Characterizing the Role of the Na+‐H+ Exchanger Isoform 1 (NHE1) in Pulmonary Fibrosis

Abstract

Pulmonary fibrosis is a chronic, progressive lung disease characterized by stiffening and thickening of the lung tissue leading to reduced respiratory function. When lung tissue becomes damaged, the response is to increase recruitment and proliferation of fibroblasts and increase deposition of extracellular matrix (ECM) proteins such as collagen. This initiates the release of transforming growth factor beta 1 (TGF‐β1), a cytokine known to enhance fibrosis. TGF‐β1 induces myofibroblast differentiation and further stiffening of the ECM by stimulating formation of cytoplasmic microfilament bundles and increasing expression of alpha‐smooth muscle actin (α‐SMA). Signal molecules such as serotonin (5‐HT), and lysophosphatidic acid (LPA) contribute to this by binding to G‐protein coupled receptors that support increased release of TGF‐β1. Fibrosis ultimately results in a state of low blood flow and hypoxia in the lung tissue, a microenvironment associated with upregulation of the sodium‐hydrogen exchanger isoform 1 (NHE1). NHE1 is a ubiquitously expressed protein that regulates intracellular pH. Upregulation of NHE1 supports increased cell proliferation and migration, indicating that it may play a role in the behavior of fibroblasts in pulmonary fibrosis. The proliferation, collagen deposition, and myofibroblast differentiation of two fibroblast cell lines will be characterized. CCL39, Chinese hamster lung fibroblasts, and WI‐38, normal human fibroblast cells, will both be studied. CCL39 cells treated with EIPA, a chemical inhibitor of NHE1, show reduced proliferative rates. This suggests that proliferation in these cells is NHE1‐dependent. In addition to proliferation, it is hypothesized that the collagen deposition and myofibroblast differentiation of this cell line will be NHE1‐dependent. Furthermore, it is hypothesized that WI‐38 cells will display similar NHE1‐dependent proliferation, collagen deposition and myofibroblast differentiation as the CCL39 cells. This suggests that CCL39 cells can serve as a predictor of human fibroblast cell behaviors.