Prolyl Hydroxylase Inhibition Mitigates Pouchitis

Harnoss, Jonathan M.; Gebhardt, Jasper; Radhakrishnan, P.; Leowardi, Christine; Burmeister, Julius; Halligan, Doug N.; Yuan, Shuai; Kennel, Kilian B; Strowitzki, Moritz J.; Schaible, Anja; Lasitschka, Felix; Taylor, Cormac T.; Schneider, Martin

doi:10.1093/ibd/izz218

Cited by 5 publications

(5 citation statements)

References 52 publications

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“…In defined experiments (“pretreatment”), WT mice were (pre-)treated with daily i.p. injections of vehicle (Aqua; MilliporeSigma) or DMOG, 100 μg/g BW ( 18 , 48 ) (PubChem CID: 560326; Biomol), for the whole duration of the experiment (day –3 to day 3). The generation of globally Phd1 -deficient ( Phd1 –/– ), Phd2 -haplodeficient ( Phd2 +/– ), and Phd3 -deficient ( Phd3 –/– ) mice has previously been described ( 25 , 39 ).…”

Section: Methodsmentioning

confidence: 99%

“…Female and male wildtype (WT) mice aged 10-15 weeks were randomly assigned to different treatment groups and operated by the same surgeon. In defined experiments ("Pretreatment"), WT mice were (pre-)treated with daily intraperitoneal injections of vehicle (Aqua; Sigma-Aldrich, Taufkirchen, Germany) or dimethyloxalylglycine (DMOG, 100μg/g BW (18,49); PubChem CID: 560326; Biomol, Hamburg, Germany) for the whole duration of the experiment (day -3 to day 3). The generation of globally Phd1-deficient (Phd1 -/-), Phd2-haplodeficient (Phd2 +/-), and Phd3-deficient (Phd3 -/-) mice has previously been described (25,39).…”

Section: Mouse Model Of Colonic Anastomosesmentioning

confidence: 99%

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Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

Strowitzki¹,

Kimmer²,

Wehrmann³

et al. 2021

JCI Insight

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Anastomotic leakage (AL) accounts for a major part of in-house mortality in patients undergoing colorectal surgery. Local ischemia and abdominal sepsis are common risk factors contributing to AL and are characterized by upregulation of the hypoxia-inducible factor (HIF) pathway. The HIF pathway is critically regulated by HIF-prolyl hydroxylases (PHDs). Here, we investigated the significance of PHDs and the effects of pharmacologic PHD inhibition (PHI) during anastomotic healing. Ischemic or septic colonic anastomoses were created in mice by ligation of mesenteric vessels or lipopolysaccharide-induced abdominal sepsis, respectively. Genetic PHD-deficiency (Phd1 -/-, Phd2 +/-, and Phd3 -/-) or PHI were applied to manipulate PHD activity. Pharmacologic PHI and genetic PHD2-haplodeficiency (Phd2 +/-) significantly improved healing of ischemic or septic colonic anastomoses, as indicated by increased bursting pressure and reduced AL rates. Only Phd2 +/-(but not PHI or Phd1 -/-) protected from sepsis-related mortality. Mechanistically, PHI and Phd2 +/induced immuno-modulatory (M2) polarization of macrophages, resulting in increased collagen content and attenuated inflammation-driven immune cell recruitment. We conclude that PHI improves healing of colonic anastomoses in ischemic or septic conditions by Phd2 +/--mediated M2 polarization of macrophages, conferring a favourable microenvironment for anastomotic healing. Patients with critically perfused colorectal anastomosis or abdominal sepsis could benefit from pharmacologic PHI.

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Section: Methodsmentioning

confidence: 99%

Section: Mouse Model Of Colonic Anastomosesmentioning

confidence: 99%

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

Strowitzki¹,

Kimmer²,

Wehrmann³

et al. 2021

JCI Insight

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“…Sixteen were at least partially relevant, mostly discussing probiotics and their effect on enhancing the mucosal "barrier." 7,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] Three were about tight junctions, 17,25,26 and 5 described various defects of mucosal permeability. [27][28][29][30][31] No article discussed the epithelial mucus coat as a barrier to bacterial invasion of the epithelium, although 1 article by Kroesen et al 29 examined the issue of bacterial "permeation" of pouch mucosa.…”

