Abstract:Pulmonary fibrosis results from the excessive deposition of collagen fibers and scarring in the lungs with or without an identifiable cause. The mechanism(s) underlying lung fibrosis development is poorly understood, and effective treatment is lacking. Here we compared mouse lung fibrosis induced by pulmonary exposure to prototypical particulate (crystalline silica) or soluble chemical (bleomycin or paraquat) fibrogenic agents to identify the underlying mechanisms. Young male C57BL/6J mice were given silica (2… Show more
“…Moreover, TIMP1 is secreted into the plasma in certain fibrosing diseases and cancers and, therefore, affects distant tissues in a manner analogous to an endocrine factor. Consistent with this notion, TIMP1 is highly induced during fibrosis in a number of animal models, such as bleomycin- and paraquat-induced lung fibrosis, and fibrosing diseases in humans, such as IPF and liver cirrhosis, implicating dysregulation of TIMP1 expression in the development of fibrosis (Dong et al, 2016; Hayashi et al, 1996; Madtes et al, 2001; Manoury et al, 2006; Selman et al, 2000; Tomita et al, 2007). Nonetheless, the function of TIMP1 in fibrosis, in particular, in the development of lung fibrosis remains largely unclear.…”
Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) may cause fibrosing lesions in animal lungs, raising health concerns about such exposure in humans. The mechanisms underlying fibrosis development remain unclear, but they are believed to involve the dysfunction of fibroblasts and myofibroblasts. Using a mouse model of MWCNT exposure, we found that the tissue inhibitor of metalloproteinase 1 (Timp1) gene was rapidly and highly induced in the lungs by MWCNTs in a time- and dose-dependent manner. Concomitantly, a pronounced elevation of secreted TIMP1 was observed in the bronchoalveolar lavage (BAL) fluid and serum. Knockout (KO) of Timp1 in mice caused a significant reduction in fibrotic focus formation, collagen fiber deposition, recruitment of fibroblasts and differentiation of fibroblasts into myofibroblasts in the lungs, indicating that TIMP1 plays a critical role in the pulmonary fibrotic response to MWCNTs. At the molecular level, MWCNT exposure significantly increased the expression of the cell proliferation markers Ki-67 and PCNA and a panel of cell cycle-controlling genes in the lungs in a TIMP1-dependent manner. MWCNT-stimulated cell proliferation was most prominent in fibroblasts but not myofibroblasts. Furthermore, MWCNTs elicited a significant induction of CD63 and integrin β1 in lung fibroblasts, leading to the formation of a TIMP1/CD63/integrin β1 complex on the surface of fibroblasts in vivo and in vitro, which triggered the phosphorylation and activation of Erk1/2. Our study uncovers a new pathway through which induced TIMP1 critically modulates the pulmonary fibrotic response to MWCNTs by promoting fibroblast activation and proliferation via the TIMP1/CD63/integrin β1 axis and ERK signaling.
“…Moreover, TIMP1 is secreted into the plasma in certain fibrosing diseases and cancers and, therefore, affects distant tissues in a manner analogous to an endocrine factor. Consistent with this notion, TIMP1 is highly induced during fibrosis in a number of animal models, such as bleomycin- and paraquat-induced lung fibrosis, and fibrosing diseases in humans, such as IPF and liver cirrhosis, implicating dysregulation of TIMP1 expression in the development of fibrosis (Dong et al, 2016; Hayashi et al, 1996; Madtes et al, 2001; Manoury et al, 2006; Selman et al, 2000; Tomita et al, 2007). Nonetheless, the function of TIMP1 in fibrosis, in particular, in the development of lung fibrosis remains largely unclear.…”
Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) may cause fibrosing lesions in animal lungs, raising health concerns about such exposure in humans. The mechanisms underlying fibrosis development remain unclear, but they are believed to involve the dysfunction of fibroblasts and myofibroblasts. Using a mouse model of MWCNT exposure, we found that the tissue inhibitor of metalloproteinase 1 (Timp1) gene was rapidly and highly induced in the lungs by MWCNTs in a time- and dose-dependent manner. Concomitantly, a pronounced elevation of secreted TIMP1 was observed in the bronchoalveolar lavage (BAL) fluid and serum. Knockout (KO) of Timp1 in mice caused a significant reduction in fibrotic focus formation, collagen fiber deposition, recruitment of fibroblasts and differentiation of fibroblasts into myofibroblasts in the lungs, indicating that TIMP1 plays a critical role in the pulmonary fibrotic response to MWCNTs. At the molecular level, MWCNT exposure significantly increased the expression of the cell proliferation markers Ki-67 and PCNA and a panel of cell cycle-controlling genes in the lungs in a TIMP1-dependent manner. MWCNT-stimulated cell proliferation was most prominent in fibroblasts but not myofibroblasts. Furthermore, MWCNTs elicited a significant induction of CD63 and integrin β1 in lung fibroblasts, leading to the formation of a TIMP1/CD63/integrin β1 complex on the surface of fibroblasts in vivo and in vitro, which triggered the phosphorylation and activation of Erk1/2. Our study uncovers a new pathway through which induced TIMP1 critically modulates the pulmonary fibrotic response to MWCNTs by promoting fibroblast activation and proliferation via the TIMP1/CD63/integrin β1 axis and ERK signaling.
