Identification of Genes as Potential Biomarkers for Sepsis-related ARDS
using Weighted Gene Co-expression Network Analysis

Xiaowan      Wang; Aihua      Fei

doi:10.2174/1386207325666220509180737

Abstract

Background: Acute respiratory distress syndrome (ARDS) caused by sepsis presents a high mortality rate; therefore, identification of susceptibility genes of sepsis to ARDS at an early stage is particularly critical.

Methods: The GSE66890 dataset was downloaded and analyzed by WGCNA to obtain modules. Then, GO and KEGG analyses of the module genes were performed. Then, the PPI network and LASSO model were constructed to identify the key genes. Finally, expression levels of the screened genes were validated in clinical subjects.

Results: We obtained 17 genes merged modules via WGCNA, and the dark module and tan module were the most positively and negatively correlated with sepsis-induced ARDS, respectively. Based on gene intersections of the module genes, 11 hub genes were identified in the dark module, and 5 hub genes were identified in the tan module. Finally, the six key genes were identified by constructing the LASSO model. We further detected the screened genes expression in clinical samples, and as the bioinformatics analysis revealed, the expressions of NANOG, RAC1, TWIST1, and SNW1 were significantly upregulated in the ARDS group compared to the sepsis group, and IMP3 and TUBB4B were significantly downregulated.

Conclusion: We identified six genes as the potential biomarkers in sepsis-related ARDS. Our findings may enhance the knowledge of the molecular mechanisms behind the development of sepsisinduced ARDS.

Keywords: ARDS, sepsis, WGCNA, differentially expressed genes, biomarkers, hub genes.

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[1]
Fan, E.; Brodie, D.; Slutsky, A.S. Acute respiratory distress syndrome: Advances in diagnosis and treatment. JAMA,  2018, 319(7), 698-710.
 [http://dx.doi.org/10.1001/jama.2017.21907] [PMID: 29466596]

[2]
Saguil, A.; Fargo, M.V. Acute respiratory distress syndrome: Diagnosis and management. Am. Fam. Physician,  2020, 101(12), 730-738.
 [PMID: 32538594]

[3]
Auriemma, C.L.; Zhuo, H.; Delucchi, K.; Deiss, T.; Liu, T.; Jauregui, A.; Ke, S.; Vessel, K.; Lippi, M.; Seeley, E.; Kangelaris, K.N.; Gomez, A.; Hendrickson, C.; Liu, K.D.; Matthay, M.A.; Ware, L.B.; Calfee, C.S. Acute respiratory distress syndrome-attributable mortality in critically ill patients with sepsis. Intensive Care Med.,  2020, 46(6), 1222-1231.
 [http://dx.doi.org/10.1007/s00134-020-06010-9] [PMID: 32206845]

[4]
De Freitas Caires, N.; Gaudet, A.; Portier, L.; Tsicopoulos, A.; Mathieu, D.; Lassalle, P. Endocan, sepsis, pneumonia, and acute respiratory distress syndrome. Crit. Care,  2018, 22(1), 280.
 [http://dx.doi.org/10.1186/s13054-018-2222-7] [PMID: 30367649]

[5]
Reilly, J.P.; Calfee, C.S.; Christie, J.D. Acute respiratory distress syndrome phenotypes. Semin. Respir. Crit. Care Med.,  2019, 40(1), 19-30.
 [http://dx.doi.org/10.1055/s-0039-1684049] [PMID: 31060085]

[6]
Spadaro, S.; Park, M.; Turrini, C.; Tunstall, T.; Thwaites, R.; Mauri, T.; Ragazzi, R.; Ruggeri, P.; Hansel, T.T.; Caramori, G.; Volta, C.A. Biomarkers for acute respiratory distress syndrome and prospects for personalised medicine. J. Inflamm. (Lond.),  2019, 16, 1.
 [http://dx.doi.org/10.1186/s12950-018-0202-y] [PMID: 30675131]

[7]
Zhou, M.; Fang, H.; Du, M.; Li, C.; Tang, R.; Liu, H.; Gao, Z.; Ji, Z.; Ke, B.; Chen, X.L. The modulation of regulatory T cells via HMGB1/PTEN/β-ss in LPS induced acute lung injury. Front. Immunol.,  2019, 10, 1612.
 [http://dx.doi.org/10.3389/fimmu.2019.01612] [PMID: 31402909]

[8]
Liu, J.; Sala, M.A.; Kim, J. Dampening the fire: A negative feedback loop in acute respiratory distress syndrome. Am. J. Respir. Cell Mol. Biol.,  2021, 64(2), 158-160.
 [http://dx.doi.org/10.1165/rcmb.2020-0487ED] [PMID: 33522886]

