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Vasdev N, Martin N, Hackney AB, Piedad J, Hampson A, Shan G, Prasad V, Chilvers M, Ebon M, Smith P, Tegan G, Decaestecker K, Baydoun A. Comparing different pneumoperitoneum (12 vs. 15 mmHg) pressures with cytokine analysis to evaluate clinical outcomes in patients undergoing robotic-assisted laparoscopic radical cystectomy and intracorporeal robotic urinary diversion. BJUI COMPASS 2023; 4:575-583. [PMID: 37636200 PMCID: PMC10447212 DOI: 10.1002/bco2.240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 03/05/2023] [Accepted: 03/17/2023] [Indexed: 08/29/2023] Open
Abstract
Background Robotic cystectomy is the mainstay surgical intervention for treatment-refractory nonmuscle-invasive and muscle-invasive bladder cancer. However, paralytic ileus may complicate the postoperative recovery and may be a consequence of an inflammatory response associated with transient gut ischaemia. We have therefore investigated clinical, operative and inflammatory biomarker associations between paralytic ileus in the context of robotic cystectomy and intracorporeal ileal conduit urinary diversion. Methods Prospective consective patients referred for robotic cystectomy were consented and included in the study, while patients >75 years old and converted to open procedure were excluded. The pneumoperitoneum pressure (PP) for carbon dioxide insufflation required to perform the procedure efficiently and safely was recorded (12 or 15 mmHg). We also recorded the postoperative days patients passed flatus and stools, whether they developed ileus, as well as other standard clinical and demographic data. The expression of select proinflammatory and anti-inflammatory cytokines was determined by multiplex analysis using a cytometric bead array with changes in profiles correlated with the pressures applied and with the existence of an ileus. Results Twenty-seven patients were recruited, but only 20 were used in the study with 10 patients in each PP group. Seven patients were excluded all of whom had an extracorporeal ileal conduit formation. There were differences in the 40-min shorter operative time and 1 day shorter length of stay, as well as passing flatus 1 day and stools 1.5 days earlier in the 12 mmHg compared with the 15 mmHg group. More patients had ileus in the 15 mmHg group vs 12 mmHg group (30% vs. 10.0%). These were not statistically significant. Similarly, there were no statistical differences in the expression of proinflammatory cytokines at the two different pressures or between patient groups, but there were outliers, with the median indicating nonsymmetrical distribution. By comparison, anti-inflammatory cytokines showed some significant differences between groups, with IL-6 and IL-10 showing elevated levels postsurgery. No statistical difference was observed between pressures or the existence of an ileus, but the maximum levels of IL-6 and IL-10 detected in some patients reflect a pressure difference. Conclusions The initial findings of this novel scientific study indicated a higher risk of paralytic ileus postrobotic cystectomy and robotic intracorporeal urinary diversion when a higher pressure of 15 mmHg is used compared with 12 mmHg. Although further studies are required to establish the linkage between cytokine profile expression, pressure and ileus, our initial data reinforces the advantages of lower pressure robotic cystectomy and intracorporeal urinary diversion in patient outcomes.
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Affiliation(s)
- Nikhil Vasdev
- Department of Urology, Lister HospitalEast and North Hertfordshire NHS TrustStevenageUK
- School of Life and Medical SciencesUniversity of HertfordshireHatfieldUK
| | - Naomi Martin
- Faulty of Health and Life SciencesDe Montfort UniversityLeicesterUK
- Department of Respiratory SciencesUniversity of LeicesterLeicesterUK
| | - Amon B. Hackney
- Department of Respiratory SciencesUniversity of LeicesterLeicesterUK
| | - John Piedad
- Department of Urology, Lister HospitalEast and North Hertfordshire NHS TrustStevenageUK
| | - Alexander Hampson
- Department of Urology, Lister HospitalEast and North Hertfordshire NHS TrustStevenageUK
| | - Gowrie‐Mohan Shan
- Department of Anaesthetics, Lister HospitalEast and North Hertfordshire NHS TrustStevenageUK
| | - Venkat Prasad
- Department of Anaesthetics, Lister HospitalEast and North Hertfordshire NHS TrustStevenageUK
| | - Michael Chilvers
- Department of Anaesthetics, Lister HospitalEast and North Hertfordshire NHS TrustStevenageUK
| | - Martin Ebon
- Department of Research, Lister HospitalEast and North Hertfordshire NHS TrustStevenageUK
| | - Philip Smith
- Department of Research, Lister HospitalEast and North Hertfordshire NHS TrustStevenageUK
| | - Gary Tegan
- Research and DevelopmentCONMED CorporationLargoFloridaUSA
| | - Karel Decaestecker
- Department of UrologyMaria Middelares General HospitalGhentBelgium
- Department of UrologyGhent University HospitalGhentBelgium
| | - Anwar Baydoun
- Department of Respiratory SciencesUniversity of LeicesterLeicesterUK
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Bayram S, Parlar A, Arslan SO. The curative effect of cannabinoid 2 receptor agonist on functional failure and disruptive inflammation caused by intestinal ischemia and reperfusion. Fundam Clin Pharmacol 2019; 34:80-90. [DOI: 10.1111/fcp.12502] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 07/26/2019] [Accepted: 07/30/2019] [Indexed: 12/19/2022]
Affiliation(s)
- Sait Bayram
- Department of Medical Pharmacology, Medical Faculty University of Duzce Duzce Turkey
| | - Ali Parlar
- Department of Medical Pharmacology, Medical Faculty University of Adiyaman Adiyaman Turkey
| | - Seyfullah Oktay Arslan
- Department of Medical Pharmacology, Medical Faculty University of Ankara Yildirim Beyazit Bilkent yolu 3.Km. Çankaya Ankara 06010 Turkey
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Blockage of the P2X7 Receptor Attenuates Harmful Changes Produced by Ischemia and Reperfusion in the Myenteric Plexus. Dig Dis Sci 2019; 64:1815-1829. [PMID: 30734238 DOI: 10.1007/s10620-019-05496-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 01/24/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Our work analyzed the effects of a P2X7 receptor antagonist, Brilliant Blue G (BBG), on rat ileum myenteric plexus following ischemia and reperfusion (ISR) induced by 45 min of ileal artery occlusion with an atraumatic vascular clamp with 24 h (ISR 24-h group) or 14 d of reperfusion (ISR 14-d group). MATERIAL AND METHODS Either BBG (50 mg/kg or 100 mg/kg, BBG50 or BBG100 groups) or saline (vehicle) was administered subcutaneously 1 h after ischemia in the ISR 24-h group or once daily for the 5 d after ischemia in the ISR 14-d group (n = 5 per group). We evaluated the neuronal density and profile area by examining the number of neutrophils in the intestinal layers, protein expression levels of the P2X7 receptor, intestinal motility and immunoreactivity for the P2X7 receptor, nitric oxide synthase, neurofilament-200, and choline acetyl transferase in myenteric neurons. RESULTS The neuronal density and profile area were restored by BBG following ISR. The ischemic groups showed alterations in P2X7 receptor protein expression and the number of neutrophils in the intestine and decreased intestinal motility, all of which were recovered by BBG treatment. CONCLUSION We concluded that ISR morphologically and functionally affected the intestine and that its effects were reversed by BBG treatment, suggesting the P2X7 receptor as a therapeutic target.
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Huang HH, Lee YC, Chen CY. Effects of burns on gut motor and mucosa functions. Neuropeptides 2018; 72:47-57. [PMID: 30269923 DOI: 10.1016/j.npep.2018.09.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 08/16/2018] [Accepted: 09/19/2018] [Indexed: 02/08/2023]
Abstract
This review analyzed the published studies on the effects of thermal injury on gastrointestinal motility and mucosal damage. Our strategy was to integrate all available evidence to provide a complete review on the prokinetic properties of variable reagents and the potential clinical treatment of mucosal damage and gastrointestinal dysmotility after thermal injury. We classified the studies into two major groups: studies on gastrointestinal dysmotility and studies on mucosal damage. We also subclassified the studies into 3 parts: stomach, small intestine, and colon. This review shows evidence that ghrelin can recover burn-induced delay in gastric emptying and small intestinal transit, and can protect the gastric mucosa from burn-induced injury. Oxytocin and β-glucan reduced the serum inflammatory mediators, and histological change and mucosal damage indicators, but did not show evidence of having the ability to recover gastrointestinal motility. Using a combination of different reagents to protect the gastrointestinal mucosa against damage and to recover gastrointestinal motility is an alternative treatment for thermal injury.
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Affiliation(s)
- Hsien-Hao Huang
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Yu-Chi Lee
- Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Yen Chen
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Taiwan Association for the Study of Small Intestinal Diseases, Guishan, Taiwan.
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Almohanna AM, Wray S. Hypoxic conditioning in blood vessels and smooth muscle tissues: effects on function, mechanisms, and unknowns. Am J Physiol Heart Circ Physiol 2018; 315:H756-H770. [PMID: 29702009 DOI: 10.1152/ajpheart.00725.2017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hypoxic preconditioning, the protective effect of brief, intermittent hypoxic or ischemic episodes on subsequent more severe hypoxic episodes, has been known for 30 yr from studies on cardiac muscle. The concept of hypoxic preconditioning has expanded; excitingly, organs beyond the heart, including the brain, liver, and kidney, also benefit. Preconditioning of vascular and visceral smooth muscles has received less attention despite their obvious importance to health. In addition, there has been no attempt to synthesize the literature in this field. Therefore, in addition to overviewing the current understanding of hypoxic conditioning, in the present review, we consider the role of blood vessels in conditioning and explore evidence for conditioning in other smooth muscles. Where possible, we have distinguished effects on myocytes from other cell types in the visceral organs. We found evidence of a pivotal role for blood vessels in conditioning and for conditioning in other smooth muscle, including the bladder, vascular myocytes, and gastrointestinal tract, and a novel response in the uterus of a hypoxic-induced force increase, which helps maintain contractions during labor. To date, however, there are insufficient data to provide a comprehensive or unifying mechanism for smooth muscles or visceral organs and the effects of conditioning on their function. This also means that no firm conclusions can be drawn as to how differences between smooth muscles in metabolic and contractile activity may contribute to conditioning. Therefore, we have suggested what may be general mechanisms of conditioning occurring in all smooth muscles and tabulated tissue-specific mechanistic findings and suggested ideas for further progress.
