Combinatorial Treatment with a Hif-Hydroxylase Inhibitor and Cyclosporine Provides Enhanced Protection in Colitis Through Improved Barrier Function

Doug Halligan, Mohammed Khan, Ivan S Coulter, Eric Brown, Ivan S Coulter, Glen Doherty, Murtaza M Tambuwala, Cormac T. Taylor

Research output: Contribution to conferenceAbstract

Abstract

Background: Hypoxia is a prominent microenvironmental feature during active mucosal inflammation in ulcerative colitis patients (UC). HIF hydroxylases are key oxygen-sensing enzymes which link microenvironmental hypoxia to the control of inflammatory pathways. The pharmacologic HIF-hydroxylase inhibitor DMOG, which activates the HIF pathway, is protective in experimental colitis through the upregulation of genes promoting epithelial barrier function and preventing apoptosis. Cyclosporine, on the other hand, is protective through suppression of immune cell activation. Given the distinct barrier protective and anti-inflammatory roles of DMOG and cyclosporine respectively, we hypothesised that combining these drugs may provide an additive benefit in UC. Methods: The DSS model of colitis was used to determine the combinatorial efficacy of DMOG and cyclosporine. Caco2 cells were used to examine the effect of DMOG on transepithelial electrical resistance (TEER) and caspase activity. ZO-1 expression was analysed in cells as well as mouse and human colon tissue by immunofluorescence. Results: While both DMOG and cyclosporine ameliorated colitic disease progression in DSS treated mice, combinatorial treatment with both drugs simultaneously provided an additive benefit that surpassed the level of protection afforded by either drug alone as assessed by using multiple clinical and molecular markers of disease progression. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was predominantly due to preservation of barrier function and at least in part due to ZO-1 regulation specifically. Conclusions: Given their distinct mechanisms of action, we propose that combinatorial treatment with hydroxylase inhibitors and anti-inflammatory agents provide a new treatment strategy in UC. Figure: Combinatorial cyclosporine A (CyA) and DMOG provides additive protection in DSS colitis as demonstrated by disease activity index (Left) and colon shortening

Conference

Conference Digestive Disease Week
Abbreviated titleDDW
CountryUnited States
CityChicago
Period3/12/187/12/18
Internet address

Fingerprint

Colitis
Mixed Function Oxygenases
Cyclosporine
Ulcerative Colitis
Anti-Inflammatory Agents
Disease Progression
Colon
Therapeutics
Pharmaceutical Preparations
Caspases
Electric Impedance
Fluorescent Antibody Technique
Up-Regulation
Biomarkers
Apoptosis
Oxygen
Inflammation
Enzymes
Genes

Cite this

Halligan, D., Khan, M., Coulter, I. S., Brown, E., Coulter, I. S., Doherty, G., ... Taylor, C. T. (2019). Combinatorial Treatment with a Hif-Hydroxylase Inhibitor and Cyclosporine Provides Enhanced Protection in Colitis Through Improved Barrier Function. Abstract from Digestive Disease Week, Chicago, United States. https://doi.org/10.1016/s0016-5085(19)38447-1
Halligan, Doug ; Khan, Mohammed ; Coulter, Ivan S ; Brown, Eric ; Coulter, Ivan S ; Doherty, Glen ; Tambuwala, Murtaza M ; Taylor, Cormac T. / Combinatorial Treatment with a Hif-Hydroxylase Inhibitor and Cyclosporine Provides Enhanced Protection in Colitis Through Improved Barrier Function. Abstract from Digestive Disease Week, Chicago, United States.
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title = "Combinatorial Treatment with a Hif-Hydroxylase Inhibitor and Cyclosporine Provides Enhanced Protection in Colitis Through Improved Barrier Function",
abstract = "Background: Hypoxia is a prominent microenvironmental feature during active mucosal inflammation in ulcerative colitis patients (UC). HIF hydroxylases are key oxygen-sensing enzymes which link microenvironmental hypoxia to the control of inflammatory pathways. The pharmacologic HIF-hydroxylase inhibitor DMOG, which activates the HIF pathway, is protective in experimental colitis through the upregulation of genes promoting epithelial barrier function and preventing apoptosis. Cyclosporine, on the other hand, is protective through suppression of immune cell activation. Given the distinct barrier protective and anti-inflammatory roles of DMOG and cyclosporine respectively, we hypothesised that combining these drugs may provide an additive benefit in UC. Methods: The DSS model of colitis was used to determine the combinatorial efficacy of DMOG and cyclosporine. Caco2 cells were used to examine the effect of DMOG on transepithelial electrical resistance (TEER) and caspase activity. ZO-1 expression was analysed in cells as well as mouse and human colon tissue by immunofluorescence. Results: While both DMOG and cyclosporine ameliorated colitic disease progression in DSS treated mice, combinatorial treatment with both drugs simultaneously provided an additive benefit that surpassed the level of protection afforded by either drug alone as assessed by using multiple clinical and molecular markers of disease progression. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was predominantly due to preservation of barrier function and at least in part due to ZO-1 regulation specifically. Conclusions: Given their distinct mechanisms of action, we propose that combinatorial treatment with hydroxylase inhibitors and anti-inflammatory agents provide a new treatment strategy in UC. Figure: Combinatorial cyclosporine A (CyA) and DMOG provides additive protection in DSS colitis as demonstrated by disease activity index (Left) and colon shortening",
author = "Doug Halligan and Mohammed Khan and Coulter, {Ivan S} and Eric Brown and Coulter, {Ivan S} and Glen Doherty and Tambuwala, {Murtaza M} and Taylor, {Cormac T.}",
year = "2019",
month = "5",
doi = "10.1016/s0016-5085(19)38447-1",
language = "English",
note = "Digestive Disease Week, DDW ; Conference date: 03-12-2018 Through 07-12-2018",
url = "https://ddw.org/presenters/submit-an-abstract",

