Vimentin is sufficient and required for wound repair and remodeling in alveolar epithelial cells

Abstract

The physiological and pathophysiological implications of the expression of vimentin, a type III intermediate filament protein, in alveolar epithelial cells (AECs) are unknown. We provide data demonstrating that vimentin is regulated by TGFβ1, a major cytokine released in response to acute lung injury and that vimentin is required for wound repair and remodeling of the alveolar epithelium. Quantitative real-time PCR shows a 16-fold induction of vimentin mRNA in TGFβ1-treated transformed AECs. Luciferase assays identify a Smad-binding element in the 5' promoter of vimentin responsible for TGFβ1-induced transcription. Notably, TGFβ1 induces vimentin protein expression in AECs, which is associated with a 2.5-fold increase in cell motility, resulting in increased rates of migration and wound closure. These effects are independent of cell proliferation. TGFβ1-mediated vimentin protein expression, cell migration, and wound closure are prevented by a pharmacological inhibitor of the Smad pathway and by expression of Ad-shRNA against vimentin. Conversely, overexpression of mEmerald-vimentin is sufficient for increased cell-migration and wound-closure rates. These results demonstrate that vimentin is required and sufficient for increased wound repair in an in vitro model of lung injury.

The Role of Vimentin Intermediate Filaments in the Progression of Lung Cancer

“…The vimentin promoter is composed of many elements, including a TATA box, eight putative GC boxes (35), Activator protein 1 (AP-1) binding sites (36), the NF-kB-binding site (37), and a Smad binding element (38,39). Hypoxia-inducible factor-1 (HIF-1) is a major regulator of the cellular response to hypoxia, which has been shown to regulate vimentin gene expression (40).…”

“…Therefore, vimentin transcriptional regulation by HIF-1 may be a potential driver of EMT. In addition, the Smad binding element was found within the activated protein complex-1 region of the vimentin promoter, and was shown to be involved in the regulation of vimentin expression in alveolar epithelial cells and to induce phenotypic change toward EMT (2,21,38).…”

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

“…In many cases, these studies are still at the in vitro stages, such as the use of vimentin to improve wound repair [30], or just suggest a possible benefi cial role (e.g., connexins [31], adrenomedullin [32] or a possible modulation of the transcription factors, FoxM1 and Runx3 [33,34]) and need further research to prove their viability in vivo. Improvement of plasma membrane repair is a possible direct treatment.…”

Immunomodulatory and Antibacterial Effects of Cystatin 9 against Francisella tularensis

“…There was also an upregulation of proteins in rCST9-treated MDM that have been shown to temper inflammation that is, glutaredoxin-1, whose expression is key in the activation of alveolar macrophages by regulating the production of inflammatory mediators through control of S-glutathionylation-sensitive signaling pathways such as NF-κB (33). Further, we observed a moderate upregulation of vimentin in rCST9-treated MDM, which can suppress the production of reactive oxygen intermediates (ROIs) (34) but is also involved in wound healing and remodeling during pulmonary injury (35). Alternatively, S100-A10 and cathepsin B proteins were downregulated in rCST9-treated MDM ( Table 2).…”

“…Interestingly, there was a moderate but notable upregulation of vimentin in rCST9-treated MDM. Vimentin is another multifaceted protein that, among its various functions, has been shown to suppress the production of ROIs, thus attenuating their organ-damaging effects as seen during sepsis and septic shock (34,35). Conversely, rCST9 downregulated S100-A10, a protein also known as an alarmin.…”