Figure 3.

Pathways implicated in pulmonary inflammation-to-fibrosis progression. Inflammatory cells are recruited and enriched in the lung upon CNT exposure. In the early acute phase, CNTs stimulate the secretion of pro-inflammatory mediators via phagocytosis and type 1 immune response to boost acute inflammation, which requires the activation of the NLRP3 inflammasome. On the other hand, Th2-dependent type 2 immune response is activated in the late acute phase and signals the inhibition and resolution of acute inflammation and the progression to chronic inflammation, interstitial fibrosis, and granuloma through the action of type 2 cells, such as M2 macrophages and type 2 mediators, such as IL-4, IL-13, TGF-β1, TIMP1, and OPN. The type 2 immune response and fibrotic response prolong to the chronic phase. Both inflammation and fibrosis would lead to tissue hypoxia and activate HIF-1α to stimulate angiogenesis and metabolic adaptation. This time-dependent alteration in signaling pathways during pulmonary inflammation-to-fibrosis progression in part reflects the adaptation of innate immune functions to exposure of pathogenic CNTs and tissue injury in the lung.