Molecular Mechanisms Of Pulmonary Fibrosis Research Articles

Carbon nanotubes promote alveolar macrophages toward M2 polarization mediated epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation

With substantial progress of nanotechnology, carbon nanotubes (CNTs) are widely used in a variety of industrial and commercial applications. There is rising concern about potential adverse health effects, such as pulmonary fibrosis, related to inhalation of CNTs. The detailed cellular and molecular mechanisms of pulmonary fibrosis induced by CNTs are still not clear. Epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) are considered as critical events in pathogenesis of pulmonary fibrosis. Alveolar macrophages (AMs) polarization plays a key role of regulating EMT and FMT in pulmonary fibrosis. In this study, we applied CNTs to stimulate primary mouse AMs under M1 or M2 polarization conditions, then analyzed the proportion of F4/80+CD11c+ or F4/80+CD206+ AMs, mRNA expression and activities of iNOS or Arg-1, as well as mRNA expression and content of TNF-α and IL-6 or TGF-β and IL-10 to evaluate dynamic phenotypic and functional changes of AMs. Single-walled CNT (SWCNT), short-type multi-walled CNT (MWCNT), and long-type MWCNT exposure at dose of 50 µg/ml promote AMs polarization toward M1 phenotype at early stage, while promote AMs polarization toward M2 phenotype at late stage. The roles of AMs polarization during development of EMT and FMT were further investigated by conditioned medium (CM) experiments. CNTs-activated M2 AMs promote progression of EMT and FMT via secreting TGF-β. Furthermore, up-regulating IRF4 may be involved in CNTs-induced M2 AMs polarization. In conclusion, this study demonstrates a new insight that CNTs exposure promotes AMs polarization toward M2 phenotype which facilitate EMT and FMT through secreting TGF-β.

A Passion for Scleroderma Research

My research experience in the field of scleroderma began in year 2000 when I was recruited as a postdoctoral fellow to the laboratory of Dr. Richard M. Silver. Since that time my research interests has focused on understanding the cellular and molecular mechanisms of pulmonary fibrosis in scleroderma patients.

Integrating mechanisms of pulmonary fibrosis

Pulmonary fibrosis is a highly heterogeneous and lethal pathological process with limited therapeutic options. Although research on the pathogenesis of pulmonary fibrosis has frequently focused on the mechanisms that regulate the proliferation, activation, and differentiation of collagen-secreting myofibroblasts, recent studies have identified new pathogenic mechanisms that are critically involved in the initiation and progression of fibrosis in a variety of settings. A more detailed and integrated understanding of the cellular and molecular mechanisms of pulmonary fibrosis could help pave the way for effective therapeutics for this devastating and complex disease.

Involvement of Epithelial Cell Apoptosis in Interstitial Lung Diseases

Lung epithelium is the primary site of lung damage in interstitial lung diseases. Although there are various initiating factors, the terminal stages are characterized by pulmonary fibrosis. Conventional therapy consisting of glucocorticoids or immunosuppressive drugs is usually ineffective. Epithelial cell apoptosis have been considered to be initial events in interstitial lung diseases. The death receptor-mediated signaling pathway directly induces caspase activation and apoptosis. Other stresses induce the release of cytochrome from mitochondria and caspase activation. Endoplasmic reticulum stress also induces apoptosis. Epithelial cell death is followed by remodeling processes, which consist of epithelial and fibroblast activation, cytokine production, activation of the coagulation pathway, neoangiogenesis, re-epithelialization and fibrosis. Epithelial and mesenchymal interaction plays important roles in these processes. Further understanding of apoptosis signaling may lead to effective strategies against devastating lung diseases. We review the role of epithelial cell apoptosis in the molecular mechanisms of pulmonary fibrosis.

Proapoptotic Bid is required for pulmonary fibrosis

The molecular mechanisms of pulmonary fibrosis are poorly understood. Previous reports indicate that activation of TGF-beta1 is essential for the development of pulmonary fibrosis. Here, we report that the proapoptotic Bcl-2 family member Bid is required for the development of pulmonary fibrosis after the intratracheal instillation of bleomycin. Mice lacking Bid exhibited significantly less pulmonary fibrosis in response to bleomycin compared with WT mice. The attenuation in pulmonary fibrosis was observed despite similar levels of inflammation, lung injury, and active TGF-beta1 in bronchoalveolar lavage fluid 5 days after the administration of bleomycin in mice lacking Bid and in WT controls. Bleomycin induced similar levels cell death in vitro in alveolar epithelial cells isolated from WT and bid(-/-) mice. By contrast, alveolar epithelial cells from bid(-/-) mice were resistant to TGF-beta1-induced cell death. These results indicate that Bcl-2 family members are critical regulators for the development of pulmonary fibrosis downstream of TGF-beta1 activation.

Molecular Mechanisms of and Possible Treatment Strategies for Idiopathic Pulmonary Fibrosis

Pulmonary fibrosis is characterized by lung inflammation and abnormal tissue repair, resulting in the replacement of normal functional tissue with an abnormal accumulation of fibroblasts and deposition of collagen in the lung. This process involves cellular interactions via a complex cytokine-signaling mechanism and heightened collagen gene expression, ultimately resulting in its abnormal collagen deposition in the lung. Our current understanding of the pathogenesis of pulmonary fibrosis suggests that in addition to inflammatory cells, the fibroblast and signaling events that mediate fibroblast proliferation and myofibroblasts, play important roles in the diverse processes that constitute fibrosis. Increasing knowledge of cytokine biology, cytokine-signaling and cell matrix interactions have shed some light on the genesis of pulmonary fibrosis; however, the importance of inflammation in pulmonary fibrosis remains controversial. This remains true because the inflammatory component is variable at the time of diagnosis, and the most potent anti-inflammatory drugs that have been widely used in the treatment of pulmonary fibrosis do not seem to interfere with the fibrotic disease progression. Pulmonary fibrosis is a highly lethal disorder, which continues to pose major clinical challenges because an effective therapeutic regimen is yet to be determined. This review summarizes recent progress in understanding the molecular mechanisms of pulmonary fibrosis, and includes a more detailed discussion of the potential points of therapeutic attack in pulmonary fibrosis. In addition, a detailed discussion is presented regarding each of the potential therapies which have emerged from the animal models of pulmonary fibrosis, and which have been developed through advances in cellular and molecular biology.

