Pathogenesis Of Postoperative Ileus Research Articles

Large Peritoneal Macrophages Play No Role in the Pathogenesis of Postoperative Ileus Induced by Intestinal Manipulation.

Postoperative ileus (POI) is an iatrogenic disorder marked by temporary impaired gastrointestinal (GI) motility post-abdominal surgery. Surgical handling of the intestine activates resident macrophages (Mfs), leading to inflammatory cytokine release and leukocyte recruitment into the muscularis, which compromises intestinal contractility. The mechanisms behind this activation are unclear. Recent studies suggest peritoneal Mfs, particularly large peritoneal macrophages (LPMs), might play a role in sterile intestinal inflammation by rapidly recruiting to the serosal layer of the gut and aiding in tissue damage resolution. To identify immune cells involved in the early phase of POI, single-cell RNA sequencing (scRNA-seq) was conducted. The migration of LPMs post-surgery was studied using adoptive transfer techniques. LPMs were depleted via intraperitoneal injection of clodronate liposomes. Subsequently, flow cytometry, quantitative PCR (qPCR), and immunofluorescence were performed to assess the impact of LPM depletion and analyze cell populations and inflammatory effects. (1) Intestinal manipulation (IM) leads to the accumulation of monocytes, neutrophils, mature Mfs, CD8+ T cells, and LPMs within 2 h post-surgery. (2) Heparin treatment does not affect gut transit or reduce IL-6, IL-1a, and IL-1b expression in the early phase of POI. (3) Depletion of LPMs via clodronate liposome does not prevent monocyte, neutrophil, and Mfs infiltration in the muscularis externa, nor does it improve gut transit or reduce cytokine expression. (4) LPMs migrate to the serosa after IM but do not enter the muscularis externa. LPMs adhere to the intestinal serosa following intestinal manipulation but do not migrate into the intestinal muscularis or participate in the inflammatory response and delayed transit. Consequently, LPMs are not involved in the pathogenesis of POI.

Molecular and cellular mechanisms underlying postoperative paralytic ileus by various immune cell types.

Postoperative ileus (POI) is a well-known complication following gut manipulation or surgical trauma, leading to an impaired gut motility and prolonged postoperative recovery time. Few current therapeutic strategies can prevent POI, and this disorder remains to be a major clinical challenge for patients undergoing surgery. Comprehensive understanding of cellular and molecular mechanisms related to the pathogenesis of POI stimulates the discovery of more promising targets for treatment. POI is closely associated with a series of inflammatory events within the bowel wall, and as key components of inflammatory mechanisms, different types of immune cells, including macrophages, dendritic cells, and T lymphocytes, play significant roles during the development of POI. A variety of immune cells are recruited into the manipulation sites after surgery, contributing to early inflammatory events or impaired gut motility. Our review intends to summarize the specific relationship between different immune cells and POI, mainly focusing on the relevant mechanisms underlying this disorder.

Prevention and Management of Postoperative Ileus: A Review of Current Practice.

Postoperative ileus (POI) has long been a challenging clinical problem for both patients and healthcare physicians alike. Although a standardized definition does not exist, it generally includes symptoms of intolerance to diet, lack of passing stool, abdominal distension, or flatus. Not only does prolonged POI increase patient discomfort and morbidity, but it is possibly the single most important factor that results in prolongation of the length of hospital stay with a significant deleterious effect on healthcare costs in surgical patients. Determining the exact pathogenesis of POI is difficult to achieve; however, it can be conceptually divided into patient-related and operative factors, which can further be broadly classified as neurogenic, inflammatory, hormonal, and pharmacological mechanisms.Different strategies have been introduced aimed at improving the quality of perioperative care by reducing perioperative morbidity and length of stay, which include Enhanced Recovery After Surgery (ERAS) protocols, minimally invasive surgical approaches, and the use of specific pharmaceutical therapies. Recent studies have shown that the ERAS pathway and laparoscopic approach are generally effective in reducing patient morbidity with early return of gut function. Out of many studies on pharmacological agents over the recent years, alvimopan has shown the most promising results. However, due to its potential complications and cost, its clinical use is limited. Therefore, this article aimed to review the pathophysiology of POI and explore recent advances in treatment modalities and prevention of postoperative ileus.

