Klinische Rolle der lokalen Gewebehypoxie bei entzündlichen Darmerkrankungen
Gastroenterologie
Zusammenfassung der Projektergebnisse
Despite mounting preclinical evidence showing that pharmacologic and genetic up-regulation of the evolutionary conserved gene program, the hypoxia-inducible factor (HIF) pathway, mitigate colitis there is currently a lack of clinical data on how oxygen deprivation (known as hypoxia) affects disease progression in patients with ulcerative colitis (UC). Moreover, many patients with UC need to undergo surgery due to severe complications of inflammation or due to colitis-associated cancer. Thus the present project analyzed the clinical significance of hypoxia and hypoxia-adaptive pathways in UC patients. Additionally, the role of HIF prolyl hydroxylases (PHDs) and pharmacologic PHD inhibition (PHI) was determined in a novel preclinical mouse model of “high-risk” intestinal anastomoses, mimicking the clinical situation of UC patients with septic-like conditions undergoing colorectal surgery. Our clinical data show that local hypoxia (analyzed by endoscopic oxygen saturation measurements) and HIF-signaling correlate with disease progression and inflammation in UC patients. Part of the inflammatory response includes a transcriptional reprogramming of the HIF pathway to promote a protective HIF-1𝛼 response which promotes tissue healing and is due, in part, to downregulation of the inflammation sensitive PHD1 regulator, C/EBP𝛼. Furthermore, PHI by dimethyloxalylglycine (DMOG) and partial loss of PHD2 (Phd2+/- ) enhance collagen deposition within intestinal anastomoses and thereby improve healing of ischemic or septic (“high-risk”) anastomoses in a preclinical mouse model. In this context, both DMOG and Phd2+/- reduced the infiltration of pro-inflammatory cells and induced M2- polarization of macrophages in vivo and in vitro, conferring a favorable micro-environment during healing of intestinal anastomoses. The effects of DMOG and Phd2+/ on M2-polarization of macrophages were even more pronounced under hypoxia. DMOG reduced interleukin 6 and matrix metalloproteinase (MMP) 9 protein expression, which both play an important role during collagen degradation, within ischemic intestinal anastomoses. In summary, the pharmacologic and genetic inhibition of PHDs reduce murine colitis. Patient data from the presented project further substantiate the clinical significance of PHD1 during disease progression of UC. Moreover, PHI could improve healing of intestinal anastomoses in these “high-risk” patients. Currently ongoing follow-up projects investigate whether the effects of PHI and Phd2+/ on M2-polarization of macrophages are HIF-1 or HIF-2 dependent. Furthermore, we will screen and compare several novel pharmacologic PHD inhibitors and determine the clinical significance of PHI during healing of gastro-intestinal anastomoses. PHI could ultimately mitigate disease progression of UC patients and improve healing of gastro-intestinal anastomoses in high-risk patients.
Projektbezogene Publikationen (Auswahl)
- Loss of prolyl-hydroxylase 1 protects against biliary fibrosis via attenuated activation of hepatic stellate cells. Am. J. Pathol. 188, 2826-2838 (2018)
Strowitzki MJ, Kirchberg J, Tuffs C, Schiedeck M, et al.
(Siehe online unter https://doi.org/10.1016/j.ajpath.2018.08.003) - High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases. Br. J. Cancer. 120, 675-688 (2019)
Strowitzki MJ, Radhakrishnan P, Pavicevic S, Scheer J, et al.
(Siehe online unter https://doi.org/10.1038/s41416-019-0406-9) - Hypoxia-adaptive pathways: A pharmacological target in fibrotic disease? Pharmacol. Res. 147, 104364 (2019)
Strowitzki MJ, Ritter AS, Kimmer G, Schneider M
(Siehe online unter https://doi.org/10.1016/j.phrs.2019.104364) - Pharmacologic inhibition of hypoxia inducible factor (HIF)-hydroxylases ameliorates allergic contact dermatitis. Allergy.74, 753-766 (2019)
Manresa MC, Smith L, Casals-Diaz L, Fagundes RR, Brown E, Radhakrishnan P, Murphy SJ, Crifo B, Strowitzki MJ, Halligan DN, van den Bogaard EH, Niehues N, Schneider M, Taylor CT, Steinhoff M
(Siehe online unter https://doi.org/10.1111/all.13655) - Protein hydroxylation by hypoxia-inducible factor (HIF) hydroxylases: Unique or ubiquitous? Cells. 8, 384 (2019)
Strowitzki MJ, Cummins EP, Taylor CT
(Siehe online unter https://doi.org/10.3390/cells8050384) - Mechanisms and consequences of oxygen- and carbon dioxide-sensing in mammalian systems. Phy. Reviews. 100, 463-488 (2020)
Cummins EP, Strowitzki MJ, Taylor CT
(Siehe online unter https://doi.org/10.1152/physrev.00003.2019) - microRNA-155 is decreased during atherosclerosis regression and is increased in urinary extracellular vesicles during atherosclerosis progression. Front Immunol. 11, 576516 (2020)
Fitzsimons S, Oggero S, Bruen R, McCarthy C, Strowitzki MJ, Mahon NG, et al.
(Siehe online unter https://doi.org/10.3389/fimmu.2020.576516) - Mucosal inflammation downregulates PHD1 expression promoting a barrier-protective HIF-1α response in ulcerative colitis patients. FASEB journal. 34, 3732-3742 (2020)
Brown E, Rowan C, Strowitzki MJ, Fagundes R, et al.
(Siehe online unter https://doi.org/10.1096/fj.201902103r) - Prolyl hydroxylase inhibition mitigates pouchitis. Inflamm. Bowel Dis. 26, 192-205 (2020)
Harnoss JM, Gebhardt JM, Radhakrishnan P, Leowardi C, Burmeister J, Halligan DN, Yuan S, Kennel KB, Strowitzki MJ, Schaible A, Lasitschka F, Taylor CT, Schneider M
(Siehe online unter https://doi.org/10.1093/ibd/izz218) - Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses. JCI Insight. 6, e139191 (2021)
Strowitzki MJ, Kimmer G, Wehrmann J, Ritter AS, et al.
(Siehe online unter https://doi.org/10.1172/jci.insight.139191)