The transcription factor NRF2 protects against pulmonary fibrosis.

The molecular mechanisms of pulmonary fibrosis are poorly understood, although reactive oxygen species are thought to have an important role. NRF2 is a transcription factor that protects cells and tissues from oxidative stress by activating protective antioxidant and detoxifying enzymes. We hypothesized that NRF2 protects lungs from injury and fibrosis induced by bleomycin, an anti-neoplastic agent that causes pulmonary fibrosis in susceptible patients. To test this hypothesis, mice with targeted deletion of Nrf2 (Nrf2-/-) and wild-type (Nrf2+/+) mice were treated with bleomycin or vehicle, and pulmonary injury and fibrotic responses were compared. Bleomycin-induced increases in lung weight, epithelial cell death, and inflammation were significantly greater in Nrf2-/- mice than in Nrf2+/+ mice. Indices of lung fibrosis (hydroxyproline content, collagen accumulation, fibrotic score, cell proliferation) were significantly greater in bleomycin-treated Nrf2-/- mice, compared with Nrf2+/+ mice. NRF2 expression and activity were elevated in Nrf2+/+ mice by bleomycin. Bleomycin caused greater up-regulation of several NRF2-inducible antioxidant enzyme genes and protein products in Nrf2+/+ mice compared with Nrf2-/- mice. Further, bleomycin-induced transcripts and protein levels of lung injury and fibrosis markers were significantly attenuated in Nrf2+/+ mice compared with Nrf2-/- mice. Results demonstrated that NRF2 has a critical role in protection against pulmonary fibrosis, presumably through enhancement of cellular antioxidant capacity. This study has important implications for the development of intervention strategies against fibrosis.

Molecular mechanisms of pulmonary fibrosis

Molecular mechanisms of pulmonary fibrosis

Molecular mechanisms of pulmonary fibrosis

Pulmonary fibrosis is the end-point of a numerous and heterogeneous group of disorders known as interstitial lung diseases (ILD). Lung fibrotic remodeling is characterized by fibroblast/myofibroblast activation, and excessive extracellular matrix accumulation leading to progressive organ dysfunction and usually terminal outcome. Treatment is largely ineffective primarily because few of the molecular mechanisms have been well defined to design appropriate targets for therapy. While the pathogenesis is incompletely understood, a growing body of evidence suggests two different pathogenic routes for developing pulmonary fibrosis. The inflammatory pathway, where a shift to the so-called T-helper 2 type cytokine networks is critical, and the epithelial pathway represented by idiopathic pulmonary fibrosis, by far the most aggressive ILD. In this pathway the inflammatory process is irrelevant, and the physiopathology seems to be dominated by epithelial cell injury and activation. Both routes may trigger a number of cytokines/growth factors inducing fibroblast migration/proliferation and phenotype change to myofibroblasts, with a consequent accumulation of extracellular matrix. An imbalance in matrix metalloproteinase/tissue inhibitors of metalloproteinases may contribute to alteration in extracellular matrix turnover and remodeling. This review will focus in some of the mechanisms involved in both prefibrotic pathways, as well as those involved in fibroblast activation and abnormal matrix deposition.

Molecular mechanisms of pulmonary fibrosis and current treatment.

Pulmonary fibrosis is a common response to various insults or injuries to the lung. Although there are various initiating factors or causes, the terminal stages are characterized by proliferation and progressive accumulation of connective tissue replacing normal functional parenchyma. The pathogenesis of pulmonary fibrosis includes endothelial and epithelial cell injury, production of inflammatory cells and their mediators, and fibroblast activation. Conventional therapy consisting of glucocorticoids or cytotoxic drugs is usually ineffective in preventing progression of the disease. Further understanding of the molecular mechanisms of endothelial and epithelial cell injury, inflammatory reaction, fibroblast proliferation, collagen deposition and lung repair, should lead to the development of effective treatments against pulmonary fibrosis. Accordingly, this review summarizes recent progress made in understanding the molecular mechanisms of pulmonary fibrosis. A detailed discussion is presented regarding each of the potential new therapies which have emerged from the animal models of pulmonary fibrosis and which have been developed through advances in cellular and molecular biology.

Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis.

The molecular mechanisms of pulmonary fibrosis are poorly understood. We have used oligonucleotide arrays to analyze the gene expression programs that underlie pulmonary fibrosis in response to bleomycin, a drug that causes lung inflammation and fibrosis, in two strains of susceptible mice (129 and C57BL/6). We then compared the gene expression patterns in these mice with 129 mice carrying a null mutation in the epithelial-restricted integrin beta6 subunit (beta6(-/-)), which develop inflammation but are protected from pulmonary fibrosis. Cluster analysis identified two distinct groups of genes involved in the inflammatory and fibrotic responses. Analysis of gene expression at multiple time points after bleomycin administration revealed sequential induction of subsets of genes that characterize each response. The availability of this comprehensive data set should accelerate the development of more effective strategies for intervention at the various stages in the development of fibrotic diseases of the lungs and other organs.