Treatment with the 5-Lipoxygenase Antagonist Zileuton Protects Mice from Postoperative Ileus

Introduction: Previous work of our group showed that lipoxygenase (LOX) pathways become activated upon surgical manipulation of the bowel wall and revealed a beneficial immune modulating role of the LOX-derived anti-inflammatory mediator protectin DX in postoperative ileus (POI). While we found a particular role of 12/15-LOX in the anti-inflammatory LOX action during POI, the role of 5-LOX, which produces the pro-inflammatory leukotriene B4 (LTB4), remained unknown. The purpose of this study was to investigate the role of 5-LOX within the pathogenesis of POI in a mouse model. Methods: POI was induced by intestinal manipulation (IM) of the small bowel in C57BL/6, 5-LOX−/−, and CX3CR1GFP/+. Mice were either treated with a vehicle or with the synthetic 5-LOX antagonist zileuton or were left untreated. Cellular localization of 5-LOX and LTB4 release were visualized by immunofluorescence or ELISA, respectively. POI severity was quantified by gastrointestinal transit (GIT) and leukocyte extravasation into the muscularis externa (ME) by immunohistochemistry. Results: 5-LOX expression was detected 24 h after IM within infiltrating leukocytes in the ME. LTB4 levels increased during POI in wild type but not in 5-LOX−/− after IM. POI was ameliorated in 5-LOX−/− as shown by decreased leukocyte numbers and normalized GIT. Zileuton normalized the postoperative GIT and reduced the numbers of infiltrating leukocytes into the ME. Discussion/Conclusion: Our data demonstrate that 5-LOX and its metabolite LTB4 play a crucial role in POI. Genetic deficiency of 5-LOX and pharmacological antagonism by zileuton protected mice from POI. 5-LOX antagonism might be a promising target for prevention of POI in surgical patients.

Altered Intestinal Permeability and Drug Repositioning in a Post-operative Ileus Guinea Pig Model.

Background/AimsThe aim of this study is to identify the alteration in intestinal permeability with regard to the development of post-operative ileus (POI). Moreover, we investigated drug repositioning in the treatment of POI.MethodsAn experimental POI model was developed using guinea pigs. To measure intestinal permeability, harvested intestinal membranes of the ileum and proximal colon was used in an Ussing chamber. To identify the mechanisms associated with altered permeability, we measured leukocyte count and expression of calprotectin, claudin-1, claudin-2, and mast cell tryptase. We compared control, POI, and drug groups (mosapride [0.3 mg/kg and 1 mg/kg, orally], glutamine [500 mg/kg, orally], or ketotifen [1 mg/kg, orally] with regard to these parameters.ResultsIncreased permeability after surgery significantly decreased after administration of mosapride, glutamine, or ketotifen. Leukocyte counts increased in the POI group and decreased significantly after administration of mosapride (0.3 mg/kg) in the ileum, and mosapride (0.3 mg/kg and 1 mg/kg), glutamine, or ketotifen in the proximal colon. Increased expression of calprotectin after surgery decreased after administration of mosapride (0.3 mg/kg), glutamine, or ketotifen in the ileum and proximal colon, and mosapride (1 mg/kg) in the ileum. The expression of claudin-1 decreased significantly and that of claudin-2 increased after operation. After administration of glutamine, the expression of both proteins was restored. Finally, mast cell tryptase levels increased in the POI group and decreased significantly after administration of ketotifen.ConclusionsThe alteration in intestinal permeability is one of the factors involved in the pathogenesis of POI. We repositioned 3 drugs (mosapride, glutamine, and ketotifen) as novel therapeutic agents for POI.

Postoperative Ileus: Comparative Pathophysiology and Future Therapies.

