Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways

Abstract

Inflammation is an important biological process involved in many target organ toxicities. However, there has been little consensus on how to represent inflammatory processes using the adverse outcome pathway (AOP) framework. In particular, there were concerns that inflammation was not being represented in a way that it would be recognized as a highly connected, central node within the global AOP network. The consideration of salient features common to the inflammatory process across tissues was used as a basis to propose 3 hub key events (KEs) for use in AOP network development. Each event, "tissue resident cell activation", "increased pro-inflammatory mediators", and "leukocyte recruitment/activation," is viewed as a hallmark of inflammation, independent of tissue, and can be independently measured. Using these proposed hub KEs, it was possible to link together a series of AOPs that previously had no shared KEs. Significant challenges remain with regard to accurate prediction of inflammation-related toxicological outcomes even if a broader and more connected network of inflammation-centered AOPs is developed. Nonetheless, the current proposal addresses one of the major hurdles associated with representation of inflammation in AOPs and may aid fit-for-purpose evaluations of other AOPs operating in a network context.

Figure 1.

Generalized model of sequential steps involved in inflammatory response in a tissue. Sequence of chevrons indicates anticipated adaptive/protective response to a damage signal. Arrows indicate trajectory diverging from an adaptive homeostatic state to a maladaptive/adverse response. DAMPs = damage associated molecular patterns; PAMPs = pathogen associated molecular patterns; BM = bone marrow.

Figure 2.

Overview of three key events (KEs, blue boxes) associated with hallmarks of inflammation that were proposed for use as potential hub KEs in inflammation-related adverse outcome pathway (AOP) networks. The three events are viewed as points of convergence between a wide range of potential stressor-dependent upstream signals that can induce inflammatory response and points of divergence toward a wide range tissue and context-dependent adverse outcomes. One or all of these KEs may be included in a given AOP, and in some cases the order, particularly of the first two, may be reversed, consequently no arrows between the blue boxes are shown. Note “Tissue Resident Cell Activation” may also include activation of resident/patrolling leukocytes.

Figure 3.

Four adverse outcome pathways (AOPs) shown before (above the horizontal dashed line) and after (below the horizontal dashed line) incorporation of the proposed hub key events (blue shaded). A. A network of two AOPs linking induction and secretion of inflammatory cytokines to lung fibrosis (AOP 173; https://aopwiki.org/aops/173) or lung emphysema (novel AOP not yet entered in the AOP-Wiki). Revised titles, resident cell activation leading to lung fibrosis or lung emphysema, respectively. B. AOP linking chronic binding of antagonists to N-methyl-D-aspartate receptors (NMDARs) during brain development to neurodegeneration with impairment of learning and memory in aging (AOP 13; https://aopwiki.org/aops/13). C. AOP linking protein alkylation to liver fibrosis (AOP 38; https://aopwiki.org/aops/38).

Figure 4.

Network composed of four adverse outcome pathways (AOPs; https://aopwiki.org/aops; AOPs 13, 38, 173 and one novel AOP not yet in the AOP-Wiki) illustrating how incorporation of the proposed hub key events facilitates improved connectivity of disparate inflammation-related AOPs within a broader AOP network.