Stratified hierarchical response to air pollutants. Macrophages exposed to particulate matter components (e.g. DEP) respond in a dose-dependent fashion via the activation of pathways and mechanisms at various levels of action (tiers). For example, Nrf2 can induce the transcription of antioxidant genes via the antioxidant response element (ARE) in the earliest level of defense (tier 1). When the mechanisms of defense involved in one tier are not sufficient to contain the injurious stimuli, signaling pathways of the subsequent(s) tier of action may get activated, such as MAPK pathways that regulate proinflammatory genes via Activating Protein (AP) transcription factors (tier 2) or proapoptotic signals triggered by mitochondrial perturbation that can lead to activation of the mitochondrial permeability transition (PT) pore and cellular toxicity (tier 3). Modified from Li et al .