Pulmonary fibrosis in response to environmental cues and molecular targets involved in its pathogenesis

Abstract

Chronic lung injury resulting from a variety of different causes is frequently associated with the develop ment of pulmonary fibrosis in humans. Although the etiology of pulmonary fibrosis is generally unknown, several sources of evidence support the hypothesis that a number of environmental and occupational agents play an etiologic role in the pathogenesis of this disease. The agents discussed in this review include beryllium, nylon flock, textile printing aerosols, polyvinyl chloride and didecyldimethylammonium chloride. The authors also describe a variety of animal models, including genetically modified mice, in order to investigate the molecular mechanism of pulmonary fibrosis, focusing on chemokine receptors, regulatory T cells and transforming growth factor-β and bone morphogenetic protein signaling. Overall, we propose the concept of toxicological pulmonary fibrosis as a lung disease induced in response to environmental cues.

Keywords: DDAC; TGF-β; beryllium; chemokine receptor; nylon flock; regulatory T cell.

Fig. 1.

DDAC induces inflammation and fibroproliferation in the lungs. Mice were intratracheally instilled with 0.01% of DDAC or the vehicle control and were sacrificed on day 7, 13, or 20 after the treatment. Lung tissue samples were subjected to histopathological examination. Representative images of the lung tissues stained with hematoxylin and eosin (A–D) and Masson trichrome (E–H) from the vehicle control (A, E) and DDAC-treated mice on day 7 (B,F), 13 (C,G) or 20 (D,H). Scale bar: 50 µm.

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.