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Affiliation(s)
- Asmaa M Almohanna
- Department of Molecular and Cellular Physiology, Institute of Translational Medicine University of Liverpool , Liverpool , United Kingdom.,Princess Nourah bint Abdulrahman University , Riyadh , Saudi Arabia
| | - Susan Wray
- Department of Molecular and Cellular Physiology, Institute of Translational Medicine University of Liverpool , Liverpool , United Kingdom
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Filpa V, Carpanese E, Marchet S, Pirrone C, Conti A, Rainero A, Moro E, Chiaravalli AM, Zucchi I, Moriondo A, Negrini D, Crema F, Frigo G, Giaroni C, Porta G. Nitric oxide regulates homeoprotein OTX1 and OTX2 expression in the rat myenteric plexus after intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 2017; 312:G374-G389. [PMID: 28154013 DOI: 10.1152/ajpgi.00386.2016] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 01/27/2017] [Accepted: 01/27/2017] [Indexed: 01/31/2023]
Abstract
Neuronal and inducible nitric oxide synthase (nNOS and iNOS) play a protective and damaging role, respectively, on the intestinal neuromuscular function after ischemia-reperfusion (I/R) injury. To uncover the molecular pathways underlying this dichotomy we investigated their possible correlation with the orthodenticle homeobox proteins OTX1 and OTX2 in the rat small intestine myenteric plexus after in vivo I/R. Homeobox genes are fundamental for the regulation of the gut wall homeostasis both during development and in pathological conditions (inflammation, cancer). I/R injury was induced by temporary clamping the superior mesenteric artery under anesthesia, followed by 24 and 48 h of reperfusion. At 48 h after I/R intestinal transit decreased and was further reduced by Nω-propyl-l-arginine hydrochloride (NPLA), a nNOS-selective inhibitor. By contrast this parameter was restored to control values by 1400W, an iNOS-selective inhibitor. In longitudinal muscle myenteric plexus (LMMP) preparations, iNOS, OTX1, and OTX2 mRNA and protein levels increased at 24 and 48 h after I/R. At both time periods, the number of iNOS- and OTX-immunopositive myenteric neurons increased. nNOS mRNA, protein levels, and neurons were unchanged. In LMMPs, OTX1 and OTX2 mRNA and protein upregulation was reduced by 1400W and NPLA, respectively. In myenteric ganglia, OTX1 and OTX2 staining was superimposed with that of iNOS and nNOS, respectively. Thus in myenteric ganglia iNOS- and nNOS-derived NO may promote OTX1 and OTX2 upregulation, respectively. We hypothesize that the neurodamaging and neuroprotective roles of iNOS and nNOS during I/R injury in the gut may involve corresponding activation of molecular pathways downstream of OTX1 and OTX2.NEW & NOTEWORTHY Intestinal ischemia-reperfusion (I/R) injury induces relevant alterations in myenteric neurons leading to dismotility. Nitrergic neurons seem to be selectively involved. In the present study the inference that both neuronal and inducible nitric oxide synthase (nNOS and iNOS) expressing myenteric neurons may undergo important changes sustaining derangements of motor function is reinforced. In addition, we provide data to suggest that NO produced by iNOS and nNOS regulates the expression of the vital transcription factors orthodenticle homeobox protein 1 and 2 during an I/R damage.
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Affiliation(s)
- Viviana Filpa
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Elisa Carpanese
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Silvia Marchet
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Cristina Pirrone
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Andrea Conti
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Alessia Rainero
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Elisabetta Moro
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
| | | | - Ileana Zucchi
- ITB Consiglio Nazionale delle Ricerche, Segrate, Milan, Italy
| | - Andrea Moriondo
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Daniela Negrini
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Francesca Crema
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Gianmario Frigo
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy;
| | - Giovanni Porta
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
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Marr AB, McQuiggan MM, Kozar R, Moore FA. Gastric Feeding as an Extension of an Established Enteral Nutrition Protocol. Nutr Clin Pract 2017; 19:504-10. [PMID: 16215146 DOI: 10.1177/0115426504019005504] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Indiscriminate gastric feeding in ICU patients imposes unacceptable risks of aspiration. Believing that a subset of ICU patients can be fed safely via the stomach, we have developed a protocol to identify appropriate patients and guide the bedside clinician in how to safely and effectively feed via the stomach. METHODS A literature search was done to identify appropriate medical literature. High grade evidence along with local expert opinions were used to develop a protocol. This protocol has been refined and implemented. RESULTS Based on perceived risk of aspiration, patients are assigned enteral access (ie, stomach vs. distal post-pyloric). Enteral formula is selected based on patient characteristics. It is then advanced by a standard protocol with specific precautions while monitoring for symptoms of intolerance. Management of intolerance is dictated by the type and severity of intolerance. CONCLUSION We have implemented a gastric feeding into a subset of our ICU patients. Gastric feeding requires certain precautions but appears to be safe. With more experience and better understanding of the pathogenesis gastroparesis, we believe that most ICU patients should be able to safely feed into the stomach. This is logistically easier than post-pyloric feeding and offers physiologic advantages.
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Affiliation(s)
- Alan B Marr
- Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, USA
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Öztürk T, Vural K, Tuğlu İ, Var A, Kurdal T, Aydemir I. Acute and Chronic Pretreatment With Atenolol Attenuates Intestinal Ischemia and Reperfusion Injury in Hypercholesterolemic Rats. J Cardiothorac Vasc Anesth 2016; 30:985-92. [PMID: 27521968 DOI: 10.1053/j.jvca.2016.03.140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To evaluate the protective effects of preinjury atenolol (acute v chronic) on apoptosis, contractility, oxidative stress, and inflammatory markers in hypercholesterolemic rats undergoing intestinal ischemia-reperfusion (I/R) injury. DESIGN Prospective, experimental animal study. SETTING University laboratory. PARTICIPANTS Male Wistar rats (n = 32). INTERVENTIONS Rats were divided into the following 4 groups: 1 group was fed a normal diet (ND) (group ND+NoAT [no atenolol]), and the other 3 groups were fed a high-cholesterol diet (HCD)-group HCD+NoAT, group HCD+ChAT (chronic atenolol, 3 mg/kg/day for 8 weeks), and group HCD+AcAT (acute atenolol, 1.5 mg/kg, given 5 minutes before intestinal clamping). All rats underwent I/R injury. The superior mesenteric artery was clamped for 60 minutes, then opened for 120 minutes (reperfusion). Apoptotic cells and stimulated contractions of ileal segments were examined. Tissue markers of intestinal I/R injury were examined. Intestinal malondialdehyde, superoxide dismutase, and nitrate/nitrite levels were measured. MEASUREMENTS AND MAIN RESULTS The chronic atenolol group had fewer apoptotic cells and higher superoxide dismutase activity compared with the other groups. Intestinal contraction was higher in both atenolol pretreatment groups compared with the NoAT groups. Chronic and acute atenolol resulted in lower ileal levels of malondialdehyde and immunolabeling-positive cells (intestinal inducible nitric oxide synthase, endothelial nitric oxide synthase, interleukin-1, and interleukin-8) after I/R injury compared with the no atenolol groups. CONCLUSIONS Both chronic and acute pre-I/R injury treatment with atenolol attenuated I/R injury in this hypercholesterolemic rat model. These findings should encourage future studies of atenolol in hypercholesterolemic patients undergoing procedures with a high risk of intestinal ischemia.
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Affiliation(s)
- Tülün Öztürk
- Departments of Anaesthesiology and Reanimation, Celal Bayar University, Faculty of Medicine, Uncubozköy, Manisa, Turkey.
| | - Kamil Vural
- Pharmacology, Celal Bayar University, Faculty of Medicine, Uncubozköy, Manisa, Turkey
| | - İbrahim Tuğlu
- Histology, Celal Bayar University, Faculty of Medicine, Uncubozköy, Manisa, Turkey
| | - Ahmet Var
- Biochemistry, Celal Bayar University, Faculty of Medicine, Uncubozköy, Manisa, Turkey
| | - Taner Kurdal
- Cardiovascular Surgery, Celal Bayar University, Faculty of Medicine, Uncubozköy, Manisa, Turkey
| | - Işıl Aydemir
- Pharmacology, Celal Bayar University, Faculty of Medicine, Uncubozköy, Manisa, Turkey; Histology, Celal Bayar University, Faculty of Medicine, Uncubozköy, Manisa, Turkey
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Pré‐tratamento com remifentanil protege contra a redução da contratilidade intestinal relacionada à lesão de isquemia e reperfusão em ratos. Braz J Anesthesiol 2015; 65:483-90. [DOI: 10.1016/j.bjan.2013.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 09/02/2013] [Indexed: 11/19/2022] Open
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Sayan-Ozacmak H, Ozacmak VH, Turan I, Barut F, Hanci V. Pretreatment with remifentanil protects against the reduced-intestinal contractility related to the ischemia and reperfusion injury in rat. Braz J Anesthesiol 2015; 65:483-90. [DOI: 10.1016/j.bjane.2013.09.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 09/02/2013] [Indexed: 11/29/2022] Open
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Pharmacokinetic and Other Considerations for Drug Therapy During Targeted Temperature Management. Crit Care Med 2015; 43:2228-38. [DOI: 10.1097/ccm.0000000000001223] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Sun Y, Gao Q, Wu N, Li SDE, Yao JX, Fan WJ. Protective effects of dexmedetomidine on intestinal ischemia-reperfusion injury. Exp Ther Med 2015; 10:647-652. [PMID: 26622369 DOI: 10.3892/etm.2015.2561] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 02/09/2015] [Indexed: 01/17/2023] Open
Abstract
Dexmedetomidine (DEX) has been hypothesized to possess anti-oxidative properties that may mitigate the damage caused by ischemia-reperfusion (IR) injury. The aim of the present study was to examine the effects of DEX on intestinal contractile activity, inflammation and apoptosis following intestinal IR injury. Intestinal IR injury was induced in rats by complete occlusion of the superior mesenteric artery for 60 min, followed by a 60-min reperfusion period. Rats received an intraperitoneal injection of 25 µg/kg DEX at 30 min prior to the mesenteric IR injury. Following reperfusion, segments of the terminal ileum were rapidly extracted and transferred into an isolated organ bath. The contractile responses to receptor-mediated acetylcholine (Ach) and non-receptor-mediated potassium chloride (KCl) were subsequently examined. Nitric oxide (NO) levels were determined and the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, Bax and Bcl-2 were measured using an enzyme-linked immunosorbent assay. The levels of telomerase and caspase-3 were determined using reverse transcription-quantitative polymerase chain reaction. The results indicated that DEX treatment produced a significant reduction in the IR-induced contractile response to Ach and KCl in the intestinal tissue. Furthermore, DEX appeared to significantly ameliorate intestinal IR injury, in addition to reducing the production of NO. Similar reductions were observed in the intestinal expression levels of TNF-α and IL-6. In addition, DEX treatment resulted in a reduction in the expression levels of Bax in the intestinal tissues, while increasing those of Bcl-2, in addition to significantly increasing the mRNA levels of telomerase and caspase-3. Therefore, the present study indicated that NO, TNF-α and IL-6 may partially contribute to the pathogenesis of intestinal IR injury in addition to the increased expression levels of Bax, Bcl-2, telomerase and caspase-3. These findings suggest that DEX possesses beneficial anti-apoptotic and anti-inflammatory effects in intestinal tissue following bowel injury.
