Anthony Bauer | Liberty University (original) (raw)

Papers by Anthony Bauer

The Journal of Physiology, 1985

With 7 text-figures

The Journal of Physiology, 1985

Slow waves decay in amplitude as they propagate through the thickness of circular muscle of the c... more Slow waves decay in amplitude as they propagate through the thickness of circular muscle of the canine antrum. Slow waves are the excitable events that initiate contractions in the antrum. Excitation-contraction coupling occurs if slow wave depolarizations surpass a 'mechanical threshold'. 2. The amplitude of slow waves recorded from circular muscle cells near the submucosa was insufficient to reach the mechanical threshold previously determined for muscle near the myenteric plexus, suggesting that either submucosal cells are normally mechanically quiescent, or that contractions of submucosal cells are initiated at more polarized levels. 3. Experiments were performed to determine the voltage-tension relationships in adjacent 'myenteric' and 'submucosal' circular muscles. Membrane potentials of the muscles were depolarized by elevated concentrations of potassium. 4. Submucosal muscles were stimulated to contract at lower potassium concentrations than were myenteric muscles. Contractions of submucosal muscles at each potassium concentration studied were more forceful than contractions of myenteric muscles. 5. Plots of membrane potential vs. potassium concentration on a logarithmic scale showed that the membrane potential of myenteric cells was more dependent upon the potassium gradient than the membrane potential of submucosal cells. The potassium permeability of both groups of cells increased when depolarized, and the slopes of these plots approached Nernstian levels when depolarized below-55 mV. 6. Force developed in submucosal strips at more polarized levels than in myenteric muscles. The 'mechanical threshold' of submucosal muscles was 5-10 mV above resting potential, whereas myenteric muscles had to be depolarized by 25-30 mV before contraction was initiated. 7. The mechanisms responsible for the difference in mechanical thresholds are not known, but differences in the voltage dependence of calcium channels, in calcium release mechanisms, or in the sensitivity of the contractile proteins to calcium could be involved.

The Journal of Physiology, 1991

1. Experiments were designed to determine in circular muscle of the canine jejunum whether exogen... more 1. Experiments were designed to determine in circular muscle of the canine jejunum whether exogenous nitric oxide (NO) mimics the non-adrenergic, noncholinergic inhibitory junction potential (NANC IJP), and whether changes in the availability of endogenous NO affects IJP amplitude. 2. Mechanical and intracellular electrical activity were recorded simultaneously from circular muscle of the canine jejunum. Electrical field stimulation evoked NANC IJPs and inhibited spontaneous contractions. 3. Infusions of NO solutions evoked immediate dose-dependent and transient hyperpolarizations and transiently inhibited spontaneous contractions. NO-evoked hyperpolarizations were unaffected by atropine, propranolol, phentolamine and tetrodotoxin. 4. The maximum IJP amplitude and the maximum amplitude of NO-evoked hyperpolarization were similar. 5. NG-Mono-methyl-L-arginine (L-NMMA), which inhibits synthesis of NO from Larginine, reduced IJP amplitudes but did not reduce the response to exogenous NO. L-Arginine, but not D-arginine, reversed the effect of L-NMMA on IJP amplitude. 6. Oxyhaemoglobin, which binds and inactivates NO, reduced IJP amplitude and abolished the response to exogenous NO. 7. Exogenous NO mimicked the effects of NANC inhibitory input. Reducing the availability of endogenous NO reduced NANC inhibitory input. 8. It was concluded that NO mediates NANC neural inhibition and may act as a NANC inhibitory neurotransmitter in the canine jejunum.