Postoperative ileus (POI), a decrease in gastrointestinal motility after surgery, is an important problem facing human and veterinary patients. 37.5% of horses that develop POI following small intestinal (SI) resection will not survive to discharge. The two major components of POI pathophysiology are a neurogenic phase which is then propagated by an inflammatory phase. Perioperative care has been implicated, namely the use of opioid therapy, inappropriate fluid therapy and electrolyte imbalances. Current therapy for POI variably includes an early return to feeding to induce physiological motility, reducing the inflammatory response with agents such as non-steroidal anti-inflammatory drugs (NSAIDs), and use of prokinetic therapy such as lidocaine. However, optimal management of POI remains controversial. Further understanding of the roles of the gastrointestinal microbiota, intestinal barrier function, the post-surgical inflammatory response, as well as enteric glial cells, a component of the enteric nervous system, in modulating postoperative gastrointestinal motility and the pathogenesis of POI may provide future targets for prevention and/or therapy of POI.

Men and Those With a History of Smoking Are Associated With the Development of Postoperative Ileus Following Elective Colorectal Cancer Resection at a Private Academic Hospital in Johannesburg, South Africa: A Retrospective Cohort Study.

Introduction: A scarcity of local published data on colorectal cancer (CRC) postoperative complications, including postoperative ileus (POI), exists. POI is a temporary gastrointestinal (GI) state of absent or reduced gastric motility shown to increase patient morbidity, prolong length-of-stay (LOS), and intensify the healthcare resource burden. The pathogenesis of POI involves a neurogenic and inflammatory phase plus a pharmacological component.Aim and Objectives: This study aimed to determine centre-specific preoperative risk factors associated with the development of ileus post elective therapeutic CRC resection. The objectives were to determine whether patient demographics; functional status; comorbidities; GI history; pharmacotherapy (including neoadjuvant chemotherapy); and lastly neoadjuvant radiation and chemoradiation were associated with the development of POI.Method: Patients who underwent CRC resection between January 2016 and May 2019 were retrospectively identified from an existing database. Urgent—or non-therapeutic surgeries; surgeries with the complication anastomotic leak or GI obstruction; patients under 18 at the time of surgery or surgeries preceded by preoperative parenteral nutrition were excluded. A comparison was done of the incidence of exposure in the study cohort to investigated variables as potential risk factors for the complication POI.Results: A total of 155 patient cases were included, and 56 (36%) of them developed POI. Univariate comparison of patients who developed POI with demographic characteristics of patients who did not suggested that women were at lower risk to develop POI compared to men (p = 0,013; RR 0,56; 95% CI 0,36–0,89). Functional status suggested that all previous smokers were at a higher risk to develop POI compared to lifetime non-smokers (p = 0,0069; RR 1,78; 95% CI 1,17–2,70). Multivariable comparison of ≤ 5 qualifying parameters showed no significance.Conclusion: The high local incidence of POI in this patient population shows that intervention is required to reduce the POI rate and improve postoperative outcomes. This study suggests that for men and all patients with a history of smoking both, CRC resection preoperative recommendations with the intention to prevent POI should include instructions initiating the activation of preventive strategies like the Enhanced Recovery After Surgery (ERAS) programme. More studies are needed to adequately determine local perioperative risk factors for POI.

Goal-directed Therapy and Postcystectomy Ileus: Comment.