[9]
Zhou, H.; Wang, X.; Zhang, B. Depression of lncRNA NEAT1 antagonizes LPS-Evoked acute injury and inflammatory response in alveolar epithelial cells via HMGB1-RAGE signaling. Mediators Inflamm.,  2020, 2020, 8019467.
 [http://dx.doi.org/10.1155/2020/8019467] [PMID: 32089649]

[10]
Sinha, P.; Churpek, M.M.; Calfee, C.S. Machine learning classifier models can identify acute respiratory distress syndrome phenotypes using readily available clinical data. Am. J. Respir. Crit. Care Med.,  2020, 202(7), 996-1004.
 [http://dx.doi.org/10.1164/rccm.202002-0347OC] [PMID: 32551817]

[11]
Ware, L.B.; Koyama, T.; Billheimer, D.D.; Wu, W.; Bernard, G.R.; Thompson, B.T.; Brower, R.G.; Standiford, T.J.; Martin, T.R.; Matthay, M.A. Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest,  2010, 137(2), 288-296.
 [http://dx.doi.org/10.1378/chest.09-1484] [PMID: 19858233]

[12]
Viswan, A.; Ghosh, P.; Gupta, D.; Azim, A.; Sinha, N. Distinct metabolic endotype mirroring Acute Respiratory Distress Syndrome (ARDS) subphenotype and its heterogeneous biology. Sci. Rep.,  2019, 9(1), 2108.
 [http://dx.doi.org/10.1038/s41598-019-39017-4] [PMID: 30765824]

[13]
Hernández-Beeftink, T.; Guillen-Guio, B.; Villar, J.; Flores, C. Genomics and the acute respiratory distress syndrome: Current and future directions. Int. J. Mol. Sci.,  2019, 20(16), 4004.
 [http://dx.doi.org/10.3390/ijms20164004] [PMID: 31426444]

[14]
Guillen-Guio, B.; Lorenzo-Salazar, J.M.; Ma, S.F.; Hou, P.C.; Hernandez-Beeftink, T.; Corrales, A.; García-Laorden, M.I.; Jou, J.; Espinosa, E.; Muriel, A.; Domínguez, D.; Lorente, L.; Martín, M.M.; Rodríguez-Gallego, C.; Solé-Violán, J.; Ambrós, A.; Carriedo, D.; Blanco, J.; Añón, J.M.; Reilly, J.P.; Jones, T.K.; Ittner, C.A.; Feng, R.; Schöneweck, F.; Kiehntopf, M.; Noth, I.; Scholz, M.; Brunkhorst, F.M.; Scherag, A.; Meyer, N.J.; Villar, J.; Flores, C. Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: A genome-wide association study. Lancet Respir. Med.,  2020, 8(3), 258-266.
 [http://dx.doi.org/10.1016/S2213-2600(19)30368-6] [PMID: 31982041]

[15]
Hinz, J.; Büttner, B.; Kriesel, F.; Steinau, M.; Frederik Popov, A.; Ghadimi, M.; Beissbarth, T.; Tzvetkov, M.; Bergmann, I.; Mansur, A. The FER rs4957796 TT genotype is associated with unfavorable 90-day survival in Caucasian patients with severe ARDS due to pneumonia. Sci. Rep.,  2017, 7(1), 9887.
 [http://dx.doi.org/10.1038/s41598-017-08540-7] [PMID: 28851893]

[16]
Breuer, K.; Foroushani, A.K.; Laird, M.R.; Chen, C.; Sribnaia, A.; Lo, R.; Winsor, G.L.; Hancock, R.E.; Brinkman, F.S.; Lynn, D.J. Innate DB: Systems biology of innate immunity and beyond-recent updates and continuing curation. Nucleic Acids Res.,  2013, 41(Database issue), D1228-D1233.
 [http://dx.doi.org/10.1093/nar/gks1147] [PMID: 23180781]

[17]
Yang, C.Y.; Chen, C.S.; Yiang, G.T.; Cheng, Y.L.; Yong, S.B.; Wu, M.Y.; Li, C.J. New insights into the immune molecular regulation of the pathogenesis of acute respiratory distress syndrome. Int. J. Mol. Sci.,  2018, 19(2), 588.
 [http://dx.doi.org/10.3390/ijms19020588] [PMID: 29462936]

[18]
Yang, J.X.; Li, M.; Chen, X.O.; Lian, Q.Q.; Wang, Q.; Gao, F.; Jin, S.W.; Zheng, S.X. Lipoxin A4 ameliorates lipopolysaccharide-induced lung injury through stimulating epithelial proliferation, reducing epithelial cell apoptosis and inhibits epithelial-mesenchymal transition. Respir. Res.,  2019, 20(1), 192.
 [http://dx.doi.org/10.1186/s12931-019-1158-z] [PMID: 31438948]

