|
1
|
Guo M, Wang X. Pathological mechanism and targeted drugs of ulcerative colitis: A review. Medicine (Baltimore) 2023; 102:e35020. [PMID: 37713856 PMCID: PMC10508406 DOI: 10.1097/md.0000000000035020] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/09/2023] [Indexed: 09/17/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with abdominal pain, diarrhea, and mucopurulent stools as the main symptoms. Its incidence is increasing worldwide, and traditional treatments have problems such as immunosuppression and metabolic disorders. In this article, the etiology and pathogenesis of ulcerative colitis are reviewed to clarify the targeted drugs of UC in the latest research. Our aim is to provide more ideas for the clinical treatment and new drug development of UC, mainly by analyzing and sorting out the relevant literature on PubMed, summarizing and finding that it is related to the main genetic, environmental, immune and other factors, and explaining its pathogenesis from the NF-κB pathway, PI3K/Akt signaling pathway, and JAK/STAT signaling pathway, and obtaining anti-TNF-α monoclonal antibodies, integrin antagonists, IL-12/IL-23 antagonists, novel UC-targeted drugs such as JAK inhibitors and SIP receptor agonists. We believe that rational selection of targeted drugs and formulation of the best dosing strategy under the comprehensive consideration of clinical evaluation is the best way to treat UC.
Collapse
Affiliation(s)
- Meitong Guo
- Changchun University of Chinese Medicine, Changchun City, China
| | - Xiaoyan Wang
- Jilin Academy of Chinese Medicine, Chaoyang District, China
| |
Collapse
|
|
2
|
Costa Silva RCM, Correa LHT. Heme Oxygenase 1 in Vertebrates: Friend and Foe. Cell Biochem Biophys 2021; 80:97-113. [PMID: 34800278 DOI: 10.1007/s12013-021-01047-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/07/2021] [Indexed: 10/19/2022]
Abstract
HO-1 is the inducible form of the enzyme heme-oxygenase. HO-1 catalyzes heme breakdown, reducing the levels of this important oxidant molecule and generating antioxidant, anti-inflammatory, and anti-apoptotic byproducts. Thus, HO-1 has been described as an important stress response mechanism during both physiologic and pathological processes. Interestingly, some findings are demonstrating that uncontrolled levels of HO-1 byproducts can be associated with cell death and tissue destruction as well. Furthermore, HO-1 can be located in the nucleus, influencing gene transcription, cellular proliferation, and DNA repair. Here, we will discuss several studies that approach HO-1 effects as a protective or detrimental mechanism in different pathological conditions. In this sense, as the major organs of vertebrates will deal specifically with distinct types of stresses, we discuss the HO-1 role in each of them, exposing the contradictions associated with HO-1 expression after different insults and circumstances.
Collapse
Affiliation(s)
- Rafael Cardoso Maciel Costa Silva
- Laboratory of Immunoreceptors and Signaling, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Leonardo Holanda Travassos Correa
- Laboratory of Immunoreceptors and Signaling, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| |
Collapse
|
|
3
|
Korbut E, Brzozowski T, Magierowski M. Carbon Monoxide Being Hydrogen Sulfide and Nitric Oxide Molecular Sibling, as Endogenous and Exogenous Modulator of Oxidative Stress and Antioxidative Mechanisms in the Digestive System. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:5083876. [PMID: 32377300 PMCID: PMC7180415 DOI: 10.1155/2020/5083876] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 02/06/2020] [Accepted: 02/13/2020] [Indexed: 12/17/2022]
Abstract
Oxidative stress reflects an imbalance between oxidants and antioxidants in favor of the oxidants capable of evoking tissue damage. Like hydrogen sulfide (H2S) and nitric oxide (NO), carbon monoxide (CO) is an endogenous gaseous mediator recently implicated in the physiology of the gastrointestinal (GI) tract. CO is produced in mammalian tissues as a byproduct of heme degradation catalyzed by the heme oxygenase (HO) enzymes. Among the three enzymatic isoforms, heme oxygenase-1 (HO-1) is induced under conditions of oxidative stress or tissue injury and plays a beneficial role in the mechanism of protection against inflammation, ischemia/reperfusion (I/R), and many other injuries. According to recently published data, increased endogenous CO production by inducible HO-1, its delivery by novel pharmacological CO-releasing agents, or even the direct inhalation of CO has been considered a promising alternative in future experimental and clinical therapies against various GI disorders. However, the exact mechanisms underlying behind these CO-mediated beneficial actions are not fully explained and experimental as well as clinical studies on the mechanism of CO-induced protection are awaited. For instance, in a variety of experimental models related to gastric mucosal damage, HO-1/CO pathway and CO-releasing agents seem to prevent gastric damage mainly by reduction of lipid peroxidation and/or increased level of enzymatic antioxidants, such as superoxide dismutase (SOD) or glutathione peroxidase (GPx). Many studies have also revealed that HO-1/CO can serve as a potential defensive pathway against oxidative stress observed in the liver and pancreas. Moreover, increased CO levels after treatment with CO donors have been reported to protect the gut against formation of acute GI lesions mainly by the regulation of reactive oxygen species (ROS) production and the antioxidative activity. In this review, we focused on the role of H2S and NO molecular sibling, CO/HO pathway, and therapeutic potential of CO-releasing pharmacological tools in the regulation of oxidative stress-induced damage within the GI tract with a special emphasis on the esophagus, stomach, and intestines and also two solid and important metabolic abdominal organs, the liver and pancreas.