We read the article by Arslan-Carlon et al.1 with great interest. The authors are to be congratulated for their research on the impact of fluid therapy on postoperative ileus. In this recent randomized, controlled trial including 283 patients, they found no difference in the incidence of postoperative ileus between patients treated with a goal-directed therapy compared with a standard procedure in a homogenous open radical cystectomy patient cohort from a high caseload center.The pathogenesis of postoperative ileus is clearly multifactorial (fluid overload, opioids, neurohormonal dysregulation, gastrointestinal stretch, inflammatory response).2,3 In the era of enhanced recovery protocols including multiple preoperative, intraoperative, and postoperative optimization steps, it is not surprising to find that intraoperative goal-directed therapy alone has no impact on the return of bowel function compared with a moderate liberal fluid standard fluid administration. Furthermore, it remains questionable whether postoperative fluid substitution should be uniformly managed in patients who received either an intraoperative goal-directed therapy or a restrictive or relatively liberal fluid administration. Indeed, in this study net fluid during the hospitalization was higher in the standard group (−1,986 ml vs. −1,296 ml) but resulted in similar maximum body weight changes (2.7 kg vs. 3.0 kg) and could be interpreted as the consequence of a more aggressive diuretic therapy in the standard group postoperatively. This is of importance because postoperative submucosal edema has been postulated as a risk factor for a delayed return of gastrointestinal function.3 Unfortunately, the authors did not give any information on the postoperative administration of diuretics.The problem of adequate terminology is another ongoing issue. We were surprised by the authors’ comment in the discussion that the term constipation was not adequately described in the article by Wuethrich et al., as both the term constipation as well as the term ileus were defined in the appendix. Constipation was defined as no passage of stool without signs of ileus by postoperative day 5 and could be considered similar to what was considered a primary postoperative ileus in the article by Arslan-Carlon et al. This definition was based on the nomenclature resulting from a well-performed case series analysis aiming to standardize complications after cystectomy from the Department of Urology at the Sloan-Kettering Cancer Center (New York, New York).5 Perhaps the authors could specify why they did not apply their own above-mentioned definition in the present study. We recognize that the publication by Shabsigh et al. is more than 10 yr old, but the goal of a good standardized reporting methodology should be its continued long-term applicability. The Clavien Dindo classification remains the best example hereof.4,6 In the context of prevention of postoperative ileus, it would also be interesting to know which opioid antagonist was administered subcutaneously perioperatively.Finally, no data are presented about the systemic administration of opioids, a known risk factor for delayed return of bowel function. We only learn that patients received an epidural analgesia with a mixture containing a very low dose of bupivacaine (0.05%) and a relatively high dosage of opioid (8 μg/ml hydromorphone).In conclusion, the saying “one size does not fit all” can also be applied to fluid therapy. This study is of importance because it shows no benefit of goal-directed therapy in terms of reducing gastrointestinal-related complication rates. A more selective and differentiated approach in fluid management is needed. In some cases, restrictive fluid therapy may be beneficial, and in other cases, a modestly liberal fluid administration resulting in a postoperative weight gain of approximately 2 to 3 kg would make no difference in outcome. Fluid management is only part of a complex battery of interventions affecting outcome after open radical cystectomy.The authors declare no competing interests.

Steroid Receptor Coactivator-3 Is Required for Inhibition of the Intestinal Muscularis Inflammatory Response of Postoperative Ileus in Mice.

Inflammation theory has suggested that the pathogenesis of postoperative ileus (POI) involves the steroid receptor coactivator-3 (SRC-3). Therefore, we investigated the role of SRC-3 in the muscles of the small intestine using a mouse POI model. Here, we reported that intestinal manipulation (IM) significantly reduced the extent of phenol red migration in the entire gastrointestinal tract, and the calculated geometric center (GC) value in wild-type (WT) mice at 24 h after surgery was higher than that in the knockout (KO) mice and in the sham-operated control group. The expression of SRC-3 was upregulated in the mouse intestinal muscularis at 24 h after surgical manipulation, and the mRNA and protein levels of inflammatory cytokines were upregulated compared with those in the control group. At 24 h after IM, the number of neutrophils in the experimental group was significantly higher than that in the control group; in the IM group, the number of neutrophils in the SRC-3-/- mice was markedly higher than that in the WT mice. At 24 h after IM, the myeloperoxidase (MPO) activity in the experimental group was significantly higher than that in the control group. In the IM group, the MPO activity of the SRC-3-/- mice was markedly higher than that of the WT mice. In summary, proinflammatory cytokines, the number of neutrophils, and the MPO activity were significantly increased in the muscularis of the jejunum and ileum of KO mice after IM compared with those of the WT mice, indicating that SRC-3 might play a protective role in POI.