“…The lung fibrotic response to CNT exposure resembles the pulmonary response to deposition of fibrogenic foreign bodies in the lungs. In particular, the pathologic features and dynamics of the pulmonary interstitial fibrosis induced by CNTs display a high similarity to those of pneumoconiosis and IPF, both of which are progressive, incurable, and poorly understood human fibrotic lung diseases [24, 28]. Fig.…”
“…It is known that both MWCNTs and SWCNTs stimulate the production of ROS in vitro and in the lungs [95, 96, 101, 125], which would induce the activation of TGF-β1 in a manner analogous to that of asbestos [126, 127]. In recent studies, we have shown that the lung expression of TSP-1 was significantly induced by MWCNTs in vivo [101], whereas that of MMP-2 was induced during lung fibrosis from exposure to silica, paraquat, or bleomycin [28]. Direct evidence supporting a role of these mediators in the activation of latent TGF-β1 in CNT-induced lung fibrosis awaits further investigation.…”
Section: Tgf-β1mentioning
confidence: 99%
“…The pathologic development and features of CNT-induced pulmonary interstitial fibrosis overlap with those of IPF and pneumoconiosis considerably. From the experimental research point of view, this finding suggests a possible application of CNT-induced lung fibrosis in the study of the human lung fibrosing diseases with regard to their pathogenesis, therapeutic targeting, and biomarkers for exposure and disease monitoring [18, 24, 28]. Recent field studies on CNT-exposed populations demonstrate marked accumulation of inflammatory and fibrotic mediators and biomarkers in the body fluids of workers manufacturing MWCNTs, highlighting a need to protect humans from nano exposure from occupational, environmental, and commercial sources [29–31].…”
Carbon nanotubes (CNTs) are newly developed materials with unique properties and a range of industrial and commercial applications. A rapid expansion in the production of CNT materials may increase the risk of human exposure to CNTs. Studies in rodents have shown that certain forms of CNTs are potent fibrogenic inducers in the lungs to cause interstitial, bronchial, and pleural fibrosis characterized by the excessive deposition of collagen fibers and the scarring of involved tissues. The cellular and molecular basis underlying the fibrotic response to CNT exposure remains poorly understood. Myofibroblasts are a major type of effector cells in organ fibrosis that secrete copious amounts of extracellular matrix proteins and signaling molecules to drive fibrosis. Myofibroblasts also mediate the mechano-regulation of fibrotic matrix remodeling via contraction of their stress fibers. Recent studies reveal that exposure to CNTs induces the differentiation of myofibroblasts from fibroblasts in vitro and stimulates pulmonary accumulation and activation of myofibroblasts in vivo. Moreover, mechanistic analyses provide insights into the molecular underpinnings of myofibroblast differentiation and function induced by CNTs in the lungs.In view of the apparent fibrogenic activity of CNTs and the emerging role of myofibroblasts in the development of organ fibrosis, we discuss recent findings on CNT-induced lung fibrosis with emphasis on the role of myofibroblasts in the pathologic development of lung fibrosis. Particular attention is given to the formation and activation of myofibroblasts upon CNT exposure and the possible mechanisms by which CNTs regulate the function and dynamics of myofibroblasts in the lungs. It is evident that a fundamental understanding of the myofibroblast and its function and regulation in lung fibrosis will have a major influence on the future research on the pulmonary response to nano exposure, particle and fiber-induced pneumoconiosis, and other human lung fibrosing diseases.
“…The lung lesions elicited by CNT, either multi-walled (MWCNT) or single-walled (SWCNT), resemble the pulmonary response to deposition of foreign bodies such as insoluble dusts (i.e., silica, asbestos, and coal dust) and large biologic masses (i.e., inhaled allergens and microbes, and invading parasites), all of which are capable of inducing lung fibrosis (Dong and Ma 2015a; Dong et al 2015a, b; Husain and Kumar 2005; Morgan and Seaton 1995). The response initiates with a prominent acute inflammation, indicated by recruitment and accumulation of inflammatory cells and elevated secretion of cytokines and growth factors.…”
Pulmonary exposure to certain forms of carbon nanotubes (CNT) induces fibrosing lesions in the lungs that manifest an acute inflammation followed by chronic interstitial fibrosis. The mechanism of CNT-induced fibrogenesis is largely unknown. The biphasic development with drastically distinct pathologic manifestations suggests a junction of acute-to-chronic transition. Here we analyzed the molecular pathways and regulators underlying the pathologic development of CNT-induced lung fibrosis. Mice were exposed to multi-walled CNT (MWCNT; XNRI MWNT-7, Mitsui; 40 μg) by pharyngeal aspiration for 7 days along with vehicle and carbonaceous controls. Genome-wide microarray analyses of the lungs identified a range of differentially expressed genes that potentially function in the acute-to-chronic transition through pathways involving immune and inflammatory regulation, responses to stress and extracellular stimuli, and cell migration and adhesion. In particular, a T helper 2 (Th2)-driven innate immune response was significantly enriched. We then demonstrated that MWCNT induced the expression of Th2 cytokines interleukin (IL)-4 and IL-13, and a panel of signature downstream genes, such as Il4i1, Chia, and Ccl11/Eotaxin, time dependently. Induction of Th2 cytokines took place in CD4+ T lymphocytes indicating activation of Th2 cells. Furthermore, induction involved activation of a Th2 cell-specific signaling pathway through phosphorylation of STAT6 and up-regulation of GATA-3 to mediate the transcription of Th2 target genes. Our study uncovers activation of a Th2-driven immune/inflammatory response during pulmonary fibrosis development induced by MWCNT. The findings provide novel insights into the molecular events that control the transition from an acute inflammatory response to chronic fibrosis through Th2 functions in CNT-exposed lungs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
