Abstract
Dysfunctional pulmonary homeostasis and repair, including diseases such as pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), and tumorigenesis have been increasing over the past decade, a fact that heavily implicates environmental influences. Several investigations have suggested that in response to increased transforming growth factor - beta (TGFβ) signaling, the alveolar type II (ATII) epithelial cell undergoes phenotypic changes that may contribute to the complex pathobiology of PF. We have previously demonstrated that increased tissue stiffness associated with PF is a potent extracellular matrix (ECM) signal for epithelial cell activation of TGFβ. The work reported here explores the relationship between tissue stiffness and exposure to environmental stimuli in the activation of TGFβ. We hypothesized that exposure of ATII cells to fine particulate matter (PM2.5) will result in enhanced cell contractility, TGFβ activation, and subsequent changes to ATII cell phenotype. ATII cells were cultured on increasingly stiff substrates with or without addition of PM2.5. Exposure to PM2.5 resulted in increased activation of TGFβ, increased cell contractility, and elongation of ATII cells. Most notably, on 8 kPa substrates, a stiffness greater than normal but less than established fibrotic lung, addition of PM2.5 resulted in increased cortical cell stiffness, enhanced actin staining and cell elongation; a result not seen in the absence of PM2.5. Our work suggests that PM2.5 exposure additionally enhances the existing interaction between ECM stiffness and TGFβ that has been previously reported. Furthermore, we show that this additional enhancement is likely a consequence of intracellular reactive oxygen species (ROS) leading to increased TGFβ signaling events. These results highlight the importance of both the micromechanical and biochemical environment in lung disease initiation and suggest that individuals in early stages of lung remodeling during fibrosis may be more susceptible than healthy individuals when exposed to environmental injury adjuvants.
Highlights
Dysfunctional pulmonary homeostasis and repair, including diseases such as pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), and tumorigenesis, have been steadily increasing over the past decade
We have previously shown that substrate stiffness induces changes to alveolar epithelial cell phenotype and may be a regulator of processes that drive PF [16,70]
Since we saw increases in cell-stiffness with the addition of PM2.5, we investigated if the addition of PM2.5 resulted in differences in transforming growth factor beta (TGFb) activation, which could lead to further changes in alveolar type II (ATII) cell phenotype
Summary
Dysfunctional pulmonary homeostasis and repair, including diseases such as pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), and tumorigenesis, have been steadily increasing over the past decade. During the course of pulmonary fibrosis, functional lung tissue of the alveoli is replaced with collagen-rich ECM, which leads to rapid and severe decreases in lung compliance and irreversible loss of lung function [1,2] Another hallmark of PF and other fibrotic conditions is the influx of contractile myofibroblasts. Myofibroblasts are recruited from a variety of sources including local mesenchymal cells, bone marrow progenitors, and via a process of epithelial to mesenchymal transition (EMT), where epithelial cells transdifferentiate into fibroblast like cells. Once these fibroblasts become activated, they transform into myofibroblasts that are capable of secreting ECM components. Fibrosis is thought to occur when this process becomes dysregulated, resulting in persistent matrix production and the formation of a scar
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