PMID- 37342339 OWN - NLM STAT- MEDLINE DCOM- 20230623 LR - 20231227 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Free heme exacerbates colonic injury induced by anti-cancer therapy. PG - 1184105 LID - 10.3389/fimmu.2023.1184105 [doi] LID - 1184105 AB - Gastrointestinal inflammation and bleeding are commonly induced by cancer radiotherapy and chemotherapy but mechanisms are unclear. We demonstrated an increased number of infiltrating heme oxygenase-1 positive (HO-1+) macrophages (Mo, CD68+) and the levels of hemopexin (Hx) in human colonic biopsies from patients treated with radiation or chemoradiation versus non-irradiated controls or in the ischemic intestine compared to matched normal tissues. The presence of rectal bleeding in these patients was also correlated with higher HO-1+ cell infiltration. To functionally assess the role of free heme released in the gut, we employed myeloid-specific HO-1 knockout (LysM-Cre : Hmox1(flfl)), hemopexin knockout (Hx(-/-)) and control mice. Using LysM-Cre : Hmox1(flfl) conditional knockout (KO) mice, we showed that a deficiency of HO-1 in myeloid cells led to high levels of DNA damage and proliferation in colonic epithelial cells in response to phenylhydrazine (PHZ)-induced hemolysis. We found higher levels of free heme in plasma, epithelial DNA damage, inflammation, and low epithelial cell proliferation in Hx(-/-) mice after PHZ treatment compared to wild-type mice. Colonic damage was partially attenuated by recombinant Hx administration. Deficiency in Hx or Hmox1 did not alter the response to doxorubicin. Interestingly, the lack of Hx augmented abdominal radiation-mediated hemolysis and DNA damage in the colon. Mechanistically, we found an altered growth of human colonic epithelial cells (HCoEpiC) treated with heme, corresponding to an increase in Hmox1 mRNA levels and heme:G-quadruplex complexes-regulated genes such as c-MYC, CCNF, and HDAC6. Heme-treated HCoEpiC cells exhibited growth advantage in the absence or presence of doxorubicin, in contrast to poor survival of heme-stimulated RAW247.6 Mo. In summary, our data indicate that accumulation of heme in the colon following hemolysis and/or exposure to genotoxic stress amplifies DNA damage, abnormal proliferation of epithelial cells, and inflammation as a potential etiology for gastrointestinal syndrome (GIS). CI - Copyright (c) 2023 Seika, Janikova, Asokan, Janovicova, Csizmadia, O'Connell, Robson, Glickman and Wegiel. FAU - Seika, Philippa AU - Seika P AD - Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. FAU - Janikova, Monika AU - Janikova M AD - Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. AD - Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia. FAU - Asokan, Sahana AU - Asokan S AD - Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. AD - Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. AD - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. FAU - Janovicova, Lubica AU - Janovicova L AD - Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. AD - Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia. FAU - Csizmadia, Eva AU - Csizmadia E AD - Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. FAU - O'Connell, Mckenzie AU - O'Connell M AD - Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. FAU - Robson, Simon C AU - Robson SC AD - Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. FAU - Glickman, Jonathan AU - Glickman J AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. FAU - Wegiel, Barbara AU - Wegiel B AD - Department of Surgery, Division of Surgical Sciences, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. LA - eng GR - R01 DK125846/DK/NIDDK NIH HHS/United States GR - R01 DK104714/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230605 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 42VZT0U6YR (Heme) RN - 9013-71-2 (Hemopexin) RN - 80168379AG (Doxorubicin) SB - IM MH - Mice MH - Humans MH - Animals MH - *Heme MH - *Hemolysis MH - Hemopexin MH - Mice, Knockout MH - Inflammation/drug therapy MH - Doxorubicin MH - Colon PMC - PMC10277564 OTO - NOTNLM OT - free heme OT - gastrointestinal syndrome OT - heme oxygenase-1 OT - hemopexin OT - radiation enteritis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/06/21 13:04 MHDA- 2023/06/23 06:42 PMCR- 2023/01/01 CRDT- 2023/06/21 11:59 PHST- 2023/03/11 00:00 [received] PHST- 2023/05/22 00:00 [accepted] PHST- 2023/06/23 06:42 [medline] PHST- 2023/06/21 13:04 [pubmed] PHST- 2023/06/21 11:59 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1184105 [doi] PST - epublish SO - Front Immunol. 2023 Jun 5;14:1184105. doi: 10.3389/fimmu.2023.1184105. eCollection 2023.