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.

ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling

“…MSC were treated in vitro with bleomycin or TGF-␤1 and analyzed changes in gene expression indicative of myofibroblast transition. TGF-␤1 was chosen because it is a known regulator of fibrosis in many adult tissues as well as in response to bleomycin injury (11,64,71,73). TGF-␤1 target genes were also upregulated in the MSC during the inflammatory phase of bleomycin injury (Fig.…”

“…Taken together, these results demonstrated that lung MSC protect lung integrity following injury and when endogenous MSC are lost due to abnormal differentiation, their protective function is compromised. In addition to their reparative properties, several studies indicate that lung MSC can instead mediate pathogenic changes within the lung (11,80). Indeed, the behavior of MSC is highly sensitive to the microenvironment to which these cells are exposed (100).…”

Nickel Nanoparticles Enhance Platelet-Derived Growth Factor–Induced Chemokine Expression by Mesothelial Cells via Prolonged Mitogen-Activated Protein Kinase Activation

“…NiNPs are used as a catalyst in the fabrication of MWCNTs, and there are concerns that they could be a contributing factor to pulmonary fibrosis or mesothelioma (5,6,12). We have previously reported a significant fibrotic response in the lungs and pleura of mice after inhalation exposure to MWCNTs containing residual Ni (8,32).…”

“…In addition, PDGF production by macrophages can be increased in a hypoxic environment stimulated by exposure to Ni (10,11). PDGF acts as a stimulant of fibroblast growth and chemotaxis through the activation of the mitogen-activated protein kinases (MAPKs) termed extracellular signal-regulated kinase (ERK) -1 and -2 (collectively referred to as ERK), and plays a major role in fibroblast survival (10,12). Fibroblasts are critical to fibrogenesis, as they differentiate into myofibroblasts in response to transforming growth factor (TGF)-b1 to produce collagen, which defines fibrotic lesions (10).…”

Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogenesis and adiponectin secretion

“…In support of this, we have shown that functional blocking antibodies to PDGFR promote adipogenesis and adiponectin secretion when used at concentrations that suppress cell proliferation and PDGF-induced Akt activation similar to that achieved with imatinib. We therefore hypothesise that, in cultures treated with physiological levels of glucocorticoid alone, the basal adipogenic response to glucocorticoid is suppressed by PDGF, which is present in bovine serum, and is secreted in an autocrine and/or paracrine fashion by MSCs (Bonner 2010). Addition of imatinib or functional blocking antibodies ameliorates this inhibitory effect allowing differentiation to proceed unabated.…”