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Affiliation(s)
- Yong Sun
- Department of Surgery, Qingdao Women and Children's Hospital, Qingdao, Shandong 266034, P.R. China
| | - Qiang Gao
- Department of Surgery, Qingdao Women and Children's Hospital, Qingdao, Shandong 266034, P.R. China
| | - Nan Wu
- Department of Anesthesia, Qingdao Women and Children's Hospital, Qingdao, Shandong 266034, P.R. China
| | - Sheng-DE Li
- Department of Anesthesia, Qingdao Women and Children's Hospital, Qingdao, Shandong 266034, P.R. China
| | - Jing-Xin Yao
- Department of Anesthesia, Qingdao Women and Children's Hospital, Qingdao, Shandong 266034, P.R. China
| | - Wen-Jie Fan
- Department of Anesthesia, Qingdao Women and Children's Hospital, Qingdao, Shandong 266034, P.R. China
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Interaction between NMDA glutamatergic and nitrergic enteric pathways during in vitro ischemia and reperfusion. Eur J Pharmacol 2015; 750:123-31. [DOI: 10.1016/j.ejphar.2015.01.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 01/14/2015] [Accepted: 01/15/2015] [Indexed: 11/23/2022]
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Moore-Olufemi SD, Olsen AB, Hook-Dufresne DM, Bandla V, Cox CS. Transforming growth factor-beta 3 alters intestinal smooth muscle function: implications for gastroschisis-related intestinal dysfunction. Dig Dis Sci 2015; 60:1206-14. [PMID: 25431043 PMCID: PMC4427617 DOI: 10.1007/s10620-014-3439-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 11/11/2014] [Indexed: 12/31/2022]
Abstract
BACKGROUND Gastroschisis (GS) is a congenital abdominal wall defect that results in the development of GS-related intestinal dysfunction (GRID). Transforming growth factor-β, a pro-inflammatory cytokine, has been shown to cause organ dysfunction through alterations in vascular and airway smooth muscle. The purpose of this study was to evaluate the effects of TGF-β3 on intestinal smooth muscle function and contractile gene expression. METHODS Archived human intestinal tissue was analyzed using immunohistochemistry and RT-PCR for TGF-β isoforms and markers of smooth muscle gene and micro-RNA contractile phenotype. Intestinal motility was measured in neonatal rats ± TGF-β3 (0.2 and 1 mg/kg). Human intestinal smooth muscle cells (hiSMCs) were incubated with fetal bovine serum ± 100 ng/ml of TGF-β 3 isoforms for 6, 24 and 72 h. The effects of TGF-β3 on motility, hiSMC contractility and hiSMC contractile phenotype gene and micro-RNA expression were measured using transit, collagen gel contraction assay and RT-PCR analysis. Data are expressed as mean ± SEM, ANOVA (n = 6-7/group). RESULTS GS infants had increased immunostaining of TGF-β3 and elevated levels of micro-RNA 143 & 145 in the intestinal smooth muscle. Rats had significantly decreased intestinal transit when exposed to TGF-β3 in a dose-dependent manner compared with Sham animals. TGF-β3 significantly increased hiSMC gel contraction and contractile protein gene and micro-RNA expression. CONCLUSION TGF-β3 contributed to intestinal dysfunction at the organ level, increased contraction at the cellular level and elevated contractile gene expression at the molecular level. A hyper-contractile response may play a role in the persistent intestinal dysfunction seen in GRID.
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Affiliation(s)
- S. D. Moore-Olufemi
- Department of Pediatric Surgery, The University of Texas Medical School at Houston, 6431 Fannin Street, MSB 5.222, Houston, TX 77030 USA
| | - A. B. Olsen
- Department of Pediatric Surgery, The University of Texas Medical School at Houston, 6431 Fannin Street, MSB 5.222, Houston, TX 77030 USA
| | - D. M. Hook-Dufresne
- Department of Surgery, The University of Texas Medical School at Houston, Houston, TX USA
| | - V. Bandla
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX USA
| | - C. S. Cox
- Department of Pediatric Surgery, The University of Texas Medical School at Houston, 6431 Fannin Street, MSB 5.222, Houston, TX 77030 USA
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Role of nitric oxide in development of centralization of blood circulation upon experimental hemorrhagic shock. Bull Exp Biol Med 2014; 157:22-4. [PMID: 24906962 DOI: 10.1007/s10517-014-2482-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Indexed: 10/25/2022]
Abstract
Effects of a NO donor L-arginine and a non-selective NO-synthase inhibitor N(G)-nitro-Larginine methyl ester on BP, microcirculation, acid-base balance, and gas content of blood were examined on rat model of hemorrhagic shock; the substances were administered without infusion media before blood loss. Bloodletting was stopped after manifestation of marked microcirculation disorders. Inhibition of NO synthesis in response to blood loss resulted in pronounced centralization of blood circulation with microcirculation disturbances, which was accompanied by metabolic changes aggravating hemorrhagic shock. Administration of NO donor reduced the degree of circulation centralization, maintained vasodilatatory vascular tone and perfusion of vital organs, improved animal resistance to blood loss, and prolonged their lifespan. Enhanced NO generation after administration of NO donor promoted longer microcirculation maintenance, which suggests that the so-called basal level of NO is essential at early stages of hemorrhagic shock.
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Study of the influence of anti-inflammatory and antioxidative substances on rat kidneys in ischaemia-reperfusion of the superior mesenteric artery. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s13126-013-0050-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Giaroni C, Marchet S, Carpanese E, Prandoni V, Oldrini R, Bartolini B, Moro E, Vigetti D, Crema F, Lecchini S, Frigo G. Role of neuronal and inducible nitric oxide synthases in the guinea pig ileum myenteric plexus during in vitro ischemia and reperfusion. Neurogastroenterol Motil 2013; 25:e114-26. [PMID: 23279126 DOI: 10.1111/nmo.12061] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intestinal ischemia and reperfusion (I/R) injury leads to abnormalities in motility, namely delay of transit, caused by damage to myenteric neurons. Alterations of the nitrergic transmission may occur in these conditions. This study investigated whether an in vitro I/R injury may affect nitric oxide (NO) production from the myenteric plexus of the guinea pig ileum and which NO synthase (NOS) isoform is involved. METHODS The distribution of the neuronal (n) and inducible (i) NOS was determined by immunohistochemistry during 60 min of glucose/oxygen deprivation (in vitro ischemia) followed by 60 min of reperfusion. The protein and mRNA levels of nNOS and iNOS were investigated by Western-immunoblotting and real time RT-PCR, respectively. NO levels were quantified as nitrite/nitrate. KEY RESULTS After in vitro I/R the proportion of nNOS-expressing neurons and protein levels remained unchanged. nNOS mRNA levels increased 60 min after inducing ischemia and in the following 5 min of reperfusion. iNOS-immunoreactive neurons, protein and mRNA levels were up-regulated during the whole I/R period. A significant increase of nitrite/nitrate levels was observed in the first 5 min after inducing I/R and was significantly reduced by N(ω) -propyl-l-arginine and 1400 W, selective inhibitors of nNOS and iNOS, respectively. CONCLUSIONS & INFERENCES Our data demonstrate that both iNOS and nNOS represent sources for NO overproduction in ileal myenteric plexus during I/R, although iNOS undergoes more consistent changes suggesting a more relevant role for this isoform in the alterations occurring in myenteric neurons following I/R.
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Affiliation(s)
- C Giaroni
- Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
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Shah SK, Jimenez F, Letourneau PA, Walker PA, Moore-Olufemi SD, Stewart RH, Laine GA, Cox CS. Strategies for modulating the inflammatory response after decompression from abdominal compartment syndrome. Scand J Trauma Resusc Emerg Med 2012; 20:25. [PMID: 22472164 PMCID: PMC3352320 DOI: 10.1186/1757-7241-20-25] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 04/03/2012] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Management of the open abdomen is an increasingly common part of surgical practice. The purpose of this review is to examine the scientific background for the use of temporary abdominal closure (TAC) in the open abdomen as a way to modulate the local and systemic inflammatory response, with an emphasis on decompression after abdominal compartment syndrome (ACS). METHODS A review of the relevant English language literature was conducted. Priority was placed on articles published within the last 5 years. RESULTS/CONCLUSION Recent data from our group and others have begun to lay the foundation for the concept of TAC as a method to modulate the local and/or systemic inflammatory response in patients with an open abdomen resulting from ACS.
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Affiliation(s)
- Shinil K Shah
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, USA
- Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, USA
- Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas, USA
| | - Fernando Jimenez
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, USA
| | - Phillip A Letourneau
- Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, USA
| | - Peter A Walker
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, USA
- Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, USA
| | - Stacey D Moore-Olufemi
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, USA
- Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas, USA
| | - Randolph H Stewart
- Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas, USA
| | - Glen A Laine
- Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas, USA
| | - Charles S Cox
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, USA
- Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas, USA
- Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 5.236, Houston, TX 77030, USA
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McGuire MF, Sriram Iyengar M, Mercer DW. Data driven linear algebraic methods for analysis of molecular pathways: application to disease progression in shock/trauma. J Biomed Inform 2012; 45:372-87. [PMID: 22200681 PMCID: PMC3346262 DOI: 10.1016/j.jbi.2011.12.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2011] [Revised: 12/09/2011] [Accepted: 12/10/2011] [Indexed: 12/24/2022]
Abstract
MOTIVATION Although trauma is the leading cause of death for those below 45years of age, there is a dearth of information about the temporal behavior of the underlying biological mechanisms in those who survive the initial trauma only to later suffer from syndromes such as multiple organ failure. Levels of serum cytokines potentially affect the clinical outcomes of trauma; understanding how cytokine levels modulate intra-cellular signaling pathways can yield insights into molecular mechanisms of disease progression and help to identify targeted therapies. However, developing such analyses is challenging since it necessitates the integration and interpretation of large amounts of heterogeneous, quantitative and qualitative data. Here we present the Pathway Semantics Algorithm (PSA), an algebraic process of node and edge analyses of evoked biological pathways over time for in silico discovery of biomedical hypotheses, using data from a prospective controlled clinical study of the role of cytokines in multiple organ failure (MOF) at a major US trauma center. A matrix algebra approach was used in both the PSA node and PSA edge analyses with different matrix configurations and computations based on the biomedical questions to be examined. In the edge analysis, a percentage measure of crosstalk called XTALK was also developed to assess cross-pathway interference. RESULTS In the node/molecular analysis of the first 24h from trauma, PSA uncovered seven molecules evoked computationally that differentiated outcomes of MOF or non-MOF (NMOF), of which three molecules had not been previously associated with any shock/trauma syndrome. In the edge/molecular interaction analysis, PSA examined four categories of functional molecular interaction relationships--activation, expression, inhibition, and transcription--and found that the interaction patterns and crosstalk changed over time and outcome. The PSA edge analysis suggests that a diagnosis, prognosis or therapy based on molecular interaction mechanisms may be most effective within a certain time period and for a specific functional relationship.
