title: Environmental particulate (PM2.5) augments stiffness-induced alveolar epithelial cell mechanoactivation of transforming growth factor beta.
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.
authors.affiliation: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.
authors.forename: Marilyn M
authors.initials: MM
authors.lastname: Dysart
authors.affiliation: The School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Boris R
authors.initials: BR
authors.lastname: Galvis
authors.affiliation: The School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Armistead G
authors.initials: AG
authors.lastname: Russell
authors.affiliation: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America; The Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Barker
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D042541:Intracellular Space; D052638:Particulate Matter / Q000009:adverse effects* / Q000737:chemistry; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D052638:Particulate Matter; D011725:Pyridines; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; C108830:Y 27632; D054460:rho-Associated Kinases