Fig. 2.

Proposed concept of toxicological pulmonary granuloma and fibrosis as lung diseases induced in response to environmental cues. Chemicals have the potential to function as either antigens or irritants or both for alveolar macrophages, dendritic cells and/or epithelial cells. Antigens are presented to T cells by APCs, inducing Th1-type inflammation (expressing TNF-α, IFN-γ and IL-2) and recruiting many CD4⁺ and CD8⁺ T cells, which may contribute to the formation of giant and epithelioid cells. Only a few T_regs are found in affected humans and animals as compared with the controls, subsequently disturbing the Th1/Th2 balance. On the other hand, cytotoxicity by irritants induces inflammation in association with the expression of chemokines (MIP-1α, MCP-1, MCP-3, MCP-5, eotaxin-1, TARC, MDC, ELC and SLC) and recruitment of macrophages, PMN and lymphocytes (T cells/B cells), followed by the proliferation of fibroblasts and myo­fibroblasts. Circulating fibrocytes derived from the bone marrow contribute to fibrotic disorders in the lung. Profibrotic and antifibrotic signaling may be regulated by TGF-β/BMP/gremlin and PP1A/PTEN signaling. APCs, antigen-presenting cells; Th1, T helper 1; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; IL-2, interleukin-2; T_regs, regulatory T cells; Th2, T helper 2; MIP, macrophage inflammatory protein; MCP-1, monocyte chemotactic protein-1; TARC, thymus- and activation-regulated chemokine; MDC, macrophage-derived chemokine; ELC, Epstein-Barr-induced 1 (EBI1)-ligand chemokine; SLC, secondary lymphoid-tissue chemokine; PMN, polymorphonuclear neutrophils; TGF-β, transforming growth factor-β; BMP, bone morphogenetic protein; PP1A, protein phosphatase 1A; PTEN, phosphatase and tensin homolog.