MatrixmetalloproteinasesToll-like receptorsignalingTGF betasignalingDifferentiationPathwayCytokinesand inflammatoryresponseNRF2signalingApoptosis58GPCRsignalingRegulation ofreactive oxygen speciesmetabolismGTPaseactivatorChemokinesignalingPulmonary fibrosisFibroblastproliferation, resistance to apoptosis, differentiationinto myofibroblasts, collagen productionPulmonary surfactantproteinsMacrophage-relatedfrustrated phagocytosis, oxidative stressandinflammasome activationMIE2SalivarysecretionEpithelial 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)8Rtel1Cxcl2 Spp1Dpp9Fgf1Ccl4Smad7 TercCtgfSFTPA2ParnMAPKsignalingCcl2 SERPINA1Skil TnfSftpa1Il6Oxidative StressEdn1ElnCsf3 Grem1Inflammasomeactivation3DspTertMecp2Cxcl15Obfc1CalcaTgfaIl13Il1bCcr3 Ccl5Pdgfa NADPHoxidaseCcl11Atp11aFgf2InflammationCma1Il5Coagulation disturbancesEgf Timp1 NF-KBIl12bBmp7Pdgfb Ptx3Nfe2l2Mmp9Fgf7Muc5bCebpbCysltr2Hmox1 p38 MAPKMmp2 HgfSftpcCcr2Il4Csf2 Elmod2PlauFam13aCcl3Mt2Igf1 Tgfb1ROSproductionAdditional non-connected genes with direct association topulmonary fibrosis in the Comparative Toxicogenomics Database (CTD)36All genes in the network are directly associated withpulmonary fibrosis in the Comparative Toxicogenomics Database (CTD)ROSproduction4, 63NF-KBInflammasomeactivation3KE12KE1/KE32KE1/KE3KE1/KE222KE3/KE42KE3KE3/KE42KE322KE4KE422AO2KE1/KE22AE1AE12AE122AE22AE12KE3/KE42KE3/KE42KE32KE1 - Induction of inflammatory cytokines and acute phase responseKE5 - Excessive ECM depositionAE - Associative Event KE3 - TH2/M2 response, secretion/activation of interleukins and growth factorsMIE - Cellular sensing of substanceAE1 - Increase of reactive oxygen species levelsAE2 - Cellular toxicity, cell deathKE2 - a. Retention/repeated exposure, b. persistent inflammationAO - FibrosisKE4 - Fibroblast & myofibroblast proliferationKE - Key EventAO - Adverse OutcomeMIE - Molecular Initiating EventEvents related to a putative Adverse Outcome Pathway forpulmonary fibrosis2LegendAE3 - Collagen productionChondrocytedifferentiationStressfibre assembly107Excess deposition and/or reduced turnover of extracellular matrix (ECM)KE52Collagen productonAE3