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Affiliation(s)
- Mary F McGuire
- Department of Pathology and Laboratory Medicine, Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
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Nakao A, Kaczorowski DJ, Sugimoto R, Billiar TR, McCurry KR. Application of heme oxygenase-1, carbon monoxide and biliverdin for the prevention of intestinal ischemia/reperfusion injury. J Clin Biochem Nutr 2011; 42:78-88. [PMID: 18385824 PMCID: PMC2266059 DOI: 10.3164/jcbn.2008013] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2007] [Accepted: 12/19/2007] [Indexed: 12/31/2022] Open
Abstract
Intestinal ischemia/reperfusion (I/R) injury occurs frequently in a variety of clinical settings, including mesenteric artery occlusion, abdominal aneurism surgery, trauma, shock, and small intestinal transplantation, and is associated with substantial morbidity and mortality. Although the exact mechanisms involved in the pathogenesis of intestinal I/R injury have not been fully elucidated, it is generally believed that polymorphonuclear neutrophils, pro-inflammatory cytokines, and mediators generated in the setting of oxidative stress, such as reactive oxygen species (ROS), play important roles. Heme oxygenase (HO) is the rate-limiting enzyme that catalyzes the degradation of heme into equimolar quantities of biliverdin and carbon monoxide (CO), while the central iron is released. An inducible form of HO (HO-1), biliverdin, and CO, have been shown to possess generalized endogenous anti-inflammatory activities and provide protection against intestinal I/R injury. Further, recent observations have demonstrated that exogenous HO-1 expression, as well as exogenously administered CO and biliverdin, have potent cytoprotective effects on intestinal I/R injury as well. Here, we summarize the currently available data regarding the role of the HO system in the prevention intestinal I/R injury.
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Affiliation(s)
- Atsunori Nakao
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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Nebivolol has Protective Effect Against Endothelial and Ileal Dysfunction due to I/R. J Surg Res 2011; 166:156-61. [DOI: 10.1016/j.jss.2009.06.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Revised: 05/29/2009] [Accepted: 06/16/2009] [Indexed: 11/22/2022]
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Uray KS, Shah SK, Radhakrishnan RS, Jimenez F, Walker PA, Stewart RH, Laine GA, Cox CS. Sodium hydrogen exchanger as a mediator of hydrostatic edema-induced intestinal contractile dysfunction. Surgery 2011; 149:114-25. [PMID: 20553904 DOI: 10.1016/j.surg.2010.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2009] [Accepted: 04/13/2010] [Indexed: 10/19/2022]
Abstract
BACKGROUND Resuscitation-induced intestinal edema is associated with early and profound mechanical changes in intestinal tissue. We hypothesize that the sodium hydrogen exchanger (NHE), a mechanoresponsive ion channel, is a mediator of edema-induced intestinal contractile dysfunction. METHODS An animal model of hydrostatic intestinal edema was used for all experiments. NHE isoforms 1-3 mRNA and protein were evaluated. Subsequently, the effects of NHE inhibition (with 5-(N-ethyl-N-isopropyl) amiloride [EIPA]) on wet-to-dry ratios, signal transduction and activator of transcription (STAT)-3, intestinal smooth muscle myosin light chain (MLC) phosphorylation, intestinal contractile activity, and intestinal transit were measured. RESULTS NHE1-3 mRNA and protein levels were increased significantly in the small intestinal mucosa with the induction of intestinal edema. The administration of EIPA, an NHE inhibitor, attenuated validated markers of intestinal contractile dysfunction induced by edema as measured by decreased STAT-3 activation, increased MLC phosphorylation, improved intestinal contractile activity, and enhanced intestinal transit. CONCLUSION The mechanoresponsive ion channel NHE may mediate edema-induced intestinal contractile dysfunction, possibly via a STAT-3 related mechanism.
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Affiliation(s)
- Karen S Uray
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, TX 77030, USA
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Shah SK, Moore-Olufemi SD, Uray KS, Jimenez F, Walker PA, Xue H, Stewart RH, Laine GA, Cox CS. A murine model for the study of edema induced intestinal contractile dysfunction. Neurogastroenterol Motil 2010; 22:1132-e290. [PMID: 20591104 PMCID: PMC2939955 DOI: 10.1111/j.1365-2982.2010.01546.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND We have published extensively regarding the effects of edema on intestinal contractile function. However, we have found the need to expand our model to mice to take advantage of the much larger arsenal of research support, especially in terms of transgenic mouse availability and development. To that end, we have developed and validated a hydrostatic intestinal edema model in mice. METHODS Male C57 Black 6 mice were subjected to a combination of high volume crystalloid resuscitation and mesenteric venous hypertension in an effort to induce hydrostatic intestinal edema. Wet to dry ratios, myeloperoxidase activity, mucosal injury scoring, STAT-3 nuclear activation, phosphorylated STAT-3 levels, NF-κB nuclear activation, myosin light chain phosphorylation, intestinal contractile activity, and intestinal transit were measured to evaluate the effects of the model. KEY RESULTS High volume crystalloid resuscitation and mesenteric venous hypertension resulted in the development of significant intestinal edema without an increase in myeloperoxidase activity or mucosal injury. Edema development was associated with increases in STAT-3 and NF-κB nuclear activation as well as phosphorylated STAT-3. There was a decrease in myosin light chain phosphorylation, basal and maximally stimulated intestinal contractile activity, and intestinal transit. CONCLUSION & INFERENCES Hydrostatic edema in mice results in activation of a signal transduction profile that culminates in intestinal contractile dysfunction. This novel model allows for advanced studies into the pathogenesis of hydrostatic edema induced intestinal contractile dysfunction.
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Affiliation(s)
- Shinil K. Shah
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas
| | - Stacey D. Moore-Olufemi
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas
| | - Karen S. Uray
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas
| | - Fernando Jimenez
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas
| | - Peter A. Walker
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas
| | - Hasen Xue
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas
| | - Randolph H. Stewart
- Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas
| | - Glen A. Laine
- Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas
| | - Charles S. Cox
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, Texas
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Intestinal ischemic preconditioning after ischemia/reperfusion injury in rat intestine: profiling global gene expression patterns. Dig Dis Sci 2010; 55:1866-77. [PMID: 19779973 DOI: 10.1007/s10620-009-0980-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Accepted: 08/31/2009] [Indexed: 12/09/2022]
Abstract
OBJECTIVE Intestinal ischemia/reperfusion (IR) injury involves activation of inflammatory mediators, mucosal necrosis, ileus, and alteration in a variety of gene products. Ischemic preconditioning (IPC) reduced all the effects of intestinal injury seen in IR. In an effort to investigate the molecular mechanisms responsible for the protective effects afforded by IPC, we sought to characterize the global gene expression pattern in rats subjected to IPC in the setting of IR injury. METHODS Rats were randomized into five groups: (1) Sham, (2) IPC only (3) IR, (4) Early IPC + IR (IPC --> IR), and (5) Late IPC + IR (IPC --> 24 h --> IR). At 6 h after reperfusion, ileum was harvested for total RNA isolation, pooled, and analyzed on complementary DNA (cDNA) microarrays with validation using real-time polymerase chain reaction (PCR). Significance Analysis of Microarray (SAM) software was used to determine statistically significant changes in gene expression. RESULTS Early IPC + IR had 5,167 induced and 4 repressed genes compared with the other groups. SAM analysis revealed 474 out of 10,000 genes differentially expressed among the groups. Early and Late IPC + IR had more genes involved in redox hemostasis, the immune/inflammatory response, and apoptosis than either the IPC only or IR alone groups. CONCLUSION The transcriptional profile suggests that IPC exerts its protective effects by regulating the gene response to injury in the intestine.
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Evaluating the potential role of nitric oxide as a mediator of hydrostatic edema mediated intestinal contractile dysfunction. J Surg Res 2010; 163:102-9. [PMID: 20605598 DOI: 10.1016/j.jss.2010.02.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2009] [Revised: 01/26/2010] [Accepted: 02/22/2010] [Indexed: 01/25/2023]
Abstract
BACKGROUND Administration of L-nil, a selective inhibitor of inducible nitric oxide synthase (iNOS), improves ileus in an animal model of resuscitation induced intestinal edema. The purpose of this study was to elucidate the iNOS/nitric oxide (NO) signal transduction pathway in intestinal edema. MATERIALS AND METHODS Male Sprague Dawley rats were divided into two groups; CONTROL and RESUS+VH (edema, 80 cc/kg normal saline (resuscitation) with mesenteric venous hypertension). iNOS mRNA and protein, iNOS activity, NO tissue levels, soluble guanylyl cyclase (sGC) expression, and cyclic guanosine monophosphate (cGMP) levels were measured. As a functional endpoint, we evaluated intestinal contractile strength and frequency in L-nil treated animals. RESULTS Edema was associated with increased iNOS mRNA and protein expression without subsequent increases in iNOS activity or tissue NO levels. There was no significant change in sGC expression or increase in cGMP induced by edema. Administration of L-nil did not decrease edema development or preserve contractile strength, but increased contractile frequency. CONCLUSION Hydrostatic intestinal edema is not associated with increased iNOS activity or tissue NO levels. Administration of L-nil in edema increases intestinal contractile frequency. This may represent a potential mechanism for the amelioration of ileus seen with the administration of L-nil.
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Yildiz Y, Kose H, Cecen S, Ergin K, Demir EM, Serter M. Protective effects of leflunomide on intestinal ischemia-reperfusion injury: leflunomide against intestinal ischemia-reperfusion. Dig Dis Sci 2010; 55:245-52. [PMID: 19229614 DOI: 10.1007/s10620-009-0737-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2008] [Accepted: 01/16/2009] [Indexed: 12/09/2022]
Abstract
AIM The aim of this study was to investigate the possible protective effects of leflunomide, which has antioxidant and anti-inflammatory properties, against intestinal IR injury in rats. MATERIALS AND METHODS Forty female Wistar albino rats were divided into six groups: control (n = 5), drug control (n = 7), sham operated (n = 7), IR alone (n = 7), IR plus vehicle (IR + vehicle, n = 7) and IR plus 20 mg/kg leflunomide (IR + Leflunomide, n = 7). While rats were pretreated intragastrically with leflunomide (20 mg/kg) and vehicle in three doses prior to the experiment, respectively, in the IR + Leflunomide and IR + vehicle groups, no additional application was done in the IR alone group. Intestines were exteriorized, and the superior mesenteric artery was occluded for 45 min ischemia, and then the clamp was removed for 120 min reperfusion. After the experiment, the intestines were removed for biochemical and histological examinations. Additionally, blood samples were taken for measurements of antioxidant parameters. RESULTS The intestinal IR significantly increased the MDA level and MPO activity; however, treatment with leflunomide reversed those findings (P < 0.05). The CAT activity of the IR + Leflunomide group was significantly higher than in the IR groups (P < 0.05). The SOD activity was increased in the intestinal IR group, and leflunomide treatment reversed that, too (P <0.05). The light microscopic findings showed that IR caused mucosal necrosis and leflunomide treatment reduced the morphological alterations associated with IR (P < 0.05). CONCLUSION Intestinal IR injury may be reversed by the anti-inflammatory and antioxidant actions of leflunomide.
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Affiliation(s)
- Yuksel Yildiz
- Department of Physiology, Faculty of Medicine, Adnan Menderes University, Aydin 09100, Turkey.