Experimental postoperative ileus: is Th2 immune response involved?

Rationale: Postoperative ileus (POI) is a frequent complication arising after gastrointestinal surgery but pathogenesis of POI is still not fully understood. While Th1 immune cells are implicated in POI, the involvement of Th2 cells has not yet been clarified. Given the impact of reactive oxygen species (ROS) in the regulation of Th1 and Th2 balance, we hypothesized that not only Th1 but also Th2 immune response can be involved in the development of experimental POI.Methods: The intestinal transit test was performed using carbon gum arabic. Electron microscopy was employed to assess tissue morphology and the presence of immune cells. Cytokines, IgE and ROS were measured. Immune cells from Peyer's patches were analyzed by Flow Cytometry and toluidine blue staining was used for detection of mast cells. Transcriptional factors were analyzed by Western blot.Results: POI is associated with an increase in both Th2 cytokines and Th2 cells. We have further demonstrated that POI induces a Th2-dependent activation of memory and non-memory B cells. This was accompanied by an increase in a number of mast cells in the colon of POI mice as well by an increased IgE and histamine plasma levels. We found that POI-induced accumulation of ROS was associated with an increased expression of the transcriptional factors HMBGI, NF-κB, and p38. This increased expression seemed to be associated with a Th2 response.Conclusion: Th2 immune response can be involved in the activation of mast cells in POI, which was associated with ROS mediated activation of NF-κB and p38 MAPK signaling pathway.

Postoperative Ileus and Postoperative Gastrointestinal Tract Dysfunction: Pathogenic Mechanisms and Novel Treatment Strategies Beyond Colorectal Enhanced Recovery After Surgery Protocols.

Postoperative ileus (POI) and postoperative gastrointestinal tract dysfunction (POGD) are well-known complications affecting patients undergoing intestinal surgery. GI symptoms include nausea, vomiting, pain, abdominal distention, bloating, and constipation. These iatrogenic disorders are associated with extended hospitalizations, increased morbidity, and health care costs into the billions and current therapeutic strategies are limited. This is a narrative review focused on recent concepts in the pathogenesis of POI and POGD, pipeline drugs or approaches to treatment. Mechanisms, cellular targets and pathways implicated in the pathogenesis include gut surgical manipulation and surgical trauma, neuroinflammation, reactive enteric glia, macrophages, mast cells, monocytes, neutrophils and ICC’s. The precise interactions between immune, inflammatory, neural and glial cells are not well understood. Reactive enteric glial cells are an emerging therapeutic target that is under intense investigation for enteric neuropathies, GI dysmotility and POI. Our review emphasizes current therapeutic strategies, starting with the implementation of colorectal enhanced recovery after surgery protocols to protect against POI and POGD. However, despite colorectal enhanced recovery after surgery, it remains a significant medical problem and burden on the healthcare system. Over 100 pipeline drugs or treatments are listed in Clin.Trials.gov. These include 5HT4R agonists (Prucalopride and TAK 954), vagus nerve stimulation of the ENS—macrophage nAChR cholinergic pathway, acupuncture, herbal medications, peripheral acting opioid antagonists (Alvimopen, Methlnaltexone, Naldemedine), anti-bloating/flatulence drugs (Simethiocone), a ghreline prokinetic agonist (Ulimovelin), drinking coffee, and nicotine chewing gum. A better understanding of the pathogenic mechanisms for short and long-term outcomes is necessary before we can develop better prophylactic and treatment strategies.

Inflammation, Impaired Motility, and Permeability in a Guinea Pig Model of Postoperative Ileus.