Collapse
Affiliation(s)
- Edyta Korbut
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Krakow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Krakow, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Krakow, Poland
| |
Collapse
|
|
4
|
Chen S, Li X, Wang Y, Mu P, Chen C, Huang P, Liu D. Ginsenoside Rb1 attenuates intestinal ischemia/reperfusion‑induced inflammation and oxidative stress via activation of the PI3K/Akt/Nrf2 signaling pathway. Mol Med Rep 2019; 19:3633-3641. [PMID: 30864725 PMCID: PMC6471656 DOI: 10.3892/mmr.2019.10018] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 02/12/2019] [Indexed: 12/13/2022] Open
Abstract
Ginsenoside Rb1 (GRb1), one of the major active saponins isolated from ginseng, has recently been reported to protect various organs against ischemia/reperfusion (IR) injury; however, the mechanisms underlying these protective effects following intestinal IR (IIR) remain unclear. The present study aimed to evaluate the effects of GRb1 on IIR injury and determine the mechanisms involved in these effects. Sprague Dawley rats were subjected to 75 min of superior mesenteric artery occlusion, followed by 3 h of reperfusion. GRb1 (15 mg/kg) was administered intraperitoneally 1 h prior to the induction of IIR, with or without intravenous administration of Wortmannin [WM; a phosphoinositide 3-kinase (PI3K) inhibitor, 0.6 mg/kg]. The degree of intestinal injury and oxidative stress-induced damage was determined by histopathologic evaluation and measurement of the serum activity levels of D-lactate, diamine oxidase and endotoxin, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD) and 8-iso-prostaglandin F2α (8-iso-PGF2α). The protein expression levels of p85, phosphorylated (p)-p85, protein kinase B (Akt), p-Akt and nuclear factor erythroid 2-related factor 2 (Nrf2) were determined via western blotting, and the concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 were measured via ELISA. It was revealed that IIR led to severe intestinal injury (as determined by significant increases in intestinal Chiu scores), which was accompanied with disruptions in the integrity of the intestinal mucosal barrier. IIR also increased the expression levels of TNF-α, IL-1β, IL-6, MDA and 8-iso-PGF2α in the intestine, and decreased those of SOD. GRb1 reduced intestinal histological injury, and suppressed inflammatory responses and oxidative stress. Additionally, the protective effects of GRb1 were eliminated by WM. These findings indicated that GRb1 may ameliorate IIR injury by activating the PI3K/protein kinase B/Nrf2 pathway.
