GTPaseactivatorELMOD29MIE - Molecular Initiating EventAE - Associative Event KE4 - Fibroblast & myofibroblast proliferationAE2 - Cellular toxicity, cell deathKE3 - TH2/M2 response, secretion/activation of interleukins and growth factorsAE1 - Increase of reactive oxygen species levelsKE5 - Excessive ECM depositionKE2 - a. Retention/repeated exposure, b. persistent inflammationKE1 - Induction of inflammatory cytokines and acute phase responseMIE - Cellular sensing of substanceAO - FibrosisKE - Key EventAO - Adverse OutcomeChemokine signalingCollagen productonStressfibre assemblyChondrocytedifferentiationMatrixmetalloproteinases62DifferentiationPathwayNRF2signalingTGF betasignalingCytokinesand inflammatoryresponseApoptosis11GPCRsignalingRegulation ofreactive oxygen speciesmetabolismPulmonary fibrosisFibroblastproliferation, resistance to apoptosis, differentiationinto myofibroblasts, collagen productionPulmonary surfactantproteinsExcess deposition and/or reduced turnover of extracellular matrix (ECM)Macrophage-relatedoxidative stressandinflammasome activationMIE3SalivarysecretionEpithelial 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)1RTEL1CXCL2SPP1DPP9FGF1CCL4SMAD7TERCCTGFSFTPA2PARNMAPKsignalingCCL2SERPINA1SKILTNFSFTPA1IL6Oxidative StressEDN1ELNCSF3GREM1Inflammasomeactivation5DSPTERTMECP2CXCL8OBFC1CALCATGFAIL13IL1BCCR3CCL5PDGFANADPHoxidaseCCL11ATP11AFGF2InflammationCMA1IL5Coagulation disturbancesEGFTIMP1NF-KBIL12BBMP7PDGFBPTX3NFE2L2MMP9FGF7MUC5BCEBPBCYSLTR2HMOX1p38 MAPKMMP2HGFSFTPCCCR2IL4CSF2PLAUFAM13ACCL3MT2AIGF1TGFB1ROSproduction5Additional non-connected genes with direct association topulmonary fibrosis in the Comparative Toxicogenomics Database (CTD)4All genes in the network are directly associated withpulmonary fibrosis in the Comparative Toxicogenomics Database (CTD)4, 8ROSproduction5NF-KBKE1/KE2Inflammasomeactivation35KE13KE1/KE33KE1/KE33KE1/KE23KE3/KE43KE33KE3/KE43KE33KE43KE43KE53AO3AE13AE13AE13AE23AE13KE3/KE43KE3/KE43KE33Events related to a putative Adverse Outcome Pathway forpulmonary fibrosis3LegendToll-like receptorsignalingAE3AE3 - Collagen production