Background/AimsPostoperative ileus (POI) is characterized by impaired propulsive function of the gastrointestinal tract after surgery. Although inflammation is considered to be an important pathogenesis of POI, significant data are lacking. We aim to correlate the recovery time of postoperative dysmotility with that of inflammation and mucosal permeability.MethodsAn experimental POI model of guinea pig was used. Contractile activity of the circular muscle of the stomach, jejunum, ileum, and proximal colon was measured through a tissue bath study. Inflammatory cells were counted, and the expression of calprotectin and tryptase were analyzed. The expression of protease-activated receptor 2 (PAR-2), claudin-1, and claudin-2 were analyzed with immunofluorescence.ResultsThe small bowel and colon showed decreased contractile amplitude in the POI groups compared to control. In contrast to the colon, the contractile amplitude of the small bowel significantly recovered in the POI group at 6 hours after the operation compared to the control group. Inflammation was highly significant in the POI groups compared to the control and sham groups, especially in the colon. Immunofluorescence showed increased PAR-2 expression in the POI groups compared to sham. The decreased claudin-1 expression and increased claudin-2 expression may suggest increased mucosal permeability of the small bowel and colon in the POI groups.ConclusionsIncreased inflammation and mucosal permeability may play an important role in the differential recovery stages in POI. These data may provide further insights into the pathophysiology and potential new therapeutic prospects of POI.

Therapeutic management of postoperative ileus

Postoperative ileus is one of the most common complications in patients after abdominal surgery and is a major determinant of recovery after surgery. It leads to increased postoperative morbidity, prolonged hospital stay, and increased costs. The pathogenesis of postoperative ileus is multifactorial, including pharmacological, neurogenic, and inflammatory mechanisms. In this review, we discuss the current therapeutic strategies for postoperative ileus.

Smooth muscle and neural dysfunction contribute to different phases of murine postoperative ileus.

Postoperative ileus (POI) is characterized by a transient inhibition of gastrointestinal (GI) motility after abdominal surgery mediated by the inflammation of the muscularis externa (ME). The aim of this study was to identify alterations in the enteric nervous system that may contribute to the pathogenesis of POI. Gastrointestinal transit, contractility of isolated smooth muscle strips and inflammatory parameters were evaluated at different time points (1.5 h to 10 days) after intestinal manipulation (IM) in mice. Immune-labeling was used to visualize changes in myenteric neurons. Intestinal manipulation resulted in an immediate inhibition of GI transit recovering between 24 h and 5 days. In vitro contractility to K(+) (60 mM) or carbachol (10(-9) to 10(-4) M) was biphasically suppressed over 24 h after IM (with transient recovery at 6 h). The first phase of impaired myogenic contractility was associated with increased expression of TNF-α, IL-6 and IL-1α. After 24 h, we identified a significant reduction in electrical field stimulation-evoked contractions and relaxations, lasting up to 10 days after IM. This was associated with a reduced expression of chat and nos1 genes. Intestinal manipulation induces two waves of smooth muscle inhibition, most likely mediated by inflammatory cytokines, lasting up to 3 days after IM. Further, we here identify a late third phase (>24 h) characterized by impaired cholinergic and nitrergic neurotransmission persisting after recovery of muscle contractility. These findings illustrate that POI results from inflammation-mediated impaired smooth muscle contraction, but also involves a long-lasting impact of IM on the enteric nervous system.

Protective effect of exogenous nitrite in postoperative ileus.

As the pathogenesis of postoperative ileus (POI) involves inflammation and oxidative stress, comparable to ischaemia/reperfusion injury which can be ameliorated with nitrite, we investigated whether nitrite can protect against POI and explored the mechanisms involved. We used intestinal manipulation (IM) of the small intestine to induce POI in C57BL/6J mice. Sodium nitrite (48 nmol) was administered intravenously just before IM. Intestinal transit was assessed using fluorescent imaging. Bethanechol-stimulated jejunal circular muscle contractions were measured in organ baths. Inflammatory parameters, neutrophil infiltration, inducible NOS (iNOS) activity, reactive oxygen species (ROS) levels, mitochondrial complex I activity and cGMP were measured in the intestinal muscularis. Pre-treatment with nitrite markedly improved the delay in intestinal transit and restored the reduced intestinal contractility observed 24 h following IM. This was accompanied by reduced protein levels of TNF-α, IL-6 and the chemokine CCL2, along with reduced iNOS activity and ROS levels. The associated neutrophil influx at 24 h was not influenced by nitrite. IM reduced mitochondrial complex I activity and cGMP levels; treatment with nitrite increased cGMP levels. Pre-treatment with the NO scavenger carboxy-PTIO or the soluble guanylyl cyclase inhibitor ODQ abolished nitrite-induced protective effects. Exogenous nitrite deserves further investigation as a possible treatment for POI. Nitrite-induced protection of POI in mice was dependent on NO and this effect was not related to inhibition of mitochondrial complex I, but did involve activation of soluble guanylyl cyclase.