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Shah SK, Uray KS, Stewart RH, Laine GA, Cox CS. Resuscitation-induced intestinal edema and related dysfunction: state of the science. J Surg Res 2009; 166:120-30. [PMID: 19959186 DOI: 10.1016/j.jss.2009.09.010] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Revised: 07/24/2009] [Accepted: 09/04/2009] [Indexed: 11/26/2022]
Abstract
High volume resuscitation and damage control surgical methods, while responsible for significantly decreasing morbidity and mortality from traumatic injuries, are associated with pathophysiologic derangements that lead to subsequent end organ edema and dysfunction. Alterations in hydrostatic and oncotic pressures frequently result in intestinal edema and subsequent dysfunction. The purpose of this review is to examine the principles involved in the development of intestinal edema, current and historical models for the study of edema, effects of edema on intestinal function (particularly ileus), molecular mediators governing edema-induced dysfunction, potential role of mechanotransduction , and therapeutic effects of hypertonic saline. We review the current state of the science as it relates to resuscitation induced intestinal edema and resultant dysfunction.
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Affiliation(s)
- Shinil K Shah
- Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, Texas 77030, USA
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Chen H, Sun YP, Hu PF, Liu WW, Xiang HG, Li Y, Yan RL, Su N, Ruan CP, Sun XJ, Wang Q. The effects of hydrogen-rich saline on the contractile and structural changes of intestine induced by ischemia-reperfusion in rats. J Surg Res 2009; 167:316-22. [PMID: 19932899 DOI: 10.1016/j.jss.2009.07.045] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2009] [Revised: 07/09/2009] [Accepted: 07/28/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hydrogen has been considered as a novel antioxidant that prevents injuries resulted from ischemia-reperfusion (I/R) injury in various tissues. The study was designed to determine the effect of hydrogen-rich saline on the smooth muscle contractile response to KCl, and on epithelial proliferation and apoptosis of intestine subjected to I/R. METHODS Intestinal I/R injury was induced in Sprague-Dawley rats using bulldog clamps in superior mesenteric artery by 45 min ischemia followed by 1 h reperfusion. Rats were divided randomly into four groups: sham-operated, I/R, I/R plus saline treatment, and I/R plus hydrogen-rich saline treatment groups. Hydrogen-rich saline (>0.6 mM, 6 mL/kg) or saline (6 mL/kg) was administered, respectively, via tail vein 30 min prior to reperfusion. Following reperfusion, segments of terminal jejunum were rapidly taken and transferred into isolated organ bath and responses to KCl were recorded. Samples of terminal jejunum were also taken for measuring malondialdehyde and myeloperoxidase. Apoptosis in intestinal epithelium was determined with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL). Expression and distribution of proliferating cell nuclear antigen (PCNA) were detected with immunohistochemistry. RESULTS Hydrogen-rich saline treatment significantly attenuated the severity of intestinal I/R injury, with inhibiting of I/R-induced apoptosis, and promoting enterocytes proliferation. Moreover, Hydrogen-rich saline treatment significantly limited the neutrophil infiltration, lipid oxidation, and ameliorated the decreased contractility response to KCl in the intestine subjected to I/R. CONCLUSIONS These results suggest that hydrogen treatment has a protective effect against intestinal contractile dysfunction and damage induced by intestinal I/R. This protective effect is possibly due to its ability to inhibit I/R-induced oxidative stress, apoptosis, and to promote epithelial cell proliferation.
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Affiliation(s)
- Han Chen
- Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai, PR China
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Pretreatment with bone morphogenetic protein-7 (BMP-7) mimics ischemia preconditioning following intestinal ischemia/reperfusion injury in the intestine and liver. Shock 2009; 30:532-6. [PMID: 18461025 DOI: 10.1097/shk.0b013e31816f20f1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Intestinal ischemia/reperfusion (I/R) injury has been shown to cause intestinal mucosal injury and adversely affect function. Ischemic preconditioning (IPC) has been shown to protect against intestinal I/R injury by reducing polymorphonuclear leukocyte infiltration, intestinal mucosal injury, and liver injury, and preserve intestinal transit. Bone morphogenetic protein 7 (BMP-7) has been shown to protect against I/R injury in the kidney and brain. Recently, microarray analysis has been used to examine the possible IPC candidate pathways. This work revealed that IPC may work through upregulation of BMP-7. The purpose of this study was to examine if pretreatment with BMP-7 would replicate the effects seen with IPC in the intestine and liver after intestinal I/R. Rats were randomized to six groups: sham, I/R (30 min of superior mesenteric artery occlusion and 6 h of R), IPC+R (three cycles of superior mesenteric artery occlusion for 4 min and R for 10 min), IPC+I/R, BMP-7+R (100 microm/kg recombinant human BMP-7), or BMP-7+I/R. A duodenal catheter was placed, and 30 min before sacrifice, fluorescein isothiocyanate-Dextran was injected. At sacrifice, dye concentrations were measured to determine intestinal transit. Ileal mucosal injury was determined by histology and myeloperoxidase activity was used as a marker of polymorphonuclear leukocyte infiltration. Serum levels of aspartate aminotransferase were measured at sacrifice to determine liver injury. Pretreatment with BMP-7 significantly improved intestinal transit and significantly decreased intestinal mucosal injury and serum aspartate aminotransferase levels, comparable to animals undergoing IPC. In conclusion, BMP-7 protected against intestinal I/R-induced intestinal and liver injury. Bone morphogenetic protein 7 may be a more logical surrogate to IPC in the prevention of injury in the setting of intestinal I/R.
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Soydan G, Sökmensüer C, Kilinç K, Tuncer M. The effects of sildenafil on the functional and structural changes of ileum induced by intestinal ischemia-reperfusion in rats. Eur J Pharmacol 2009; 610:87-92. [PMID: 19303867 DOI: 10.1016/j.ejphar.2009.03.038] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2008] [Revised: 02/26/2009] [Accepted: 03/10/2009] [Indexed: 10/21/2022]
Abstract
There is evidence demonstrating the protective effect of cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors against ischemic injury in certain tissues. In this study, sildenafil, a potent inhibitor of PDE5, was tested for its beneficial effects in the prevention of disrupted ileal contractility and damage to tissue caused by intestinal ischemia-reperfusion in rats. Male Sprague-Dawley rats were divided into four groups: sham-operated; sham-operated with sildenafil pretreatment; ischemia-reperfusion with vehicle pretreatment; and ischemia-reperfusion with sildenafil pretreatment. The superior mesenteric artery was occluded for 45 min to induce ischemia. The clamp was then removed for a 60 min period of reperfusion. Sildenafil (1 mg/kg, i.v.) or saline was administered prior to the surgical procedure in the ischemia-reperfusion and sham-operated groups. Isometric contractions of the ileal segments in response to acetylcholine or electrical field stimulation (120 V, 2 ms pulse for 5 s, 1-20 Hz) were recorded. Additionally, levels of thiobarbituric acid reactive substances and myeloperoxidase activity were measured in addition to a histopathological examination of the ileal tissue. The contractions induced by both acetylcholine and electrical field stimulations were markedly inhibited after ischemia-reperfusion. Sildenafil pretreatment (1 mg/kg, i.v.) abolished the inhibition of responses to acetylcholine. The increased levels of thiobarbituric acid reactive substances and myeloperoxidase activity caused by ischemia-reperfusion were reversed to control levels with sildenafil pretreatment. Intestinal ischemia-reperfusion caused severe ischemic injury in rat ileum, which was prevented by sildenafil. These results suggest that sildenafil pretreatment has a protective effect against ileal dysfunction and damage induced by intestinal ischemia-reperfusion in the rat.
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Affiliation(s)
- Güray Soydan
- Department of Pharmacology, Hacettepe University, Ankara 06100, Turkey
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Sayan H, Ozacmak VH, Sen F, Cabuk M, Atik DY, Igdem AA, Ozacmak ID. Pharmacological preconditioning with erythropoietin reduces ischemia–reperfusion injury in the small intestine of rats. Life Sci 2009; 84:364-71. [DOI: 10.1016/j.lfs.2008.12.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Revised: 12/05/2008] [Accepted: 12/30/2008] [Indexed: 12/26/2022]
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Apoptosis of interstitial cells of Cajal, smooth muscle cells, and enteric neurons induced by intestinal ischemia and reperfusion injury in adult guinea pigs. Virchows Arch 2009; 454:401-9. [DOI: 10.1007/s00428-009-0739-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2008] [Revised: 01/17/2009] [Accepted: 01/18/2009] [Indexed: 12/11/2022]
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Moore-Olufemi SD, Padalecki J, Olufemi SE, Xue H, Oliver DH, Radhakrishnan RS, Allen SJ, Moore FA, Stewart R, Laine GA, Cox CS. Intestinal edema: effect of enteral feeding on motility and gene expression. J Surg Res 2008; 155:283-92. [PMID: 19482297 DOI: 10.1016/j.jss.2008.08.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2008] [Revised: 07/29/2008] [Accepted: 08/01/2008] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Edema formation, inflammation, and ileus in the intestine are commonly seen in conditions like gastroschisis, inflammatory bowel disease, and cirrhosis. We hypothesized that early enteral feeding would improve intestinal transit. We also wanted to study the impact of early enteral feeding on global gene expression in the intestine. DESIGN Rats were divided into Sham or Edema +/- immediate enteral nutrition (IEN). At 12 h, small intestinal transit via FITC-Dextran and tissue water were measured. Ileum was harvested for total RNA to analyze gene expression using cDNA microarray with validation using real-time PCR. Data are expressed as mean +/- SEM, n = 4-6 and (*), (**) = P < 0.05 versus all groups using ANOVA. RESULTS IEN markedly improved intestinal transit with minimal genetic alterations in Edema animals. Major alterations in gene expression were detected in primary, cellular and macromolecular metabolic activities. Edema also altered more genes involved with the regulation of the actin cytoskeleton. CONCLUSIONS Intestinal edema results in impaired small intestinal transit and globally increased gene expression. Early enteral nutrition improves edema-induced impaired transit and minimizes gene transcriptional activity.
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Affiliation(s)
- Stacey D Moore-Olufemi
- Department of Surgery, University of Texas-Houston Medical School, Houston, Texas 77030, USA
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McQuiggan M, Kozar R, Sailors RM, Ahn C, McKinley B, Moore F. Enteral glutamine during active shock resuscitation is safe and enhances tolerance of enteral feeding. JPEN J Parenter Enteral Nutr 2008; 32:28-35. [PMID: 18165444 DOI: 10.1177/014860710803200128] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Feeding the hemodynamically unstable patient is increasingly practiced, yet few data exist on its safety. Because enteral glutamine is protective to the gut in experimental models of shock and improves clinical outcomes, it may benefit trauma patients undergoing shock resuscitation and improve tolerance if administered early. This pilot study aimed to evaluate gastrointestinal tolerance and safety of enteral feeding with glutamine, beginning during shock resuscitation in severely injured patients. METHODS In a prospective randomized trial, 20 patients were randomly assigned to either an enteral glutamine group (n = 10) or a control group (n = 10). Patients with severe trauma meeting standardized shock resuscitation criteria received enteral glutamine 0.5 g/kg/d during the first 24 hours of resuscitation and 10 days thereafter. Immune-enhancing diet began on postinjury day 1, with a target of 25 kcal/kg/d. Control patients received isonitrogenous whey powder plus immune-enhancing diet. Tolerance (vomiting, nasogastric output, diarrhea, and distention) was assessed throughout the study. RESULTS Glutamine was well tolerated and no adverse events occurred. Treated patients had significantly fewer instances of high nasogastric output (5 vs 23; p = .010), abdominal distention (3 vs 12; p = .021), and total instances of intolerance (8 vs 42; p = .011). Intensive care unit (ICU) and hospital length of stay were comparable. Control patients required supplemental parenteral nutrition (PN) to meet goals at day 7. CONCLUSIONS Enteral glutamine administered during active shock resuscitation and through the early postinjury period is safe and enhances gastrointestinal tolerance. A large clinical trial is warranted to determine if enteral glutamine administered to the hemodynamically unstable patient can reduce infectious morbidity and mortality.