Section: Resultsmentioning

confidence: 99%

Normal Ileal Mucus Is Inadequate for Epithelial Protection in Ileal Pouch Mucosa

Knowles,

Church

2024

Diseases of the Colon &Amp; Rectum

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BACKGROUND: Clinical, nonspecific pouchitis is common after restorative proctocolectomy for ulcerative colitis, but its cause is unknown. A possible lack of protection for the ileal mucosa in its role as a reservoir for colonic-type bacteria may be the missing piece in defining the causes of pouchitis. OBJECTIVE: Review the causes of pouchitis and introduce the hypothesis that inadequate mucus protection in the pouch combined with a predisposition to abnormal inflammation is the most common cause of nonspecific pouchitis. DATA SOURCES: Review of PubMed and Medline for articles discussing pouchitis and intestinal mucus. STUDY SELECTION: Studies published from 1960 to 2023. The main search terms were “pouchitis,”,and “intestinal mucus,” while Boolean operators were used with multiple other terms to refine the search. Duplicates and case reports were excluded. MAIN OUTCOME MEASURES: Current theories about the etiology of pouchitis, descriptions of the role of mucus in the physiology of intestinal protection, and evidence of the effects of lack of mucus on mucosal inflammation. RESULTS: The cross-reference of “intestinal mucus” with “pouchitis” produced 9 references, none of which discussed the role of mucus in the development of pouchitis. Crossing “intestinal mucus” with “pouch” resulted in 32 papers, combining “pouchitis“ with “barrier function” yielded 37 papers and “pouchitis” with “permeability” only 8. No paper discussed the mucus coat as a barrier to bacterial invasion of the epithelium or mentioned inadequate mucus as a factor in pouchitis. However, an ileal pouch produces a colonic environment in the small bowel, and the ileum lacks the mucus protection needed for this sort of environment. This predisposes pouch mucosa to bacterial invasion and chronic microscopic inflammation that may promote clinical pouchitis in patients prone to an autoimmune response. LIMITATIONS: No prior studies address inadequate mucus protection and the origin of proctitis. There is no objective way of measuring the autoimmune tendency in patients with ulcerative colitis. CONCLUSIONS: Studies of intestinal mucus in the ileal pouch and its association with pouchitis are warranted.

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“…Conversely, PHDs are increasingly considered as promising targets for various indications in surgery because of their promising druggability.. 10,12,49 Very recently, first pan-PHD inhibitors have already entered clinical phase II trials for ulcerative colitis. 50 Additionally, several nonspecific PHD inhibitors such as vadadustat, roxadustat, and daprodustat have been approved for treating anemia in patients with chronic kidney diseases.…”

Section: Discussionmentioning

confidence: 99%

Prolyl Hydroxylase Inhibition Mitigates Allograft Injury During Liver Transplantation

et al. 2022

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Background. Ischemia and reperfusion injury (IRI) determines primary allograft function after liver transplantation (LT). Primary graft dysfunction (PGD) is associated with increased morbidity and impaired graft survival and can eventually progress to graft failure requiring retransplantation. Hypoxia-inducible transcription factor–prolyl hydroxylase containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors, which control the adaptive hypoxia response through the hypoxia-inducible factor (HIF). In this study, we have investigated pharmacological activation of the HIF pathway through inhibition of PHDs as a strategy to reduce PGD after LT. Methods. Primary rat hepatocytes were isolated and the impact of the pan-PHD small-molecule inhibitor ethyl-3,4-dihydroxybenzoate (EDHB) on HIF-1 and its downstream target gene expression assessed. Subsequently, various rodent models of segmental warm liver ischemia and reperfusion and orthotopic LT were applied to study the impact of EDHB on normothermic or combined cold and warm liver IRI. Liver enzyme levels and histology were analyzed to quantify hepatic IRI. Results. In vitro, EDHB induced HIF-1 signaling and significantly upregulated its downstream target heme-oxygenase 1 in primary rat hepatocytes. In vivo, after establishment of the optimal EDHB pretreatment conditions in a murine IRI model, EDHB pretreatment significantly mitigated hepatic IRI after warm segmental liver ischemia and reperfusion and allograft injury after orthotopic LT in rats. Mechanistically, EDHB stabilized HIF-1 in the liver and subsequently increased hepatoprotective heme-oxygenase 1 levels, which correlated with reduced hepatic IRI in these models. Conclusions. This proof-of-concept study establishes a strong therapeutic rationale for targeting PHDs with small-molecule inhibitors to mitigate PGD after LT.

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Prolyl Hydroxylase Inhibition Mitigates Pouchitis

Cited by 5 publications

References 52 publications

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses

Normal Ileal Mucus Is Inadequate for Epithelial Protection in Ileal Pouch Mucosa

Prolyl Hydroxylase Inhibition Mitigates Allograft Injury During Liver Transplantation

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