Epithelial-mesenchymal transition: Insights into nickel-induced lung diseases

Abstract

Nickel compounds are environmental toxicants, prevalent in the atmosphere due to their widespread use in several industrial processes, extensive consumption of nickel containing products, as well as burning of fossil fuels. Exposure to nickel is associated with a multitude of chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. In addition, nickel exposure is implicated in the development of nasal and lung cancers. Interestingly, a common pathogenic mechanism underlying the development of diseases associated with nickel exposure is epithelial-mesenchymal transition (EMT). EMT is a process by which the epithelial cells lose their junctions and polarity and acquire mesenchymal traits, including increased ability to migrate and invade. EMT is a normal and essential physiological process involved in differentiation, development and wound healing. However, EMT also contributes to a number of pathological conditions, including fibrosis, cancer and metastasis. Growing evidence suggest that EMT induction could be an important outcome of nickel exposure. In this review, we discuss the role of EMT in nickel-induced lung diseases and the mechanisms associated with EMT induction by nickel exposure.

Keywords: Epigenetics; Epithelial-mesenchymal transition; HIF-1; Nickel; TGF-β.

Figure 1.. TGF-β signaling in nickel-induced EMT.

During TGF-β signaling, the active TGF-β binds the TGF-β receptors TGF-βR1 and TGF-βRII. The activation of the TGF-β receptor complex results in phosphorylation of the SMAD proteins, which then translocate to the nucleus and regulate target gene expression. Nickel exposure could activate TGF-β signaling via multiple mechanisms, including TLR4 signaling, TSP-1 upregulation and inhibition of H2S production. Nickel exposure induces TLR4 signaling. which has been shown to enhance TGF-β signaling. The extracellular matrix protein, TSP-1, an important activator of latent TGF-β, is one of the highest upregulated genes in the lungs of mice exposed to nickel, suggesting its role in nickel-induced TGF-β signaling. H₂S is an important negative regulator of TGF-β signaling. Nickel exposure promoted TGF-β signaling by downregulating the enzymes involved in H₂S production, CBS, CSE and 3MST, thereby increasing protein levels of TGF-β1 and phosphorylated SMAD2 and SMAD3.

Figure 2.. Activation of HIF-1 signaling in nickel-exposed cells contributes to EMT.

Under physiological conditions, HIF-1α is rapidly degraded via hydroxylation of its oxygen-dependent degradation domain by prolyl-hydroxylases (PHDs). Upon nickel exposure, Ni(II) replaces Fe(II) at the iron-binding site of PHDs causing their inactivation. This leads to the stabilization of HIF-1α, which translocates to the nucleus, dimerizes with HIF-1β and binds the HREs at the promoters of target genes, resulting in their activation. HIF-1 could directly activate EMT master regulators, SNAIL, ZEB and TWIST, by directly binding their promoters. HIF-1 could also upregulate lysyl oxidase genes Lox and LoxL2, which interact with SNAIL and cause E-cadherin repression.