Collapse
Affiliation(s)
- Sufang Chen
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiang Li
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yanling Wang
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Panwei Mu
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Chaojin Chen
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Pinjie Huang
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Dezhao Liu
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| |
Collapse
|
|
5
|
Wang Y, Guo W, Gao D, You G, Wang B, Chen G, Zhao L, Zhao J, Zhou H. Effects of Plasma-lyte A, lactated Ringer's, and normal saline on acid-base status and intestine injury in the initial treatment of hemorrhagic shock. Am J Emerg Med 2017; 35:317-321. [PMID: 27771223 DOI: 10.1016/j.ajem.2016.10.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 09/21/2016] [Accepted: 10/03/2016] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Several kinds of crystalloid solutions have been used in the treatment of hemorrhagic shock (HS). Clinicians are faced with how to select the resuscitation fluids. The aim of the present study is to compare the effects of 3 crystalloid solutions, such as normal saline (NS), lactated Ringer's (LR), and Plasma-lyte A (PA), on acid-base status and intestine injury in rats subjected to HS. METHODS Thirty Wistar rats were divided into 4 groups. The sham group had no blood withdrawal. The other groups were subjected to severe HS and then injected with NS, LR, or PA. All treatments were followed with an infusion of red blood cell suspension. The mean arterial pressure was monitored throughout the experiment. The arterial blood gas, malonaldehyde, and myeloperoxidase levels in the small intestine were assayed 120 minutes after resuscitation. RESULTS Plasma-lyte A treatment could restore the pH, base excess (BE), HCO3-, Pao2, and Paco2. Comparing with sham group, NS failed to correct the decreased pH, BE, and HCO3- (P < .05), whereas LR treatment showed the decreased BE and HCO3- (P < .05) and increased Pao2 (P < .05). There were no significant differences in malonaldehyde among the 4 groups (P > .05). Both PA and LR were more effective than NS in decreasing the myeloperoxidase level in the small intestine (P < .01). CONCLUSIONS Although the 3 crystalloid solutions play different roles, PA is better at correcting the acid-base balance and improving intestine injury during HS than NS and LR.
Collapse
Affiliation(s)
- Ying Wang
- Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China.
| | - Wei Guo
- Department of Biochemical Engineering, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, China.
| | - Dawei Gao
- Department of Biochemical Engineering, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, China.
| | - Guoxing You
- Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China.
| | - Bo Wang
- Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China.
| | - Gan Chen
- Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China.
| | - Lian Zhao
- Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China.
| | - Jingxiang Zhao
- Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China.
| | - Hong Zhou
- Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China.
| |
Collapse
|
|
6
|
Luo L, Li YC, Dai XZ, Yang Z, Song Q, Hu WS, Cao DQ, Zhang X. Effects of Proanthocyanidins on Intestinal Motility Disturbance Following Intestinal Ischemia/Reperfusion. J INVEST SURG 2016; 29:335-342. [PMID: 27050249 DOI: 10.3109/08941939.2016.1149642] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- Lan Luo
- Department of Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Yu-Cheng Li
- Center for Experimental Technology of Preclinical Medicine, Chengdu Medical College, Chengdu, China
| | - Xiao-Zhen Dai
- Department of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Zheng Yang
- Center for Experimental Technology of Preclinical Medicine, Chengdu Medical College, Chengdu, China
| | - Qiang Song
- Department of Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Wen-Si Hu
- Center for Experimental Technology of Preclinical Medicine, Chengdu Medical College, Chengdu, China
| | - De-Qi Cao
- Center for Experimental Technology of Preclinical Medicine, Chengdu Medical College, Chengdu, China
| | - Xiao Zhang
- Center for Experimental Technology of Preclinical Medicine, Chengdu Medical College, Chengdu, China
| |
Collapse
|
|
7
|
Glutamine Modulates Changes in Intestinal Intraepithelial γδT-Lymphocyte Expressions in Mice With Ischemia/Reperfusion Injury. Shock 2016; 44:77-82. [PMID: 25784526 DOI: 10.1097/shk.0000000000000375] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
This study investigated the effect of glutamine (GLN) on expressions of small intestinal intraepithelial lymphocyte (IEL) γδT-cell proinflammatory cytokines and apoptotic regulatory factor genes in a mouse model of hindlimb ischemia/reperfusion (IR) injury. Mice were assigned to a normal control group and three IR groups. Mice in the normal control group received no ischemia treatment, whereas IR groups had hindlimb ischemia for 90 min with subsequent 0 (IR0) or 24 h (IR24) of reperfusion. The IR0 group was sacrificed immediately after reperfusion. The IR24S group was injected with saline, and the IR24G group was given 0.75 g GLN/kg of body weight once via a tail vein before reperfusion. The IR24 groups were sacrificed 24 h after reperfusion. Small intestinal IEL γδT cells of the animals were isolated for further analysis. Results showed that IR injury resulted in lower small intestinal IEL γδT-cell percentages and higher proinflammatory cytokine messenger RNA expressions of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α by IEL γδT cells. Compared with the IR24S group, the IR24G group had a higher IEL γδT-cell percentage. Multiples of change of messenger RNA of proliferation gene expressions of the antiapoptotic Bcl-xl (B-cell lymphoma-extra large) and IL-7 receptor in the IR24G group were higher, whereas expressions of the keratinocyte growth factor and bacterial lectin regenerating islet-derived (Reg)IIIγ were lower in IEL γδT cells. Histological findings also showed that damage to the intestinal mucosa was less severe in the IR group with GLN. These results indicated that a single dose of GLN administered before reperfusion maintained small intestinal IEL γδT cell populations and reduced expressions of intestinal inflammatory cytokines, which may have consequently ameliorated the severity of IR-induced small intestinal epithelial injury.
