NHE1 as a Target to Block Lung Fibrosis Progression

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial pneumonia of unknown origin. Fibrosis, a wound healing process, occurs when fibroblasts increase proliferation, convert to myofibroblasts, and secrete extracellular matrix (ECM) proteins. As a result, tissue becomes scarred, reducing lung compliance and ultimately leads to organ dysfunction and death. IFP is characterized by profibrotic agonists and alpha‐smooth muscle actin (α‐SMA) expression. TGF‐β, IL‐1β, LPA, 5‐HT are agonists involved in cell migration regulation, proliferation, and cytokine production. Chronic agonists exposure causes α‐SMA expression which stiffens fibrotic tissue alongside ECM proteins. Prior studies have shown that the sodium hydrogen exchanger isoform 1 (NHE1) is a key regulator in cell migration and pathophysiological development of cancer. The characteristics of IFP are similar to that of cancer (i.e., response to growth signals, myofibroblast origin and behavior, altered cellular communications, and intercellular signaling pathways). Due to these similarities, we hypothesize that NHE1 plays a key role in IFP progression. Results show fibroblast to myofibroblast differentiation is induced in the presence of NHE1 and can also be blocked by the NHE1 inhibitor (EIPA) in mammalian hamster cells. Cells treated with agonists showed some to high α‐SMA expression. Cells treated with agonist and EIPA had no expression of α‐SMA (TGF‐β/EIPA: 35.67 ± 1.76; IL‐1β/EIPA: 11.67 ± 2.03, LPA/EIPA: 33.33 ± 2.19, 5HT/EIPA: 30.00 ± 1.15), and is comparable to the untreated control (20.83 ± 3.12). This improves our understanding of NHE1's role in IPF, and how NHE1 can be a target to impede or hopefully reverse myofibroblast differentiation in IPF patients.