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Affiliation(s)
- Margaret McQuiggan
- Department of Surgery, University of Texas Medical School Houston, Houston, Texas, USA.
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Abstract
OBJECTIVES Studies have shown that nitric oxide (NO) may play a major role in sustaining mucosal integrity; however, NO has been also implicated in the pathogenesis of ischemia/reperfusion (I/R)-related tissue injury. We investigated the effects of L-arginine and NG-nitro L-arginine methyl ester (L-NAME) on the acetylcholine-induced contractile response of ileum and the levels of malondialdehyde (MDA) and reduced glutathione (GSH). Histopathological changes were also evaluated in ileal preparations. MATERIALS AND METHODS Male Wistar Albino rats were subjected to mesenteric ischemia (30 min) followed by reperfusion (3 hours). Four groups were designed: sham-operated control; I/R; I/R and L-arginine pretreatment; and I/R and L-NAME pretreatment. After reperfusion, ileum specimens were collected to determine the parameters mentioned above. RESULTS Following reperfusion, a significant decrease in acetylcholine-induced contractile response, an increase in lipid peroxidation, a decrease in GSH content, and mucosal damage of the ileal preparations were observed. We showed that decreased contractility, increased lipid peroxidation, and reduced GSH content have been reversed by L-arginine but not by L-NAME. Mucosal injury was significantly lowered in the L-arginine group. CONCLUSIONS Treatment with L-arginine exerted a protective effect in intestinal I/R injury, which was mediated in part by regulating MDA and GSH levels, consequently ameliorating impaired contractile response and mucosal injury.
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Matsuura T, Taguchi T, Hayashida M, Ogita K, Takada N, Nishimoto Y, Taguchi S, Uesugi T, Kondo T, Hirose R, Suita S. The influence of rejection on graft motility after intestinal transplantation in swine: the possibility of using this method for the real-time monitoring of acute cellular rejection. J Pediatr Surg 2007; 42:1377-85. [PMID: 17706500 DOI: 10.1016/j.jpedsurg.2007.03.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND We have previously reported that rejected allografts show dysmotility, which can be detected by real-time monitoring in swine. We examined the correlation between the motility and the mucosal histology to detect rejection at an early stage by real-time monitoring. METHODS Intestinal transplantation was performed orthotopically using FK506. The distal segment of the allograft measuring about 20 cm was isolated and exteriorized as "Thiry-Vella" stoma for biopsies. Strain-gage force transducers were attached on a graft for the real-time monitoring of graft motility. The pigs without intestinal transplantation were used as controls (C). The rejection was classified into 4 groups based on the histologic findings: nonrejection, mild rejection, moderate rejection, and severe rejection. Migrating motor complex (MMC) phase 3 was estimated by the following parameters: duration, amplitude, interval, motility index, velocity, and frequency of the propagation. RESULTS In the nonrejection group, all parameters were almost the same as in C group. In contrast, in the moderate rejection and severe rejection groups, most of the parameters were significantly lower than those in the C group. In the mild rejection group, the contractility of the MMC was not significantly altered, but the frequency of the propagation decreased significantly. CONCLUSIONS The graft motility detected by the real-time strain-gage method correlated closely to the grade of mucosal histology. This method is therefore considered to be useful for detecting rejection at an early stage by examining the frequency of MMC propagation.
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Affiliation(s)
- Toshiharu Matsuura
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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Gan HT, Pasricha PJ, Chen JDZ. Blockade of p38 mitogen-activated protein kinase pathway ameliorates delayed intestinal transit in burned rats. Am J Surg 2007; 193:530-7. [PMID: 17368305 DOI: 10.1016/j.amjsurg.2006.05.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2006] [Revised: 05/22/2006] [Accepted: 05/22/2006] [Indexed: 01/15/2023]
Abstract
BACKGROUND Burn injury has been shown to impair intestinal transit. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of proinflammatory mediators such as interleukin (IL)-1beta, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on intestinal transit and to elucidate its possible mechanism. METHODS Burn rats and sham rats were divided into 4 groups: saline, S-methylisothiourea (a selective iNOS inhibitor), nimesulide (a selective COX-2 inhibitor), or SB203580. Intestinal transit was measured using phenol red and assessed using the geometric center. The protein or gene expression of NOS, COX-2, and IL-1beta were measured by real-time reverse-transcription polymerase chain reaction or Western blot analysis. p38 MAPK activity or myeloperoxidase (MPO) activity was determined by using the p38 MAPK assay kit or MPO assay kit. RESULTS Intestinal transit was delayed significantly with burn injury, improved significantly with S-methylisothiourea and nimesulide, but almost completely normalized with SB203580. p38 MAPK activity, MPO activity, iNOS, COX-2, and IL-1beta protein or gene expression increased markedly after burn injury. SB203580 inhibited p38 MAPK and MPO activity, and reduced iNOS, COX-2, and IL-1beta protein or gene expression. CONCLUSIONS Burn-induced delayed intestinal transit is associated with the p38 MAPK pathway. Inhibition of the p38 MAPK pathway ameliorates delayed intestinal transit, at least in part, by inhibiting iNOS, COX-2, and IL-1beta expression. Thus, p38 MAPK could represent a novel target for therapy of gut dysmotility after burn injury.
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Affiliation(s)
- Hua Tian Gan
- Department of Geriatrics Medicine, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, Sichuan 610041, China
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Radhakrishnan RS, Radhakrishnan HR, Xue H, Moore-Olufemi SD, Mathur AB, Weisbrodt NW, Moore FA, Allen SJ, Laine GA, Cox CS. Hypertonic saline reverses stiffness in a Sprague-Dawley rat model of acute intestinal edema, leading to improved intestinal function. Crit Care Med 2007; 35:538-43. [PMID: 17205008 DOI: 10.1097/01.ccm.0000254330.39804.9c] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Acute edema induced by resuscitation and mesenteric venous hypertension impairs intestinal transit and contractility and reduces intestinal stiffness. Pretreatment with hypertonic saline (HS) can prevent these changes. Changes in tissue stiffness have been shown to trigger signaling cascades via stress fiber formation. We proposed that acute intestinal edema leads to a decrease in intestinal transit that may be mediated by changes in stiffness, leading to stress fiber formation and decreased intestinal transit. Furthermore, HS administration will abolish these detrimental effects of edema. RESULTS Intestinal edema causes a significant increase in tissue water and a significant decrease in intestinal transit and stiffness compared with sham. HS reversed these changes to sham levels. In addition, tissue edema led to significant stress fiber formation and decreased numbers of focal contacts. HS preserved tissue stiffness, prevented stress fiber formation, and was associated with improved intestinal function. CONCLUSION HS eliminates intestinal tissue edema formation and improves intestinal transit. In addition, the action of HS may be mediated through its preservation of tissue stiffness, which leads to prevention of signaling via stress fiber formation, leading to preserved intestinal function. Finally, intestinal edema may provide a novel physiologic model for examining stiffness and stress fiber signaling.
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Affiliation(s)
- Ravi S Radhakrishnan
- Department of Surgery, University of Texas-Houston Medical School, Houston, TX, USA
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Ozacmak VH, Sayan H. Pretreatment with adenosine and adenosine A1 receptor agonist protects against intestinal ischemia-reperfusion injury in rat. World J Gastroenterol 2007; 13:538-47. [PMID: 17278219 PMCID: PMC4065975 DOI: 10.3748/wjg.v13.i4.538] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the effects of adenosine and A1 receptor activation on reperfusion-induced small intestinal injury.
METHODS: Rats were randomized into groups with sham operation, ischemia and reperfusion, and systemic treatments with either adenosine or 2-chloro-N6-cyclopentyladenosine, A1 receptor agonist or 8-cyclopentyl-1,3-dipropylxanthine, A1 receptor antagonist, plus adenosine before ischemia. Following reperfusion, contractions of ileum segments in response to KCl, carbachol and substance P were recorded. Tissue myeloperoxidase, malondialdehyde, and reduced glutathione levels were measured.
RESULTS: Ischemia significantly decreased both contraction and reduced glutathione level which were ameliorated by adenosine and agonist administration. Treatment also decreased neutrophil infiltration and membrane lipid peroxidation. Beneficial effects of adenosine were abolished by pretreatment with A1 receptor antagonist.
CONCLUSION: The data suggest that adenosine and A1 receptor stimulation attenuate ischemic intestinal injury via decreasing oxidative stress, lowering neutrophil infiltration, and increasing reduced glutathione content.
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Affiliation(s)
- V Haktan Ozacmak
- Department of Physiology, School of Medicine, Zonguldak Karaelmas University, Kozlu 67600, Zonguldak, Turkey.
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Chen CF, Leu FJ, Chen HI, Wang D, Chou SJ. Ischemia/Reperfusion-Induced Low Reactivity of the Rat Superior Mesenteric Vascular Bed is Associated With Expression of Nitric Oxide Synthases. Transplant Proc 2006; 38:2216-20. [PMID: 16980047 DOI: 10.1016/j.transproceed.2006.07.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
UNLABELLED Our objective was to investigate the mRNA and protein expressions of eNOS and iNOS in the mesenteric vascular bed after ischemia and reperfusion of the rat superior mesenteric artery (SMA) and the role of nitric oxide (NO) in the response of the vascular bed to vasoconstrictors following reperfusion of the SMA. METHODS Real-time polymerase chain reaction and immunohistochemistry were used to monitor the mRNA and protein expression of eNOS and iNOS after I/R challenge to the rat SMA. Ischemia was induced by clamping the SMA for 40 minutes, after which the flow was restored and the vessels were reperfused for 300 minutes. Blood samples were collected for assays of lactic dehydrogenase, tumor necrosis factor (TNF), hydroxyl radical, and NO. After ischemia/reperfusion, the vascular beds were separated for analysis of the expression of eNOS and iNOS. The SMA with its associated intestinal tissue was isolated and perfused in vitro with Tyrode's solution (N = 8) then challenged with phenylephrine. RESULTS Reperfusion of the SMA induced an increase in blood concentrations of lactic dehydrogenase (P < .001; N = 8), hydroxyl radical (P < .05), TNF (P < .001), and NO (P < .05). ENOS and iNOS mRNA expression increased 1.3 +/- 0.1-fold and 19.6 +/- 3.5-fold, respectively when compared to the sham-operated group. Protein expression increased 1.9 +/- 0.4-fold and 12.6 +/- 3.1-fold, respectively, after reperfusion (N = 3) when compared with sham-treated rats. In vitro challenge showed that administration of phenylephrine (10(-8) approximately 10(-4) nmol) produced vasoconstriction in a dose-related manner. Maximum contractile responses to phenylephrine were attenuated in reperfused SMA. Addition of the NOS inhibitor N(G)-nitro-L-arginine (L-NNA, 10(-4) M) resulted in full recovery of the response to phenylephrine. CONCLUSIONS Ischemia/reperfusion of the SMA results in a decrease in vascular reactivity of the mesenteric vessels that is dependent on NOS expression by the intestinal vascular bed.