Avicenna (IbnSina) aspect of Ileus

Dear Editor, Ileusis derived from the Greek word 'eileos,' which means twisting, a prevalent and non- prophylactic consequence in major abdominal operations (Jonson W it occurs post-operatively, ileus (PI) is a delay in the return of a normal bowel movement, which typically lasts 3-5 days dependent on the location, 0 to 24 hours in the small intestine, 24 to 48 hours in the stomach, and 48 to 72 hours in the colon respectively (Ianey2004)(RychterC and creation of wind in the intestine may be accumulated inside muscular tissues, which will be followed by pain and intestinal atony and paralysis (IbnSina 2005 p.262). With deference to the above statements previously discussed, this hypothesis purposes that one of the causes for postoperative ileus is wind. Therefore, those drugs, which remove the produced dense wind in the digestive system, may contribute to the return of intestinal movement (peristalsis) in the post-surgical patient more quickly following the operation. Additionally, this theory could possibly be used and studied as a new method for prophylactic purpose and treatment of the patient’s postoperative ileus (PI) state. We would like to continue further discussions on the aspects of Persian traditional medicinal treatment of ileus in future articles. DOI: http://dx.doi.org/10.3126/ijls.v9i5.12709

Mangiferin ameliorates the intestinal inflammatory response and the impaired gastrointestinal motility in mouse model of postoperative ileus.

Our previous study has shown that mangiferin (MGF), a glucosylxanthone from Mangifera indica, exerts gastrointestinal prokinetic action involving a cholinergic mechanism. Postoperative ileus (POI) is a temporary disturbance in gastrointestinal motility following surgery, and intestinal inflammatory response plays a critical role in the pathogenesis of POI. The present study investigated to know whether MGF having anti-inflammatory and prokinetic actions can ameliorate the intestinal inflammation and impaired gastrointestinal transit seen in the mouse model of POI. Experimental POI was induced in adult male Swiss mice by standardized small intestinal manipulation (IM). Twenty-four hours later, gastrointestinal transit was assessed by charcoal transport. MGF was administered orally 1h before the measurement of GIT. To evaluate the inflammatory response, plasma levels of proinflammatory cytokines TNF-α, IL-1β, IL-6, and chemokine MCP-1, and the myeloperoxidase activity, nitrate/nitrite level, and histological changes of ileum were determined in mice treated or not with MGF. Experimental POI in mice was characterized by decreased gastrointestinal transit and marked intestinal and systemic inflammatory response. MGF treatment led to recovery of the delayed intestinal transit induced by IM. MGF in ileum significantly inhibited the myeloperoxidase activity, a marker of neutrophil infiltration, and nitrate/nitrite level and reduced the plasma levels of TNF-α, IL-1β, IL-6, and MCP-1 as well. MGF treatment ameliorates the intestinal inflammatory response and the impaired gastrointestinal motility in the mouse model of POI.

