Mesenchymal cell survival in airway and interstitial pulmonary fibrosis

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.

Figure 1

Comparison of events that mediate "resolving fibrosis" versus "progressive chronic fibrosis." Following injury, mesenchymal cell accumulation and subsequent matrix (e.g., collagen) production occur in both resolving and progressive fibrogenesis. However, mesenchymal cell apoptosis and degradation of matrix are favored in resolving fibrosis, whereas mesenchymal survival is favored in progressive fibrosis. Mesenchymal cell survival is likely caused by enhanced growth factor responsiveness and resistance to apoptosis.

Figure 2

Mesenchymal cell survival in the progression of airway fibrosis following injury by environmental factors. Airway injury occurs after the inhalation of a variety of inhaled metals, fibers, particles or nanoparticles. After initial injury by particle insult, the airway epithelium produces chemokines that attract macrophages. Both macrophages and the epithelium produce cytokines, chemokines and growth factors that stimulate mesenchymal cell (fibroblast and myofibroblast) accumulation within days. Airway smooth muscle also undergoes hyperplasia and hypertrophy after particle injury. Mesenchymal cells undergo growth arrest and apoptosis, but leave deposited extracellular matrix (e.g., collagen) that defines the airway fibrotic lesion.

Figure 3

Growth factors and cytokines from macrophages and epithelial cells, along with the inflammatory microenvironment, influence mesenchymal cell survival and phenotype. Particle-stimulated airway epithelial cells and alveolar macrophages produce soluble cytokines and growth factors that stimulate the replication and migration of myofibroblasts. EGFR ligands (HB-EGF and TGF-α) are produced by airway epithelial cells that stimulate epithelial repair and differentiation in an autocrine manner, but also stimulate myofibroblast replication. PDGF-AA and PDGF-BB produced by epithelial cells and macrophages, respectively, drive replication and chemotactic migration of myofibroblasts. IL-1β enhances the activity of PDGF-AA and PDGF-BB by upregulating PDGF receptor-α (PDGFRα) expression. Macrophages are also an abundant source of TNF-α, which stimulates TGF-β1 production by macrophages in an autocrine manner. TGF-β1 stimulates myofibroblast collagen production and growth arrest, which defines a "matrix synthetic phenotype." The myofibroblast phenotype is further defined by a Th1 or Th2 microenvironment. In the presence of Th1 lymphocytes, IFN-γ produced by Th1 cells or IFN-β produced by myofibroblasts stimulates growth arrest and cell death of myofibroblasts and leads to the resolution of a fibrogenic response and tissue repair. In the presence of Th2 lymphocytes, IL-13 produced by Th2 cells activates myofibroblasts to produce PDGF-AA and TGF-β1 in an autocrine manner, which drives myofibroblast survival, replication and matrix production to enhance and sustain a fibrogenic response.

Figure 4

STAT transcription factor signaling outcomes in mesenchymal cells that contribute to pulmonary fibrogenesis. Multiple signals, either endogenous factors (cytokines and growth factors) or environmental factors (metals, particles, nanoparticles), activate STAT signaling that leads to outcomes involved in fibrogenesis and tissue repair. IL-13 is increased by allergens or certain metals and particles to activate STAT-6, which in turn results in Th2 inflammatory responses that include the production of profibrogenic growth factors, PDGF-AA and TGF-β1. These growth factors are also increased by metals, particles and nanoparticles. PDGF-AA and HB-EGF stimulate STAT-3 to turn on a mesenchymal cell "survival program." Metals and particles also increase the production of reactive oxygen species (ROS) through NADPH oxidase activity or increase the production of interferons (IFNs). ROS or IFNs stimulate STAT-1 to promote growth arrest and apoptosis of mesenchymal cells. Therefore, the proapoptotic action of STAT-1 opposes the prosurvival and antiapoptotic actions of STAT-3 and STAT-6 for mesenchymal cells.