Fig. 7.
Schematic representation of a simplified narrative scenario model of uncontrolled dysregulated DAMP-promoted pathways in light of the exposome and AOP concepts. The figure illustrates the sequelae of key events proposed to leading to fibrotic disorders (organ fibrosis), reflecting the adverse outcome. The stress/injury → DAMP-promoted dysregulated pathways leading to immune diseases start with the sequelae of events (MIE → KE3→n) as described for the controlled pathway (Fig. 3). However, instead of proceeding to homeostatic events, the DAMP-induced pathways now provoke “pathogenic” KEs key events resulting in an AO in terms of fibrotic disorders. The triggering “aberrant” event is the fifth KE that refers to (uncontrolled) chronic inflammation as characterized by the failure of an inflammation-resolution response (= “nonresolving inflammation”), proceeding to fibrogenic responses (fibrogenesis). The adverse outcome refers to complete organ fibrosis associated with typical organ-specific clinical symptoms. AO adverse outcome, DAMPs damage-associated molecular patterns, ECM extracellular matrix, HSCs hepatic stellate cells, KE key event, KER key event relationship, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, PRMs pattern recognition molecules, SAMPs suppressing DAMPs, TGF-β transforming growth factor-beta.
Source: Land (2018)