Collapse
|
|
8
|
Turóczi Z, Fülöp A, Czigány Z, Varga G, Rosero O, Tökés T, Kaszaki J, Lotz G, Harsányi L, Szijártó A. Improvement of small intestinal microcirculation by postconditioning after lower limb ischemia. Microvasc Res 2015; 98:119-25. [DOI: 10.1016/j.mvr.2015.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 10/05/2014] [Accepted: 02/02/2015] [Indexed: 01/28/2023]
|
|
9
|
Chang M, Xue J, Sharma V, Habtezion A. Protective role of hemeoxygenase-1 in gastrointestinal diseases. Cell Mol Life Sci 2015; 72:1161-73. [PMID: 25428780 PMCID: PMC4342274 DOI: 10.1007/s00018-014-1790-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 11/16/2014] [Accepted: 11/20/2014] [Indexed: 12/22/2022]
Abstract
Disorders and diseases of the gastrointestinal system encompass a wide array of pathogenic mechanisms as a result of genetic, infectious, neoplastic, and inflammatory conditions. Inflammatory diseases in general are rising in incidence and are emerging clinical problems in gastroenterology and hepatology. Hemeoxygenase-1 (HO-1) is a stress-inducible enzyme that has been shown to confer protection in various organ-system models. Its downstream effectors, carbon monoxide and biliverdin have also been shown to offer these beneficial effects. Many studies suggest that induction of HO-1 expression in gastrointestinal tissues and cells plays a critical role in cytoprotection and resolving inflammation as well as tissue injury. In this review, we examine the protective role of HO-1 and its downstream effectors in modulating inflammatory diseases of the upper (esophagus and stomach) and lower (small and large intestine) gastrointestinal tract, the liver, and the pancreas. Cytoprotective, anti-inflammatory, anti-proliferative, antioxidant, and anti-apoptotic activities of HO-1 make it a promising if not ideal therapeutic target for inflammatory diseases of the gastrointestinal system.
Collapse
Affiliation(s)
- Marisol Chang
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Jing Xue
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Vishal Sharma
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| |
Collapse
|
|
10
|
The severity of microvascular dysfunction due to compartment syndrome is diminished by the systemic application of CO-releasing molecule-3. J Orthop Trauma 2014; 28:e263-8. [PMID: 24675751 DOI: 10.1097/bot.0000000000000097] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVES To examine the protective effects of carbon monoxide (CO), liberated from a novel CO-releasing molecule (CORM-3), on the function of compartment syndrome (CS)-challenged muscle in a rodent model, thus providing for a potential development of a pharmacologic adjunctive treatment for CS. METHODS Wistar rats were randomized into 4 groups: sham (no CS), CS, CS with inactive CORM-3 (iCORM-3), and CS + CORM-3 (10 mg/kg intraperitoneally). CS was induced by elevation of intracompartmental pressure to 30 mm Hg through an infusion of isotonic saline into the anterior compartment of the hind limb for 2 hours. Both CORM-3 and iCORM-3 were injected immediately after fasciotomy. Microvascular perfusion, cellular tissue injury, and inflammatory response within the extensor digitorum longus muscle were assessed using intravital video microscopy 45 minutes after fasciotomy. Systemic levels of tumor necrosis factor alpha (TNF-α) were also measured. RESULTS Elevation of intracompartmental pressure resulted in significant microvascular perfusion deficits (23% ± 2% continuously perfused capillaries in CS vs. 76% ± 4% in sham, P < 0.0001; 55% ± 2% nonperfused capillaries in CS vs. 13% ± 2% in sham, P < 0.0001), significant increase in tissue injury (ethidium bromide/bisbenzimide of 0.31 ± 0.05 in CS vs. 0.05 ± 0.03 in sham, P < 0.0001) and adherent leukocytes (13.7 ± 0.9 in CS vs. 1.8 ± 0.5 in sham, P < 0.0001), and a progressive rise in systemic TNF-α. CORM-3 (but not iCORM-3) treatment restored the number of continuously perfused capillaries (57% ± 5%, P < 0.001), diminished tissue injury (ethidium bromide/bisbenzimide of 0.07 ± 0.01, P < 0.001), reversed the CS-associated rise in TNF-α, and decreased leukocyte adherence (0.6 ± 0.3, P < 0.001). CONCLUSIONS CORM-3 displays a potent protective/anti-inflammatory action in an experimental model of CS, suggesting a potential therapeutic application to patients at risk of developing CS.