The Journal of Physiology, 1991

The effects of opioid peptides on inhibitory transmission in the circular muscle layer of canine ... more The effects of opioid peptides on inhibitory transmission in the circular muscle layer of canine duodenum were investigated in vitro using simultaneous mechanical and intracellular electrical recording techniques. 2. Exogenously added [Met5]enkephalin, [Leu5]enkephalin and dynorphin (1-13) decreased the amplitude of non-adrenergic, non-cholinergic inhibitory junction potentials (IJPs) evoked by transmural nerve stimulation. 3. A selective d-receptor agonist, DPDPE ([D-Pen2, D-Pen5]enkephalin), and a selective ,u-receptor agonist, PLO17 (Try-Pro-NMePhe-D-Pro-NH2), decreased the amplitude of IJPs whereas a selective K-receptor agonist, U-50,488H ([trans-3,4dichloro-N-methyl-N-(2-91-pyrolidinyl)-cyclohexyl]-benzeneacetamide methanesulphonate), in large doses (1 /UM) produced only a small reduction. 4. A selective 8-receptor antagonist, ICI-174,864, blocked the effect of DPDPE but not that of PLO17 suggesting the presence of distinct d-and ,u-opioid receptors on inhibitory motor nerves. 5. Exogenously added dynorphin (1-13) decreased the amplitude of IJPs. 8-Opioid receptors appeared to be involved because ICI-174,864, a selective 8-antagonist, blocked the inhibitory effect of exogenously added dynorphin (1-13). 6. The inhibitory effect of the opioid peptides was still observed in preparations of circular muscle devoid of myenteric and submucosal plexuses, indicating that the site of action was on inhibitory motor nerve fibres located within the circular muscle layer and not on neuronal cell bodies in the enteric plexuses. 7. It was concluded that in the canine small intestine, opioid peptides could modulate release of inhibitory transmitter(s) at or near nerve terminals of inhibitory motor nerves innervating circular muscle cells.

Transplantation, 1997

IgG antibodies present in newborn sera are primarily directed against ex Gal epitopes and may be ... more IgG antibodies present in newborn sera are primarily directed against ex Gal epitopes and may be implicated in the pathogenesis of the xenograft rejection process. In order to permit prolonged xenograft survival in newborn primates, therapeutic strategies may need to be developed that incorporate techniques to deplete IgG antibodies pretransplant, such as plasmapheresis, together with those which prevent induction of antibody production posttransplant, such as the use of anti-B cell chemotherapeutic agents. REFERENCES 1. Good AH, Cooper DKC, Malcolm, AJ, et al. Identification of carbohydrate structures that bind human anti-pig antibodies: implications for discordant xenografting in humans. Transplant Proc 1992: 24: 559. 2. Galili U. Evolution and pathophysiology of the human natural anti-alpha-galactosyl IgG (anti-Gal) antibody. Springer Semin Immunopathol 1993; 15: 155. 3. Xu H, Edwards NM, Dong X, et al. Age-related development of human preformed anti-porcine endothelial cell xenoantibody.

Clinical cancer research : an official journal of the American Association for Cancer Research, 2002

The development of colon cancer markers that can detect liver metastases early and predict which ... more The development of colon cancer markers that can detect liver metastases early and predict which patients are at risk to develop liver metastases would have a major impact on this disease. We have previously identified G. Brunagel, et al., Cancer Research, 62:2437-2442, 2002, nuclear matrix proteins (NMPs), which are associated with colon cancer. The objective of this study is to identify the existence of a specific NMP "fingerprint" for human liver metastasis from colon cancer. Using high-resolution two-dimensional gel electrophoresis, we analyzed the NMP expression of 12 matched liver metastases and adjacent normal samples and three normal donor liver samples. These were compared with colon cancer NMP patterns, along with several primary cell systems and lines. Analysis of multiple gels for each sample revealed three proteins present in all liver metastases, which are not present in normal liver tissue and normal hepatocytes. These three proteins were also present in col...

Journal of the American College of Surgeons, 2007

cancer cell lines. This combination may have important clinical therapeutic implications.

Gastroenterology, 2010

Background & Aims-Gastroparesis is a well-recognized complication of diabetes. In diabetics, up-r... more Background & Aims-Gastroparesis is a well-recognized complication of diabetes. In diabetics, up-regulation of heme oxygenase-1 (HO1) in gastric macrophages protects against oxidative stressinduced damage. Loss of up-regulation of HO1, the subsequent increase in oxidative stress, and loss of Kit delays gastric emptying; this effect is reversed by induction of HO1. Macrophages have proand anti-inflammatory activities, depending on their phenotype. We investigated the number and phenotype of gastric macrophages in NOD/ShiLtJ (NOD) mice after onset of diabetes, when delayed gastric emptying develops, and after induction of HO1 to reverse delay. Methods-Four groups of NOD and db/db mice were studied: non-diabetic, diabetic with normal emptying, diabetic with delayed gastric emptying, and diabetic with delayed gastric emptying reversed by the HO1 inducer hemin. Whole-mount samples from stomach were labeled in triplicate with antisera against F4/80, HO1, and CD206 and macrophages were quantified in stacked confocal images. Markers for macrophage subtypes were measured by quantitative PCR.