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Affiliation(s)
- C F Chen
- Division of Gastroenterology, Department of Internal Medicine, Cheng Hsin General Hospital, and School of Health, Ming Chuan University, Taipei, Taiwan
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Gonzalez EA, Kozar RA, Suliburk JW, Weisbrodt NW, Mercer DW, Moore FA. Conventional dose hypertonic saline provides optimal gut protection and limits remote organ injury after gut ischemia reperfusion. ACTA ACUST UNITED AC 2006; 61:66-73; discussion 73-4. [PMID: 16832251 DOI: 10.1097/01.ta.0000224190.65542.e2] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Hypertonic saline (HS) resuscitation prevents neutrophil mediated injury after shock. The optimal dose is not known, but appears as a result of osmotic stress. We hypothesized that a dose dependent effect exists related to increasing tonicity and that the optimal gut protective dose would provide better protection against remote organ injury than large volume isotonic crystalloids. METHODS In experiment 1, rats were assigned to controls (sham/no resuscitation, sham/4 mL/kg 7.5% HS, superior mesenteric artery occlusion [SMAO]/no resuscitation), SMAO/equal volume (4 mL/kg 0.9% NS, 4 mL/kg 2.5% HS, 4 mL/kg 5% HS, 4 mL/kg 7.5% HS and 4 mL/kg 10% HS) or SMAO/equal sodium (33 mL/kg 0.9% NS, 12 mL/kg 2.5% HS, 6 mL/kg 5% HS, 4 mL/kg 7.5% HS, and 3 mL/kg 10% HS). In experiment 2, rats were assigned to the same control groups, and to either SMAO/NS (33 mL/kg 0.9% NS, equal salt load) or SMAO/HS (4 mL/kg 7.5% HS). The SMAO was clamped for 60 minutes and boluses given 5 minutes before clamp removal. After 6 hours of reperfusion, ileum and lungs were harvested for analysis of histologic injury, myeloperoxidase (MPO) as an index of neutrophil mediated injury, and serum ALT and AST drawn as markers of liver injury. RESULTS In experiment 1, equal volume and equal sodium decreased injury and inflammation with increasing tonicity in a dose dependent fashion, with the optimal effect seen at 7.5%. In experiment 2, NS resuscitation resulted in minimal improvement of SMAO-induced lung injury and inflammation or increases in serum ALT and AST whereas HS resuscitation significantly decreased these parameters. CONCLUSION The protective effect of HS is related to increased tonicity. While NS had little effect on SMAO-induced remote organ injury, optimal dose HS resuscitation was quite protective. This supports the growing evidence that HS protection may be because of its gut protective effects.
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Affiliation(s)
- Ernest A Gonzalez
- Department of Surgery, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
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Ozturk H, Ozturk H, Duran H, Uzunlar AK. Mibefradil, a T-type Ca2+ channel blocker, protects against mesenteric ischemia-reperfusion-induced oxidative injury and histologic alterations in intestinal mucosa in rats. Dig Dis Sci 2006; 51:1454-60. [PMID: 16868826 DOI: 10.1007/s10620-005-9060-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2005] [Accepted: 09/22/2005] [Indexed: 02/08/2023]
Abstract
The purpose of the present study was to investigate whether mibefradil can reduce oxidative stress and histologic damage in the rat small bowel subjected to mesenteric ischemia and reperfusion injury. Thirty Sprague-Dawley rats weighing between 210 and 220 g were divided into three groups, each containing 10 rats: group 1, sham operation; group 2, untreated ischemia-reperfusion; and group 3, ischemia-reperfusion plus mibefradil treatment group. Intestinal ischemia for 45 min and reperfusion for 60 min were applied. Ileal specimens were obtained to determine the tissue levels of MDA, CAT, SOD, and GSH-Px and histologic changes. In group 2, MDA values were significantly increased compared to those in groups 1 and 3. In addition, SOD, CAT, and GSH-Px values decreased significantly in group 2 compared to groups 1 and 3. The intestinal injury score increased significantly in group 2 and 3 rats compared to group 1 rats. However, this increase was reduced in group 3 rats compared to group 2. Histopathologically, the rats in group 1 had essentially normal testicular architecture. In group 2 rats, the lesions varied between grade 3 and grade 5. In contrast, most of the specimens in the mibefradil-treated group 3 showed grade 1 injury. Mibefradil plays a role in attenuating reperfusion injury of the small intestine by depressing free radical production and mucosal injury score and regulating postischemic intestinal perfusion while restoring intestinal microcirculatory blood flow and encountered histologic injury.
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Affiliation(s)
- Hayrettin Ozturk
- Department of Pediatric Surgery, Dicle University, Medical School, 21280 Diyarbakir, Turkey.
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Shimojima N, Nakaki T, Morikawa Y, Hoshino K, Ozaki H, Hori M, Kitajima M. Interstitial cells of Cajal in dysmotility in intestinal ischemia and reperfusion injury in rats. J Surg Res 2006; 135:255-61. [PMID: 16872634 DOI: 10.1016/j.jss.2006.04.022] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2005] [Revised: 03/29/2006] [Accepted: 04/24/2006] [Indexed: 01/07/2023]
Abstract
BACKGROUND Intestinal ischemia and reperfusion (I/R) injury is an obligatory occurrence in small bowel transplantation. I/R may impair the normal gastrointestinal motility. Interstitial cells of Cajal (ICC) are known as pacemaker cells in the gastrointestinal tract. The aim of this study was to assess the role of ICC in the gastrointestinal motility in a rat model of I/R injury. MATERIALS AND METHODS Wistar rats were subjected to 30- or 80-min intestinal ischemia by occluding the mesenteric vessels followed by reperfusion. Small intestinal segments were resected at 12 h or 4 days. The spontaneous mechanical activity was evaluated by organ bath technique. Immunopositivity of c-Kit and PGP9.5 at the level of the myenteric plexus was evaluated as markers of ICC and enteric nerves, respectively. RESULTS In the bowel segment with 80-min ischemia followed by 12-h reperfusion, muscles showed a 25% reduction (P < 0.05) in the frequency of contractions compared to that with 30-min ischemia followed by 12-h reperfusion, whereas amplitude of contractions was not significantly different. This change was associated with a 70% decrease (P < 0.01) of c-Kit immunopositivity. These changes of intestinal motility pattern and distribution of c-Kit-positive cells were both recovered from 80-min ischemia followed by 4 days reperfusion. In contrast, the immunopositivity of PGP9.5 was not affected in any I/R injury group. CONCLUSIONS Transient functional changes in ICC were induced by prolonged I/R injury but they recovered after 4 days, suggesting a central role of ICC in both disrupting and restoring the normal gastrointestinal motility in I/R injury.
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Affiliation(s)
- Naoki Shimojima
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
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Radhakrishnan RS, Xue H, Moore-Olufemi SD, Weisbrodt NW, Moore FA, Allen SJ, Laine GA, Cox CS. Hypertonic saline resuscitation prevents hydrostatically induced intestinal edema and ileus. Crit Care Med 2006; 34:1713-8. [PMID: 16625118 DOI: 10.1097/01.ccm.0000218811.39686.3d] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE We have shown that acute edema induced by mesenteric venous hypertension (MV-HTN) impairs intestinal transit and reduces the standardized engineering measures of intestinal stiffness (elastic modulus) and residual stress (opening angle). We hypothesized that hypertonic saline (7.5%) would reverse these detrimental effects of acute edema. DESIGN Laboratory study. SETTING University laboratory. SUBJECTS Male Sprague Dawley rats (270-330 g). INTERVENTIONS Rats were randomized to five groups: sham, MV-HTN alone, MV-HTN with 4 mL/kg normal saline resuscitation (equal volume), MV-HTN with 33 mL/kg normal saline resuscitation (equal salt), and MV-HTN with 4 mL/kg hypertonic saline. Intestinal edema was measured by wet to dry tissue weight ratio. A duodenal catheter was placed and, 30 mins before death, fluorescein isothiocyanate Dextran was injected. At death, dye concentrations were measured to determine intestinal transit. Segments of distal ileum were hung to a fixed point in a tissue bath and to a force displacement transducer and stretched in increments of 1 mm; we recorded the new length and the corresponding force from the force displacement transducer to determine elastic modulus. Next, two transverse cuts were made yielding a 1- to 2-mm thick ring-shaped segment of tissue which was then cut radially to open the ring. Then the opening angle was measured. MEASUREMENTS AND MAIN RESULTS MV-HTN, MV-HTN with 4 mL/kg normal saline, and MV-HTN with 33 mL/kg normal saline caused a significant increase in tissue edema and a significant decrease in intestinal transit, stiffness, and residual stress compared with sham. Hypertonic saline significantly lessened the effect of edema on intestinal transit and prevented the changes in stiffness and residual stress. CONCLUSIONS Hypertonic saline prevented intestinal tissue edema. In addition, hypertonic saline improved intestinal transit, possibly through more efficient transmission of muscle force through stiffer intestinal tissue.
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Affiliation(s)
- Ravi S Radhakrishnan
- Department of Surgery, University of Texas-Houston Medical School, Houston, TX, USA
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Rodriguez R, Ventura-Martinez R, Santiago-Mejia J, Avila-Costa MR, Fortoul TI. Altered responsiveness of the guinea-pig isolated ileum to smooth muscle stimulants and to electrical stimulation after in situ ischemia. Br J Pharmacol 2006; 147:371-8. [PMID: 16341232 PMCID: PMC1616997 DOI: 10.1038/sj.bjp.0706618] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
1. We evaluated changes in contractility of the guinea-pig isolated ileum, using intact segments and myenteric plexus-longitudinal muscle (MPLM) preparations, after several times (5-160 min) of ischemia in situ. 2. Intestinal ischemia was produced by clamping the superior mesenteric artery. Ischemic and nonischemic segments, obtained from the same guinea-pig, were mounted in organ baths containing Krebs-bicarbonate (K-B) solution, maintained at 37 degrees C and gassed with 95% O2/5% CO2. The preparations were allowed to equilibrate for 60 min under continuous superfusion of warm K-B solution and then electrically stimulated at 40 V (0.3 Hz, 3.0 ms). Thereafter, complete noncumulative concentration-response curves were constructed for acetylcholine (ACh), histamine (HIS), potassium chloride (KCl), and barium chloride (BaCl2). Mean Emax (maximal response) values were calculated for each drug. 3. Our study shows that alterations of chemically and electrically evoked contractions are dependent on ischemic periods. It also demonstrates that contractile responses of ischemic tissues to neurogenic stimulation decreases earlier and to a significantly greater extent than the non-nerve mediated responses of the intestinal smooth muscle. Contractile responses to smooth muscle stimulants were all similarly affected by ischemia. Electron microscopy images indicated necrotic neuronal death. The decrease in reactivity of ischemic tissues to electrical stimulation was ameliorated by dexrazoxane, an antioxidant agent. 4. We consider the guinea-pig isolated ileum as a useful model system to study the processes involved in neuronal ischemia, and we propose that the reduction in maximal responses to electrical stimulation is a useful parameter to study neuroprotection.