Collapse
|
|
11
|
Babu D, Motterlini R, Lefebvre RA. CO and CO-releasing molecules (CO-RMs) in acute gastrointestinal inflammation. Br J Pharmacol 2014; 172:1557-73. [PMID: 24641722 DOI: 10.1111/bph.12632] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 01/30/2014] [Accepted: 02/05/2014] [Indexed: 12/13/2022] Open
Abstract
Carbon monoxide (CO) is enzymatically generated in mammalian cells alongside the liberation of iron and the production of biliverdin and bilirubin. This occurs during the degradation of haem by haem oxygenase (HO) enzymes, a class of ubiquitous proteins consisting of constitutive and inducible isoforms. The constitutive HO2 is present in the gastrointestinal tract in neurons and interstitial cells of Cajal and CO released from these cells might contribute to intestinal inhibitory neurotransmission and/or to the control of intestinal smooth muscle cell membrane potential. On the other hand, increased expression of the inducible HO1 is now recognized as a beneficial response to oxidative stress and inflammation. Among the products of haem metabolism, CO appears to contribute primarily to the antioxidant and anti-inflammatory effects of the HO1 pathway explaining the studies conducted to exploit CO as a possible therapeutic agent. This article reviews the effects and, as far as known today, the mechanism(s) of action of CO administered either as CO gas or via CO-releasing molecules in acute gastrointestinal inflammation. We provide here a comprehensive overview on the effect of CO in experimental in vivo models of post-operative ileus, intestinal injury during sepsis and necrotizing enterocolitis. In addition, we will analyse the in vitro data obtained so far on the effect of CO on intestinal epithelial cell lines exposed to cytokines, considering the important role of the intestinal mucosa in the pathology of gastrointestinal inflammation.
Collapse
Affiliation(s)
- D Babu
- Heymans Institute of Pharmacology, Ghent University, Gent, Belgium
| | | | | |
Collapse
|
|
12
|
Therapeutic applications of carbon monoxide. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:360815. [PMID: 24648866 PMCID: PMC3932177 DOI: 10.1155/2013/360815] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 10/21/2013] [Accepted: 11/05/2013] [Indexed: 11/17/2022]
Abstract
Heme oxygenase-1 (HO-1) is a regulated enzyme induced in multiple stress states. Carbon monoxide (CO) is a product of HO catalysis of heme. In many circumstances, CO appears to functionally replace HO-1, and CO is known to have endogenous anti-inflammatory, anti-apoptotic, and antiproliferative effects. CO is well studied in anoxia-reoxygenation and ischemia-reperfusion models and has advanced to phase II trials for treatment of several clinical entities. In alternative injury models, laboratories have used sepsis, acute lung injury, and systemic inflammatory challenges to assess the ability of CO to rescue cells, organs, and organisms. Hopefully, the research supporting the protective effects of CO in animal models will translate into therapeutic benefits for patients. Preclinical studies of CO are now moving towards more complex damage models that reflect polymicrobial sepsis or two-step injuries, such as sepsis complicated by acute respiratory distress syndrome. Furthermore, co-treatment and post-treatment with CO are being explored in which the insult occurs before there is an opportunity to intervene therapeutically. The aim of this review is to discuss the potential therapeutic implications of CO with a focus on lung injury and sepsis-related models.
