GTPaseactivatorELMOD2AO - FibrosisKE3 - TH2/M2 response, secretion/activation of interleukins and growth factorsAE1 - Increase of reactive oxygen species levelsKE4 - Fibroblast & myofibroblast proliferationKE1 - Induction of inflammatory cytokines and acute phase responseAE - Associative Event KE2 - a. Retention/repeated exposure, b. persistent inflammationAE2 - Cellular toxicity, cell deathMIE - Cellular sensing of substanceKE5 - Excessive ECM depositionKE - Key EventAO - Adverse OutcomeChondrocytedifferentiationMatrixmetalloproteinasesStressfibre assembly68DifferentiationPathwayNRF2signalingTGF betasignalingMIE - Molecular Initiating EventCytokinesand inflammatoryresponseApoptosis44GPCRsignalingRegulation ofreactive oxygen speciesmetabolismChemokinesignalingPulmonary fibrosisFibroblastproliferation, resistance to apoptosis, differentiationinto myofibroblasts, collagen productionPulmonary surfactantproteinsExcess deposition and/or reduced turnover of extracellular matrix (ECM)Macrophage-relatedoxidative stressandinflammasome activationMIE7SalivarysecretionEpithelial injury andapoptosis:disturbed interactionwith mesenchymal cells,epithelial-mesenchymaltransition TelomereorganizationSerine-typepeptidase activityLeukocyte/Myeloid celldifferentiationIntermediatefilamentcytoskeletonMethylation/chromatin bindingLung injury (known or unknown) combined with tissue response (normal or abnormal)4RTEL1CXCL2SPP1DPP9FGF1CCL4SMAD7TERCCTGFSFTPA2PARNMAPKsignalingCCL2SERPINA1SKILTNFSFTPA1IL6Oxidative StressEDN1ELNCSF3GREM1Inflammasomeactivation5DSPTERTMECP2CXCL8OBFC1CALCATGFAIL13IL1BCCR3CCL5PDGFANADPHoxidaseCCL11ATP11AFGF2InflammationCMA1IL5Coagulation disturbancesEGFTIMP1NF-KBIL12BBMP7PDGFBPTX3NFE2L2MMP9FGF7MUC5BCEBPBCYSLTR2HMOX1p38 MAPKMMP2HGFSFTPCCCR2IL4CSF2PLAUFAM13ACCL3MT2AIGF1TGFB1Collagen productionROSproduction5Additional non-connected genes with direct association topulmonary fibrosis in the Comparative Toxicogenomics Database (CTD)2All genes in the network are directly associated withpulmonary fibrosis in the Comparative Toxicogenomics Database (CTD)2, 3ROSproduction5NF-KBKE1/KE27Inflammasomeactivation5KE17KE1/KE37KE1/KE37KE1/KE27KE3/KE47KE37KE3/KE47KE37KE47KE47KE57AO7AE17AE17AE17AE27AE17KE3/KE47KE3/KE47KE37Events related to a putative Adverse Outcome Pathway forpulmonary fibrosis7LegendToll-like receptorsignaling