.abb.2018.07.006.
Rozova EV , Mankovskaya IN , Belosludtseva NV , Khmil NV , Mironova GD . Uridine as a protector against hypoxia-induced lung injury. Sci Rep. 2019; 9(1): 9418. https://doi.org/10.1038/s41598-019-45979-2.
Krylova IB , Selina EN , Bulion VV , Rodionova OM , Evdokimova NR , Belosludtseva NV , et al. Uridine treatment prevents myocardial injury in rat models of acute ischemia and ischemia/reperfusion by activating the mitochondrial ATP-dependent potassium channel. Sci Rep. 2021; 11(1): 16999. https://doi.org/10.1038/s41598-021-96562-7.
Krylova IB , Kachaeva EV , Rodionova OM , Negoda AE , Evdokimova NR , Balina MI , et al. The cardioprotective effect of uridine and uridine-5′-monophosphate: the role of the mitochondrial ATP-dependent potassium channel. Exp Gerontol. 2006; 41(7): 697–703. https://doi.org/10.1016/j.exger.2006.03.005.