Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition

Abstract

A number of recent studies have implicated tissue hypoxia in both acute and chronic inflammatory diseases, particularly as they relate to mucosal surfaces involving epithelial cells. In this context, a protective role for the transcriptional regulator hypoxia-inducible factor (HIF) was demonstrated through conditional deletion of epithelial HIF-1α in a murine model of colitis (J. Clin. Invest. 2004; 114:1098−1106. Here, we hypothesized that pharmacologic activation of HIF would similarly provide a protective adaptation to murine colitic disease. For these purposes, we used a novel prolyl hydroxylase (PHD) inhibitor (FG-4497) which readily stabilizes HIF-1α and subsequently drives the expression downstream HIF target genes (e.g. erythropoietin). Our results show that the FG-4497-mediated induction of HIF-1α provides an overall beneficial influence on clinical symptoms (weight loss, colon length, tissue TNFα) in murine TNBS colitis, most likely due to their barrier protective function and wound healing during severe tissue hypoxia at the site of inflammation. Taken together these findings emphasize the role of epithelial HIF-1α during inflammatory diseases in the colon and may provide the basis for a therapeutic use of PHD inhibitors in inflammatory mucosal disease.

Hypoxia and gastrointestinal disease

“…PHD3 mRNA is also expressed in many tissues but is most abundant in the heart and placenta [24,28]. In mouse intestinal mucosal tissue, we have found expression all three isoforms of PHDs with a distribution of PHD1< PHD2=PHD3 [22][23].…”

“…It is interesting to note that NF-κB activates transcriptional upregulation of HIF-1a mRNA indicating one level at which these two pathways interact to regulate hypoxia-dependent gene transcription Our results show that the PHD inhibition provides an overall beneficial influence on clinical symptoms (weight loss, colon length, tissue tumor necrosis factor-α/interferon-γ) in multiple murine models of colitis. These effects are most likely due to their barrier-protective function and enhancement of wound healing at the site of inflammation [22][23]. Taken together, these findings emphasize the role of epithelial HIF-1α during inflammatory diseases in the colon and may provide the basis for a therapeutic use of PHD inhibitors in inflammatory mucosal disease.…”

“…Further evidence in support of a protective role for HIF in mucosal disease are provided by studies directed at HIF prolyl hydroxylase (PHD) inhibitors [22,23]. These enzymes were identified on the principle that other mammalian PHDs such as those which target extracellular collagen were 2-oxoglutarate dependent [24], and it was predicted that the HIF PHDs would also belong to this family of enzymes.…”

“…These observations have generated interest in identifying enzyme-modifying therapeutics. Indeed, a number of PHD inhibitors have been described, including direct inhibitors of the PHDs [31][32], analogs of naturally occurring cyclic hydroxamates [23], as well as antagonists of α-ketoglutarate [29]. As such, we hypothesized that pharmacologic activation of HIF would provide a protective adaptation to murine colitic disease.…”

Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function

“…While the underlying causes of IBD remain largely undefined, the fundamental defect involves a loss of intestinal epithelial barrier function. We and others have shown that pan-hydroxylase inhibitors such as dimethyl-oxalylglycine (DMOG) have a protective effect in murine models of colitis and thus represent a potential new therapeutic approach (13)(14). However, these studies did not identify which hydroxylase isoforms or effector pathways are involved.…”