Abstract
Fibrotic reactions in the airways of the lung or the pulmonary interstitium are a common pathologic outcome after exposure to a wide variety of toxic agents, including metals, particles or fibers. The survival of mesenchymal cells (fibroblasts and myofibroblasts) is a key factor in determining whether a fibroproliferative response that occurs after toxic injury to the lung will ultimately resolve or progress to a pathologic state. Several polypeptide growth factors, including members of the platelet-derived growth factor (PDGF) family and the epidermal growth factor (EGF) family, are prosurvival factors that stimulate a replicative and migratory mesenchymal cell phenotype during the early stages of lung fibrogenesis. This replicative phenotype can progress to a matrix synthetic phenotype in the presence of transforming growth factor-β1 (TGF-β1). The resolution of a fibrotic response requires growth arrest and apoptosis of mesenchymal cells, whereas progressive chronic fibrosis has been associated with mesenchymal cell resistance to apoptosis. Mesenchymal cell survival or apoptosis is further influenced by cytokines secreted during Th1 inflammation (e.g., IFN-γ) or Th2 inflammation (e.g., IL-13) that modulate the expression of growth factor activity through the STAT family of transcription factors. Understanding the mechanisms that regulate the survival or death of mesenchymal cells is central to ultimately developing therapeutic strategies for lung fibrosis.
Highlights
Fibrosis is a feature of many environmental and occupational lung diseases where pathological changes occur either around the conducting airways [1] or within the pulmonary interstitium of the distal lung parenchyma [2]
signal transducers and activators of transcription (STATs)-3 activation in response to platelet-derived growth factor (PDGF) or epidermal growth factor (EGF), a prosurvival signaling event for mesenchymal cells, is significantly greater in STAT-1-/- mouse lung fibroblasts compared to STAT-1+/+ fibroblasts. These findings indicate that STAT-1-/- mice are more susceptible to bleomycininduced lung fibrosis than STAT-1+/+ mice owing to enhanced fibroblast proliferation in response to growth factors (PDGF and EGF) and increased activation of STAT-3
Apoptosis of fibroblasts is required for successful wound healing and termination of collagen deposition [70], and resistance to apoptosis has been observed in fibroblasts from idiopathic pulmonary fibrosis (IPF) patients [103]
Summary
Fibrosis is a feature of many environmental and occupational lung diseases where pathological changes occur either around the conducting airways [1] or within the pulmonary interstitium of the distal lung parenchyma [2]. This study indicated that STAT-1-/mice are more susceptible than wild-type mice to bleomycin-induced lung fibrosis owing to (1) enhanced fibroblast proliferation in response to growth factors (EGF and PDGF), (2) stimulation of fibroblast growth by a STAT-1-independent IFN-g signaling pathway, and (3) increased activation of STAT-3. Our findings support the hypothesis that STAT-1, IFNs and CXCL10 are protective factors in the lung that limit the severity of a fibrogenic response and promote the resolution of fibrosis These events act in opposition to and occur after the profibrogenic actions of V2O5 in mice and rats that results from increased expression and activation of profibrogenic growth factors such as PDGF, TGF-b1, and CTGF. A common theme is that STAT-1, activated by IFNs, antagonizes STAT-6 and STAT-3 to exert opposing biological effects mediated by IL-13 or growth factors, respectively
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