}

Halligan, D, Khan, M, Coulter, IS, Brown, E, Coulter, IS, Doherty, G, Tambuwala, MM & Taylor, CT 2019, 'Combinatorial Treatment with a Hif-Hydroxylase Inhibitor and Cyclosporine Provides Enhanced Protection in Colitis Through Improved Barrier Function' Digestive Disease Week, Chicago, United States, 3/12/18 - 7/12/18, . https://doi.org/10.1016/s0016-5085(19)38447-1

Combinatorial Treatment with a Hif-Hydroxylase Inhibitor and Cyclosporine Provides Enhanced Protection in Colitis Through Improved Barrier Function. / Halligan, Doug; Khan, Mohammed; Coulter, Ivan S; Brown, Eric; Coulter, Ivan S; Doherty, Glen; Tambuwala, Murtaza M; Taylor, Cormac T.

2019. Abstract from Digestive Disease Week, Chicago, United States.

Research output: Contribution to conferenceAbstract

TY - CONF

T1 - Combinatorial Treatment with a Hif-Hydroxylase Inhibitor and Cyclosporine Provides Enhanced Protection in Colitis Through Improved Barrier Function

AU - Halligan, Doug

AU - Khan, Mohammed

AU - Coulter, Ivan S

AU - Brown, Eric

AU - Coulter, Ivan S

AU - Doherty, Glen

AU - Tambuwala, Murtaza M

AU - Taylor, Cormac T.

PY - 2019/5

Y1 - 2019/5

N2 - Background: Hypoxia is a prominent microenvironmental feature during active mucosal inflammation in ulcerative colitis patients (UC). HIF hydroxylases are key oxygen-sensing enzymes which link microenvironmental hypoxia to the control of inflammatory pathways. The pharmacologic HIF-hydroxylase inhibitor DMOG, which activates the HIF pathway, is protective in experimental colitis through the upregulation of genes promoting epithelial barrier function and preventing apoptosis. Cyclosporine, on the other hand, is protective through suppression of immune cell activation. Given the distinct barrier protective and anti-inflammatory roles of DMOG and cyclosporine respectively, we hypothesised that combining these drugs may provide an additive benefit in UC. Methods: The DSS model of colitis was used to determine the combinatorial efficacy of DMOG and cyclosporine. Caco2 cells were used to examine the effect of DMOG on transepithelial electrical resistance (TEER) and caspase activity. ZO-1 expression was analysed in cells as well as mouse and human colon tissue by immunofluorescence. Results: While both DMOG and cyclosporine ameliorated colitic disease progression in DSS treated mice, combinatorial treatment with both drugs simultaneously provided an additive benefit that surpassed the level of protection afforded by either drug alone as assessed by using multiple clinical and molecular markers of disease progression. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was predominantly due to preservation of barrier function and at least in part due to ZO-1 regulation specifically. Conclusions: Given their distinct mechanisms of action, we propose that combinatorial treatment with hydroxylase inhibitors and anti-inflammatory agents provide a new treatment strategy in UC. Figure: Combinatorial cyclosporine A (CyA) and DMOG provides additive protection in DSS colitis as demonstrated by disease activity index (Left) and colon shortening

AB - Background: Hypoxia is a prominent microenvironmental feature during active mucosal inflammation in ulcerative colitis patients (UC). HIF hydroxylases are key oxygen-sensing enzymes which link microenvironmental hypoxia to the control of inflammatory pathways. The pharmacologic HIF-hydroxylase inhibitor DMOG, which activates the HIF pathway, is protective in experimental colitis through the upregulation of genes promoting epithelial barrier function and preventing apoptosis. Cyclosporine, on the other hand, is protective through suppression of immune cell activation. Given the distinct barrier protective and anti-inflammatory roles of DMOG and cyclosporine respectively, we hypothesised that combining these drugs may provide an additive benefit in UC. Methods: The DSS model of colitis was used to determine the combinatorial efficacy of DMOG and cyclosporine. Caco2 cells were used to examine the effect of DMOG on transepithelial electrical resistance (TEER) and caspase activity. ZO-1 expression was analysed in cells as well as mouse and human colon tissue by immunofluorescence. Results: While both DMOG and cyclosporine ameliorated colitic disease progression in DSS treated mice, combinatorial treatment with both drugs simultaneously provided an additive benefit that surpassed the level of protection afforded by either drug alone as assessed by using multiple clinical and molecular markers of disease progression. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was predominantly due to preservation of barrier function and at least in part due to ZO-1 regulation specifically. Conclusions: Given their distinct mechanisms of action, we propose that combinatorial treatment with hydroxylase inhibitors and anti-inflammatory agents provide a new treatment strategy in UC. Figure: Combinatorial cyclosporine A (CyA) and DMOG provides additive protection in DSS colitis as demonstrated by disease activity index (Left) and colon shortening

U2 - 10.1016/s0016-5085(19)38447-1

DO - 10.1016/s0016-5085(19)38447-1

M3 - Abstract

ER -