Targeting HIF in IBD

Question 1

In physiological conditions

Answer 1

The intestinal epithelium forms a protective barrier
separates the anoxic, microorganism rich lumen
from perfused, sterile lamina propria
(Manresa and Taylor, 2017)

Question 2

Functions of intestinal epithelium
Absorption
Prevent infiltration of microbes

Answer 2

Permits trafficking of nutrients from lumen to blood
Prevents infiltration of harmful microorganisms and toxins
Mucins and defensins form mucosal barrier of GIT protect from microbes
Tight regulation of apoptosis and proliferation
Intestinal epithelium (3-5 days, 10 billion cells)
Intracellular tight junctions

Question 3

IBD

Answer 3

Chronic inflammation of the bowel
Crohn’s and ulcerative colitus
Environmental with genetic predisposition
Continous cycle of inflammation
Leaky intestinal barrier
Microorganisms into sterile lamina propria
Warrant an inflammatory response
Cytokine and chemokine release
Vicious cycle
Pain and discomfort for patient
Antiinflammatory not effective
Anti-TNFa - immune compromised and infection prone
(Billiet et al. 2019)

Question 4

Hypoxia in IBD

Answer 4

The inflamed human colonic mucosa is hypoxic
Continual immune activation
Sustained inflammation
Oxygen consumption high
Decreased oxygen saturation (colonoscopy probe)
Increased carbonic anhydrase 9 (CA9) protein expression
(Brown et al. 2020)

Question 5

HIF

Answer 5

Hypoxia inducible factor (HIF)
3 isoforms
Degraded in normoxia
Stabilised in hypoxia
Prolyl hydroxylases

Question 6

PHI

Answer 6

Inhibit prolyl hydroxylase activity
Activate HIF and transcription of target genes

Question 7

Cummins et al. 2008

Answer 7

Dimethyloxyglycine (DMOG)
Protective in DSS model of colitis
Reduced inflammation in mouse colon
Reduced apoptosis of epithelium
Maintain epithelial integrity

Question 8

Other ways HIF contributes to epithelial function

Answer 8

Mucins and defensins
Tight junctions (claudins and occludins)
Inhibit cell death

Question 9

Immune regulation of HIF

Answer 9

Regulation of immune cells
Immune cells sensitive to hypoxia
Inducing HIF may have an effect on immune cell function

Question 10

HIF and immune cells

Answer 10

Dendritic cells (HIF1) - survival, differentiation
Neutrophils (HIF1/2) - apoptosis
NK cell (HIF2) - cytotoxicity
T-cell (HIF1) - survival, proliferation

Question 11

DMOG and cyclosporine

Answer 11

PHD in combination with an immunosuppressant
Gives the benefits of HIF
Immunosuppressant to reduce HIF regulation of immune cells
Effective in DSS model

Question 12

DMOG localised

Answer 12

Microspheres
Targeted delivery
Because systemic HIF activation can have negative effects
Unwanted angiogenesis
Polycythemia
Increased EPO
This way is targeted to reduce systemic exposure
Still having beneficial effect in DSS
Disease activity index reduced