[19]
Zheng, X.; Zhang, W.; Hu, X. Different concentrations of lipopolysaccharide regulate barrier function through the PI3K/Akt signalling pathway in human pulmonary microvascular endothelial cells. Sci. Rep.,  2018, 8(1), 9963.
 [http://dx.doi.org/10.1038/s41598-018-28089-3] [PMID: 29967433]

[20]
Yu, J.; Wang, Y.; Li, Z.; Dong, S.; Wang, D.; Gong, L.; Shi, J.; Zhang, Y.; Liu, D.; Mu, R. Effect of Heme Oxygenase-1 on Mitofusin-1 protein in LPS-induced ALI/ARDS in rats. Sci. Rep.,  2016, 6, 36530.
 [http://dx.doi.org/10.1038/srep36530] [PMID: 27830717]

[21]
Ji, S.; Wang, L. μ-Opioid receptor signalling via PI3K/Akt pathway ameliorates lipopolysaccharide-induced acute respiratory distress syndrome. Exp. Physiol.,  2019, 104(10), 1555-1561.
 [http://dx.doi.org/10.1113/EP087783] [PMID: 31272134]

[22]
Karki, P.; Ke, Y.; Tian, Y.; Ohmura, T.; Sitikov, A.; Sarich, N.; Montgomery, C.P.; Birukova, A.A. Staphylococcus aureus-induced endothelial permeability and inflammation are mediated by microtubule destabilization. J. Biol. Chem.,  2019, 294(10), 3369-3384.
 [http://dx.doi.org/10.1074/jbc.RA118.004030] [PMID: 30622143]

[23]
Mu, S.; Liu, Y.; Jiang, J.; Ding, R.; Li, X.; Li, X.; Ma, X. Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury. Respir. Res.,  2018, 19(1), 220.
 [http://dx.doi.org/10.1186/s12931-018-0925-6] [PMID: 30442128]

[24]
Li, L.; Hu, J.; He, T.; Zhang, Q.; Yang, X.; Lan, X.; Zhang, D.; Mei, H.; Chen, B.; Huang, Y. P38/MAPK contributes to endothelial barrier dysfunction via MAP4 phosphorylation-dependent microtubule disassembly in inflammation-induced acute lung injury. Sci. Rep.,  2015, 5, 8895.
 [http://dx.doi.org/10.1038/srep08895] [PMID: 25746230]

[25]
Huang, R.T.; Wu, D.; Meliton, A.; Oh, M.J.; Krause, M.; Lloyd, J.A.; Nigdelioglu, R.; Hamanaka, R.B.; Jain, M.K.; Birukova, A.; Kress, J.P.; Birukov, K.G.; Mutlu, G.M.; Fang, Y. Experimental lung injury reduces krüppel-like factor 2 to increase endothelial permeability via regulation of RAPGEF3-Rac1 signaling. Am. J. Respir. Crit. Care Med.,  2017, 195(5), 639-651.
 [http://dx.doi.org/10.1164/rccm.201604-0668OC] [PMID: 27855271]

[26]
Su, G.; Atakilit, A.; Li, J.T.; Wu, N.; Bhattacharya, M.; Zhu, J.; Shieh, J.E.; Li, E.; Chen, R.; Sun, S.; Su, C.P.; Sheppard, D. Absence of integrin αvβ3 enhances vascular leak in mice by inhibiting endothelial cortical actin formation. Am. J. Respir. Crit. Care Med.,  2012, 185(1), 58-66.
 [http://dx.doi.org/10.1164/rccm.201108-1381OC] [PMID: 21980034]

[27]
Figueiredo, A.M.; Barbacena, P.; Russo, A.; Vaccaro, S.; Ramalho, D.; Pena, A.; Lima, A.P.; Ferreira, R.R.; Fidalgo, M.A.; El-Marjou, F.; Carvalho, Y.; Vasconcelos, F.F.; Lennon-Duménil, A.M.; Vignjevic, D.M.; Franco, C.A. Endothelial cell invasion is controlled by dactylopodia. Proc. Natl. Acad. Sci. USA,  2021, 118(18), e2023829118.
 [http://dx.doi.org/10.1073/pnas.2023829118] [PMID: 33903241]

[28]
Amado-Azevedo, J.; van Stalborch, A.D.; Valent, E.T.; Nawaz, K.; van Bezu, J.; Eringa, E.C.; Hoevenaars, F.P.M.; De Cuyper, I.M.; Hordijk, P.L.; van Hinsbergh, V.W.M.; van Nieuw Amerongen, G.P.; Aman, J.; Margadant, C. Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation. Angiogenesis,  2021, 24(3), 677-693.
 [http://dx.doi.org/10.1007/s10456-021-09781-x] [PMID: 33770321]