Factors affecting bowel motility following abdominal surgery: A clinical study

Background: Postoperative ileus (POI) is a common complication of many surgical procedures. It is generally defined as a cessation of bowel motility. The pathogenesis of POI is multifactorial with bowel dysmotility being caused by disturbances in immunologic, inflammatory, neurologic, electrolyte and receptor-mediated functioning. Materials and Methods: Between January 2013 to June 2014, 140 patients with elective abdominal surgery were included in the present prospective study. The factors that were studied to see their effect on the return of bowel motility are type of surgery, duration of surgery, handling of bowel and electrolytes level. Results: It was found that these factors were significantly associated with POI. Out of the 140 patients enrolled in the study, appearance of bowel motility within 4 days was in 126 (90.00%) while after 4 days in only 14 (10.0%) patients. Discussion: This study showed that POI was an undeniable complication of abdominal surgeries; however, it was dependent on a host of factors, including age, type of surgery, category of bowel handling, duration of surgery and electrolyte imbalance. Although most of these are unmodifiable risk factors, however, a skilful handling, selection of appropriate operative technique and fluid management could help to reduce this complication.

Peritoneal air exposure elicits an intestinal inflammation resulting in postoperative ileus.

Background. The pathogenesis of postoperative ileus (POI) is complex. The present study was designed to investigate the effects of peritoneal air exposure on the POI intestinal inflammation and the underlying mechanism. Methods. Sprague-Dawley rats were randomized into five groups (6/group): the control group, the sham group, and three exposure groups with peritoneal air exposure for 1, 2, or 3 h. At 24 h after surgery, we analyzed the gastrointestinal transit, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, the myeloperoxidase activity, and the levels of TNF-α, IL-1β, IL-6, and IL-10 in the ileum and colon. The oxidant and antioxidant levels in the ileum and colon were analyzed by measuring malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). Results. Peritoneal air exposure caused an air-exposure-time-dependent decrease in the gastrointestinal transit. The length of peritoneal air exposure is correlated with the severity of both systemic and intestinal inflammations and the increases in the levels of MDA, SOD, GSH-Px, and T-AOC. Conclusions. The length of peritoneal air exposure is proportional to the degree of intestinal paralysis and the severity of intestinal inflammation, which is linked to the oxidative stress response.

Postoperative Ileus Involves Interleukin-1 Receptor Signaling in Enteric Glia

Postoperative ileus (POI) is a common consequence of abdominal surgery that increases the risk of postoperative complications and morbidity. We investigated the cellular mechanisms and immune responses involved in the pathogenesis of POI. We studied a mouse model of POI in which intestinal manipulation leads to inflammation of the muscularis externa and disrupts motility. We used C57BL/6 (control) mice as well as mice deficient in Toll-like receptors (TLRs) and cytokine signaling components (TLR-2(-/-), TLR-4(-/-), TLR-2/4(-/-), MyD88(-/-), MyD88/TLR adaptor molecule 1(-/-), interleukin-1 receptor [IL-1R1](-/-), and interleukin (IL)-18(-/-) mice). Bone marrow transplantation experiments were performed to determine which cytokine receptors and cell types are involved in the pathogenesis of POI. Development of POI did not require TLRs 2, 4, or 9 or MyD88/TLR adaptor molecule 2 but did require MyD88, indicating a role for IL-1R1. IL-1R1(-/-) mice did not develop POI; however, mice deficient in IL-18, which also signals via MyD88, developed POI. Mice given injections of an IL-1 receptor antagonist (anakinra) or antibodies to deplete IL-1α and IL-1β before intestinal manipulation were protected from POI. Induction of POI activated the inflammasome in muscularis externa tissues of C57BL6 mice, and IL-1α and IL-1β were released in ex vivo organ bath cultures. In bone marrow transplantation experiments, the development of POI required activation of IL-1 receptor in nonhematopoietic cells. IL-1R1 was expressed by enteric glial cells in the myenteric plexus layer, and cultured primary enteric glia cells expressed IL-6 and the chemokine monocyte chemotactic protein 1 in response to IL-1β stimulation. Immunohistochemical analysis of human small bowel tissue samples confirmed expression of IL-1R1 in the ganglia of the myenteric plexus. IL-1 signaling, via IL-1R1 and MyD88, is required for development of POI after intestinal manipulation in mice. Agents that interfere with the IL-1 signaling pathway are likely to be effective in the treatment of POI.