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Affiliation(s)
- Rodolfo Rodriguez
- Department of Pharmacology, School of Medicine, National University of Mexico, Mexico City C.P. 04510, Mexico.
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Sato N, Moore FA, Kone BC, Zou L, Smith MA, Childs MA, Moore-Olufemi S, Schultz SG, Kozar RA. Differential induction of PPAR-gamma by luminal glutamine and iNOS by luminal arginine in the rodent postischemic small bowel. Am J Physiol Gastrointest Liver Physiol 2006; 290:G616-23. [PMID: 16257923 DOI: 10.1152/ajpgi.00248.2005] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Using a rodent model of gut ischemia-reperfusion (I/R), we have previously shown that the induction of inducible nitric oxide synthase (iNOS) is harmful, whereas the induction of heme oxygenase 1 (HO-1) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is protective. In the present study, we hypothesized that the luminal nutrients arginine and glutamine differentially modulate these molecular events in the postischemic gut. Jejunal sacs were created in rats at laparotomy, filled with either 60 mM glutamine, arginine, or magnesium sulfate (osmotic control) followed by 60 min of superior mesenteric artery occlusion and 6 h of reperfusion, and compared with shams. The jejunum was harvested for histology or myeloperoxidase (MPO) activity (inflammation). Heat shock proteins and iNOS were quantitated by Western blot analysis and PPAR-gamma by DNA binding activity. In some experiments, rats were pretreated with the PPAR-gamma inhibitor G9662 or with the iNOS inhibitor N-[3(aminomethyl)benzyl]acetamidine (1400W). iNOS was significantly increased by arginine but not by glutamine following gut I/R and was associated with increased MPO activity and mucosal injury. On the other hand, PPAR-gamma was significantly increased by glutamine but decreased by arginine, whereas heat shock proteins were similarly increased in all experimental groups. The PPAR-gamma inhibitor G9662 abrogated the protective effects of glutamine, whereas the iNOS inhibitor 1400W attenuated the injurious effects of arginine. We concluded that luminal arginine and glutamine differentially modulate the molecular events that regulate injurious I/R-mediated gut inflammation and injury. The induction of PPAR-gamma by luminal glutamine is a novel protective mechanism, whereas luminal arginine appears harmful to the postischemic gut due to enhanced expression of iNOS.
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Affiliation(s)
- N Sato
- Department of Surgery, Houston School of Medicine, University of Texas, 77030, USA
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Sato N, Kozar RA, Zou L, Weatherall JM, Attuwaybi B, Moore-Olufemi SD, Weisbrodt NW, Moore FA. Peroxisome proliferator-activated receptor gamma mediates protection against cyclooxygenase-2-induced gut dysfunction in a rodent model of mesenteric ischemia/reperfusion. Shock 2006; 24:462-9. [PMID: 16247333 DOI: 10.1097/01.shk.0000183483.76972.ae] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Cyclooxygenase (COX)-2 has been identified as an important mediator elaborated during ischemia/reperfusion, with pro- and anti-inflammatory properties having been reported. As the role of COX-2 in the small intestine remains unclear, we hypothesized that COX-2 expression would mediate mesenteric ischemia/reperfusion-induced gut injury, inflammation, and impaired transit and that these deleterious effects could be reversed by the selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphanamide (NS-398). Additionally, we sought to determine the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in mediating protection by NS-398 in this model. Rats underwent sham surgery or were pretreated with NS-398 (3, 10, or 30 mg/kg) intraperitoneally 1 h before 60 min of superior mesenteric artery occlusion and 30 min to 6 h of reperfusion. In some experiments, NS-398 (30 mg/kg) was administered postischemia. Ileum was harvested for COX-2 mRNA and protein, PGE2, myeloperoxidase (inflammation), histology (injury), intestinal transit and PPARgamma protein expression, and DNA-binding activity. COX-2 expression and PGE2 production increased after mesenteric ischemia/reperfusion and were associated with gut inflammation, injury, and impaired transit. Inhibition of COX-2 by NS-398 (30 mg/kg, but not 3 or 10 mg/kg) not only reversed the deleterious effects of COX-2, but additionally induced expression and nuclear translocation of PPARgamma. NS-398 given postischemia was equally protective. In conclusion, COX-2 may function as a proinflammatory mediator in a rodent model of mesenteric ischemia/reperfusion. Reversal of gut inflammation, injury, and impaired transit by high-dose NS-398 is associated with PPAR activation, suggesting a potential role for PPAR-gamma in shock-induced gut protection.
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Affiliation(s)
- Norio Sato
- Department of Surgery, The University of Texas Medical School, Houston, Texas 77030, USA
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Calcina F, Barocelli E, Bertoni S, Furukawa O, Kaunitz J, Impicciatore M, Sternini C. Effect of N-methyl-d-aspartate receptor blockade on neuronal plasticity and gastrointestinal transit delay induced by ischemia/reperfusion in rats. Neuroscience 2005; 134:39-49. [PMID: 15939544 DOI: 10.1016/j.neuroscience.2005.03.052] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2004] [Revised: 03/01/2005] [Accepted: 03/25/2005] [Indexed: 10/25/2022]
Abstract
Intestinal ischemia impairs gastrointestinal motility. The aims of this study were to investigate the effect of intestinal ischemia on gastrointestinal transit and on the expression of enteric transmitters in the rat, and whether the glutamate N-methyl-d-aspartate receptors influence these effects. Ischemia (1 h), induced by occluding the superior mesenteric artery, was followed by 0 or 24 h of reperfusion. Normal and sham-operated rats served as controls. Serosal blood flow was measured with laser Doppler flow meter. Gastrointestinal transit was measured as time of appearance of a marker in fecal pellets. Immunohistochemistry was used to evaluate the number of neurons immunoreactive for neuronal nitric oxide synthase (NOS) or vasoactive intestinal polypeptide and the density of substance P immunoreactive fibers in the myenteric plexus. The N-methyl-d-aspartate receptors antagonist, (+)-5-methyl-10,11-dihydro-5HT-[a,b] cyclohepten-5,10-imine (MK-801) (1 mg/kg i.v.) or the NOS inhibitor, N-nitro-l-arginine (10 mg/kg i.v.) was administered prior to ischemia. Serosal blood flow was decreased by 70% during ischemia, but it was not altered in sham-operated rats. Gastrointestinal transit was significantly prolonged in ischemic/reperfused rats compared with controls. There was a significant increase in the number of vasoactive intestinal polypeptide and neuronal nitric oxide synthase immunoreactive neurons, and a marked decrease of substance P immunoreactive fibers in ischemia followed by 24 h of reperfusion animals compared with controls. These alterations were not observed in ischemia without reperfusion. A significant delay of gastrointestinal transit and increase of vasoactive intestinal polypeptide neurons were also observed in sham-operated rats. The changes in transmitter expression and gastrointestinal transit in ischemic/reperfused rats were prevented by pre-treatment with the NOS inhibitor, N-nitro-l-arginine or the N-methyl-d-aspartate receptors antagonist, MK-801. This study suggests an involvement of the glutamatergic system and its interaction with nitric oxide in intestinal ischemia/reperfusion. Ischemia/reperfusion might induce local release of glutamate that activates N-methyl-d-aspartate receptors leading to increased production of nitric oxide and adaptive changes in enteric transmitters that might contribute to gastrointestinal dysmotility.
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Affiliation(s)
- F Calcina
- CURE Digestive Diseases Research Center, Division of Digestive Diseases, Building 115, Room 224, Veterans Administration Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
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Little D, Tomlinson JE, Blikslager AT. Post operative neutrophilic inflammation in equine small intestine after manipulation and ischaemia. Equine Vet J 2005; 37:329-35. [PMID: 16028622 DOI: 10.2746/0425164054529472] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
REASONS FOR PERFORMING STUDY Post operative ileus (POI) remains an important cause of post operative morbidity and mortality in the horse. However, clinical progression of naturally occurring cases of POI in both horse and man does not entirely support the 'neurogenic' hypothesis as the sole mechanism of POI; and the hypothesis that inflammation plays a major role at 12-24 h after surgery requires validation. HYPOTHESIS An inflammatory infiltrate in the muscularis externa and myenteric plexus of equine jejunum is present 18 h following a period of ischaemia. METHODS Samples of normal jejunum, jejunum from the proximal resection margins of clinical cases and jejunum obtained 18 h after 1 or 2 h ischaemia or manipulation alone were evaluated for neutrophil infiltration. Samples obtained 18 h after surgery were additionally evaluated for leucocyte activation using calprotectin immunohistochemistry. Results were evaluated by ANOVA and P < 0.05 was considered significant. RESULTS Significant neutrophilic inflammation was identified in the samples from the proximal resection margins of clinical cases compared to uninjured jejunum. In experimental cases, neutrophilic inflammation appeared to be increased further by 18 h and was identified through all intestinal layers, particularly in the serosa, fascial planes around circular and longitudinal muscle fibres, and myenteric plexus. This elevated level of neutrophilic inflammation was mirrored by an increased number of calprotectin-positive cells in these intestinal layers, indicating leucocyte activation. CONCLUSIONS Significant neutrophilic inflammation occurs in equine jejunal myenteric layers 18 h after surgery. POTENTIAL RELEVANCE This neutrophilic inflammation coincides with the clinical time point at which POI is identified and may indicate that inflammatory pathways, rather than solely neurogenic pathways, are responsible for POI in the horse.
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Affiliation(s)
- D Little
- Colic and Digestive Disease Program, Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough Street, Raleigh, North Carolina 27606, USA
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Ryan CA, Sanchez LC. Nondiarrheal Disorders of the Gastrointestinal Tract in Neonatal Foals. Vet Clin North Am Equine Pract 2005; 21:313-32, vi. [PMID: 16051052 DOI: 10.1016/j.cveq.2005.04.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Neonates can have a variety of gastrointestinal disorders, primary and secondary in nature. Important primary disorders include con-genital abnormalities and meconium retention. One of the most important secondary lesions is generalized ileus. Gastric ulceration can occur as a primary or secondary event. This article addresses the pathophysiology, diagnosis, and treatment of gastrointestinal problems commonly observed in neonatal foals.
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Affiliation(s)
- Clare A Ryan
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, 2015 SW 16th Avenue, Box 100136, Gainesville, Florida 32610-0136, USA
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