Collapse
|
|
13
|
Zhu X, Fan WG, Li DP, Kung H, Lin MCM. Heme oxygenase-1 system and gastrointestinal inflammation: A short review. World J Gastroenterol 2011; 17:4283-8. [PMID: 22090784 PMCID: PMC3214703 DOI: 10.3748/wjg.v17.i38.4283] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 03/21/2011] [Accepted: 03/28/2011] [Indexed: 02/06/2023] Open
Abstract
Heme oxygenase-1 (HO-1) system catalyzes heme to biologically active products: carbon monoxide, biliverdin/bilirubin and free iron. It is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes. A growing body of evidence indicates that HO-1 activation may play an important protective role in acute and chronic inflammation of gastrointestinal tract. This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal inflammation studied to date. The ability to upregulate HO-1 by pharmacological means or using gene therapy may offer therapeutic strategies for gastrointestinal inflammation in the future.
Collapse
|
|
14
|
Lee SE, Jeong SI, Kim GD, Yang H, Park CS, Jin YH, Park YS. Upregulation of heme oxygenase-1 as an adaptive mechanism for protection against crotonaldehyde in human umbilical vein endothelial cells. Toxicol Lett 2011; 201:240-8. [DOI: 10.1016/j.toxlet.2011.01.006] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 01/07/2011] [Accepted: 01/07/2011] [Indexed: 12/30/2022]
|
|
15
|
Xu B, Gao X, Xu J, Lei S, Xia ZY, Xu Y, Xia Z. Ischemic postconditioning attenuates lung reperfusion injury and reduces systemic proinflammatory cytokine release via heme oxygenase 1. J Surg Res 2010; 166:e157-64. [PMID: 21227458 DOI: 10.1016/j.jss.2010.11.902] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Revised: 11/04/2010] [Accepted: 11/17/2010] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Systemic inflammatory response following ischemia-reperfusion injury (IRI) to a specific organ may cause injuries in multiple remote organs. The emergence of ischemic postconditioning (IPO) provides a potential method for experimentally and clinically attenuating various types of organ postischemic injuries. We have shown that IPO can attenuate lung IRI by up-regulating the protein expression of heme oxygenase-1(HO-1). This study tested the hypothesis that IPO attenuates systemic inflammatory responses following lung IRI by activating HO-1. METHODS Anaesthetized and mechanically ventilated adult Sprague-Dawley rats were randomly assigned to one of the following groups (n = 8 each): the sham-operated control group, the ischemia-reperfusion (IR) group (40 min of left-lung ischemia and 120 min of reperfusion), the IPO group (three successive cycles of 30-s reperfusion per 30-s occlusion before restoring full perfusion), and the zinc protoporphyrin IX (ZnP) plus IPO group (ZnP, an inhibitor of HO-1, was injected intraperitoneally at 20 mg/kg 24 h prior to the experiment, and the rest of the procedures were similar to that of the IPO group). Lung injury was assessed by arterial blood gas analysis, wet-to-dry lung weight ratio and tissue histologic and biochemical changes. The lung tissue and plasma levels of lipid peroxidation were determined by measuring the contents of malondialdehyde (MDA) production. Protein expression of HO-1 was determined by Western blotting. Pulmonary neutrophil was counted. Lung tissue myeloperoxidase (MPO) activity as well as plasma levels of proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukines 6 and 8 (IL-6, IL-8) were determined by spectrophotography. RESULTS Lung ischemia-reperfusion led to severe lung pathologic morphologic changes and increased pulmonary MDA production, neutrophil count, and MPO activity and reduced arterial oxygen partial pressure (all P < 0.05 IR versus sham), accompanied with a compensatory increase in HO-1 protein and activity. Plasma levels of TNF-α, IL-6, and IL-8 were increased in the IR group (all P < 0.05 versus sham). IPO attenuated or prevented all the above changes, except that it further increased lung HO-1 activity. Treatment with ZnP abolished all the protective effects of postconditioning. CONCLUSION Postconditioning attenuated pulmonary neutrophil accumulation and activation and lung IRI and reduced systemic inflammatory responses by activating HO-1.
Collapse
Affiliation(s)
- Bo Xu
- Department of Respiratory Medicine, Beijing Friendship Hospital Affiliated to the Capital University of Medical Sciences, Beijing, China
| | | | | | | | | | | | | |
Collapse
|