[29]
Shao, M.; Tang, S.T.; Liu, B.; Zhu, H.Q. Rac1 mediates HMGB1-induced hyperpermeability in pulmonary microvascular endothelial cells via MAPK signal transduction. Mol. Med. Rep.,  2016, 13(1), 529-535.
 [http://dx.doi.org/10.3892/mmr.2015.4521] [PMID: 26549372]

[30]
Yochum, Z.A.; Cades, J.; Wang, H.; Chatterjee, S.; Simons, B.W.; O’Brien, J.P.; Khetarpal, S.K.; Lemtiri-Chlieh, G.; Myers, K.V.; Huang, E.H.; Rudin, C.M.; Tran, P.T.; Burns, T.F. Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene,  2019, 38(5), 656-670.
 [http://dx.doi.org/10.1038/s41388-018-0482-y] [PMID: 30171258]

[31]
Mammoto, T.; Jiang, E.; Jiang, A.; Lu, Y.; Juan, A.M.; Chen, J.; Mammoto, A. Twist1 controls lung vascular permeability and endotoxin-induced pulmonary edema by altering Tie2 expression. PLoS One,  2013, 8(9), e73407.
 [http://dx.doi.org/10.1371/journal.pone.0073407] [PMID: 24023872]

[32]
Ma, C.; Guo, Y.; Liu, H.; Wang, K.; Yang, J.; Li, X.; Liu, C.; Guan, W. Isolation and biological characterization of a novel type of pulmonary mesenchymal stem cells derived from Wuzhishan miniature pig embryo. Cell Biol. Int.,  2016, 40(10), 1041-1049.
 [http://dx.doi.org/10.1002/cbin.10643] [PMID: 27425208]

[33]
Liu, L.; Zhu, H.; Liao, Y.; Wu, W.; Liu, L.; Liu, L.; Wu, Y.; Sun, F.; Lin, H.W. Inhibition of Wnt/β-catenin pathway reverses multidrug resistance and EMT in Oct4+/Nanog+ NSCLC cells. Biomed. Pharmacother.,  2020, 127, 110225.
 [http://dx.doi.org/10.1016/j.biopha.2020.110225] [PMID: 32428834]

[34]
Pan, Q.; Meng, L.; Ye, J.; Wei, X.; Shang, Y.; Tian, Y.; He, Y.; Peng, Z.; Chen, L.; Chen, W.; Bian, X.; Wang, R. Transcriptional repression of miR-200 family members by Nanog in colon cancer cells induces epithelial-mesenchymal transition (EMT). Cancer Lett.,  2017, 392, 26-38.
 [http://dx.doi.org/10.1016/j.canlet.2017.01.039] [PMID: 28163188]

[35]
Duan, Z.; Ma, C.; Han, Y.; Li, Y.; Zhou, H. Nanog attenuates lipopolysaccharide-induced inflammatory responses by blocking nuclear factor-κB transcriptional activity in BV-2 cells. Neuroreport,  2013, 24(13), 718-723.
 [http://dx.doi.org/10.1097/WNR.0b013e328363fd67] [PMID: 23924954]

[36]
Del Gobbo, A.; Vaira, V.; Guerini Rocco, E.; Palleschi, A.; Bulfamante, G.; Ricca, D.; Fiori, S.; Bosari, S.; Ferrero, S. The oncofetal protein IMP3: A useful marker to predict poor clinical outcome in neuroendocrine tumors of the lung. J. Thorac. Oncol.,  2014, 9(11), 1656-1661.
 [http://dx.doi.org/10.1097/JTO.0000000000000316] [PMID: 25144243]

[37]
You, S.; Guan, Y.; Li, W. Epithelial mesenchymal-transition in colorectal carcinoma cells is mediated by DEK/IMP3. Mol. Med. Rep.,  2018, 17(1), 1065-1070.
 [PMID: 29115492]

[38]
Sobierajska, K.; Ciszewski, W.M.; Wawro, M.E.; Wieczorek-Szukała, K.; Boncela, J.; Papiewska-Pajak, I.; Niewiarowska, J.; Kowalska, M.A. TUBB4B downregulation is critical for increasing migration of metastatic colon cancer cells. Cells,  2019, 8(8), 810.
 [http://dx.doi.org/10.3390/cells8080810] [PMID: 31375012]

[39]
Verma, S.; De Jesus, P.; Chanda, S.K.; Verma, I.M. SNW1, a novel transcriptional regulator of the NF-κB pathway. Mol. Cell. Biol.,  2019, 39(3), e00415-e00418.
 [http://dx.doi.org/10.1128/MCB.00415-18] [PMID: 30397075]

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DOI https://dx.doi.org/10.2174/1386207325666220509180737	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

Identification of Genes as Potential Biomarkers for Sepsis-related ARDS using Weighted Gene Co-expression Network Analysis

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