Hypoxia Inducible Factor (HIF) Hydroxylases as Regulators of Intestinal Epithelial Barrier Function.
Cell Mol Gastroenterol Hepatol
; 3(3): 303-315, 2017 May.
Article
em En
| MEDLINE
| ID: mdl-28462372
ABSTRACT
Human health is dependent on the ability of the body to extract nutrients, fluids, and oxygen from the external environment while at the same time maintaining a state of internal sterility. Therefore, the cell layers that cover the surface areas of the body such as the lung, skin, and gastrointestinal mucosa provide vital semipermeable barriers that allow the transport of essential nutrients, fluid, and waste products, while at the same time keeping the internal compartments free of microbial organisms. These epithelial surfaces are highly specialized and differ in their anatomic structure depending on their location to provide appropriate and effective site-specific barrier function. Given this important role, it is not surprising that significant disease often is associated with alterations in epithelial barrier function. Examples of such diseases include inflammatory bowel disease, chronic obstructive pulmonary disease, and atopic dermatitis. These chronic inflammatory disorders often are characterized by diminished tissue oxygen levels (hypoxia). Hypoxia triggers an adaptive transcriptional response governed by hypoxia-inducible factors (HIFs), which are repressed by a family of oxygen-sensing HIF hydroxylases. Here, we review recent evidence suggesting that pharmacologic hydroxylase inhibition may be of therapeutic benefit in inflammatory bowel disease through the promotion of intestinal epithelial barrier function through both HIF-dependent and HIF-independent mechanisms.
CD, Crohn's disease; DMOG, dimethyloxalylglycine; DSS, dextran sodium sulfate; Epithelial Barrier; FIH, factor inhibiting hypoxia-inducible factor; HIF, hypoxia-inducible factor; Hypoxia; Hypoxia-Inducible Factor (HIF) Hydroxylases; IBD, inflammatory bowel disease; IL, interleukin; Inflammatory Bowel Disease; NF-κB, nuclear factor-κB; PHD, hypoxia-inducible factorprolyl hydroxylases; TFF, trefoil factor; TJ, tight junction; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α; UC, ulcerative colitis; ZO, zonula occludens
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MEDLINE
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En
Ano de publicação:
2017
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Article