{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T17:26:13Z","timestamp":1791134773967,"version":"4.1.0"},"reference-count":43,"publisher":"American Physiological Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2014,11,15]]},"abstract":"<jats:p> Hemeoxygenase-1 (HO-1), an inducible heat shock protein, is upregulated in response to multiple cellular insults via oxidative stress, lipopolysaccharides (LPS), and hypoxia. In this study, we investigated in vitro the role of Toll-like receptor 4 (TLR4), hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1), and iron on HO-1 expression in cystic fibrosis (CF). Immunohistochemical analysis of TLR4, HO-1, ferritin, and HIF-1\u03b1 were performed on lung sections of CFTR\u2212\/\u2212 and wild-type mice. CFBE41o- and 16HBE14o- cell lines were employed for in vitro analysis via immunoblotting, immunofluorescence, real-time PCR, luciferase reporter gene analysis, and iron quantification. We observed a reduced TLR4, HIF-1\u03b1, HO-1, and ferritin in CFBE41o- cell line and CF mice. Knockdown studies using TLR4-siRNA in 16HBE14o- revealed significant decrease of HO-1, confirming the role of TLR4 in HO-1 downregulation. Inhibition of HO-1 using tin protoporphyrin in 16HBE14o- cells resulted in increased iron levels, suggesting a probable role of HO-1 in iron accumulation. Additionally, sequestration of excess iron using iron chelators resulted in increased hypoxia response element response in CFBE41o- and 16HBE14o-, implicating a role of iron in HIF-1\u03b1 stabilization and HO-1. To conclude, our in vitro results demonstrate that multiple regulatory factors, such as impaired TLR4 surface expression, increased intracellular iron, and decreased HIF-1\u03b1, downregulate HO-1 expression in CFBE41o- cells. <\/jats:p>","DOI":"10.1152\/ajplung.00167.2014","type":"journal-article","created":{"date-parts":[[2014,9,20]],"date-time":"2014-09-20T04:47:49Z","timestamp":1411188469000},"page":"L791-L799","source":"Crossref","is-referenced-by-count":39,"title":["Impaired TLR4 and HIF expression in cystic fibrosis bronchial epithelial cells downregulates hemeoxygenase-1 and alters iron homeostasis in vitro"],"prefix":"10.1152","volume":"307","author":[{"given":"Shashi","family":"Chillappagari","sequence":"first","affiliation":[{"name":"Department of Medicine, Pulmonary Critical Care Philipps University, Marburg, Germany;"},{"name":"Institute for Lung Research, Philipps-University, Marburg, Germany;"},{"name":"Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, 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