MTF1 plays a key role in protection against vanadium-induced stress in alveolar epithelial cells

Introduction: Airborne particulate matter (PM) is a leading cause of respiratory morbidities including chronic lung disease. We previously found ultrafine PM (UFPM) associated with cruise ship emissions is enriched in vanadium (V), an element known to induce oxidative stress. However, understanding of wider cellular responses to V, including metal homeostasis, is poor. Aims: We investigated alveolar responses to V, and the role played by metal regulatory transcription factor 1 (MTF1). Methods: A human alveolar type 2 cell line was exposed to 6.25-100 µM V₂O₅ for 24h. Metal-binding and antioxidant gene expression was measured alongside inflammatory mediator release. Effect of antioxidants was studied using N-acetylcysteine and ascorbate (Asc). Role of MTF1 was studied by siRNA knockdown followed by RNA-seq. Results: V elicited significant upregulation of antioxidant genes (HMOX1, GCLM) and inflammatory cytokine release (IL-6, IL-8). This was diminished by Asc, implicating oxidative stress. A similar response was seen for metal-binding metallothioneins (MTs). In the presence of V, MTF1 knockdown inhibited MTs, but augmented oxidative stress suggesting MTF1-regulated genes protect against V-induced oxidative injury. MTF1 knockdown also resulted in V-induced upregulation of several heat shock-related genes and phosphorylation of heat shock transcription factor (HSF1), implicating MTF1 in controlling proteostasis in response to V. Conclusion: MTF1 is protective against V-induced stress. Given that impaired metal homeostasis and dysfunction of MTF1 target genes have been associated with fibrosis, this finding suggests V-containing UFPM may be important in predisposition to chronic lung diseases.