Cytokine, 2009

In hemorrhagic shock and trauma, patients are prone to develop systemic inflammation with remote ... more In hemorrhagic shock and trauma, patients are prone to develop systemic inflammation with remote organ dysfunction, which is thought to be caused by pro-inflammatory mediators. This study investigates the role of the immuno-modulatory cytokine IL-10 in the development of organ dysfunction following hemorrhagic shock. Male C57/BL6 and IL-10 KO mice were subjected to volume controlled hemorrhagic shock for 3h followed by resuscitation. Animals were either sacrificed 3 or 24h after resuscitation. To assess systemic inflammation, serum IL-6, IL-10, KC, and MCP-1 concentrations were measured with the Luminex multiplexing platform; acute lung injury (ALI) was assessed by pulmonary myeloperoxidase (MPO) activity and lung histology and acute liver injury was assessed by hepatic MPO activity, hepatic IL-6 levels, and serum ALT levels. There was a trend towards increased IL-6 and KC serum levels 3h after resuscitation in IL-10 KO as compared to C57/BL6 mice; however this did not reach statistical significance. Serum MCP-1 levels were significantly increased in IL-10 KO mice 3 and 24 h following resuscitation as compared to C57/BL6 mice. In IL-10 KO mice, pulmonary MPO activity was significantly increased 3 h following resuscitation and after 24 h histological signs of acute lung injury were more apparent than in C57/BL6 mice. In contrast, no significant differences in any liver parameters were detected between IL-10 KO and C57/BL6 mice. Our data indicate that an endogenous IL-10 deficiency augments acute lung but not liver injury following hemorrhagic shock.

American Journal of Physiology-Heart and Circulatory Physiology, 2004

The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-α r... more The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-α receptor-1 (TNFR1)-mediated pathways in a murine model of myocardial infarction and remodeling. One hundred and ninety-four wild-type (WT) and TNFR1 gene-deleted (TNFR1KO) mice underwent left coronary artery ligation to induce myocardial infarction. On days 1, 3, 7, and 42, mice underwent transesophageal echocardiography. Hearts were weighed, and the left ventricle (LV) was assayed for matrix metalloproteinase (MMP)-2 and -9 activity and for tissue inhibitor of MMP (TIMP)-1 and -2 expression. Deletion of the TNFR1 gene substantially improved survival because no deaths were observed in TNFR1KO mice versus 56.4% and 18.2% in WT males and females, respectively ( P < 0.002). At 42 days, LV remodeling, assessed by LV function (fractional area change of 31.9 ± 7.9%, 32.2 ± 7.7%, and 21.6 ± 7.1% in TNFR1KO males, TNFR1KO females, and WT females, respectively, P < 0.04), and hypertrophy (he...

Cellular and Molecular Gastroenterology and Hepatology, 2016

Interleukin 10 reversed delayed gastric emptying in diabetic mice. It increased heme oxygenase 1 ... more Interleukin 10 reversed delayed gastric emptying in diabetic mice. It increased heme oxygenase 1 expression and normalized electrical activity and networks of interstitial cells of Cajal in the stomach. Thus, interleukin 10 is a potential therapy for diabetic gastroparesis. BACKGROUND & AIMS: Gastroparesis is a complication of diabetes characterized by delayed emptying of stomach contents and accompanied by early satiety, nausea, vomiting, and pain. No safe and reliable treatments are available. Interleukin 10 (IL10) activates the M2 cytoprotective phenotype of macrophages and induces expression of heme oxygenase 1 (HO1) protein. We investigated whether IL10 administration could improve gastric emptying and reverse the associated cellular and electrical abnormalities in diabetic mice. METHODS: Nonobese diabetic mice with delayed gastric emptying were given either IL10 (0.1-1 mg, twice/day) or vehicle (controls). Stomach tissues were isolated, and sharp microelectrode recordings were made of the electrical activity in the gastric muscle layers. Changes to interstitial cells of Cajal (ICC), reduced nicotinamide adenine dinucleotide phosphate diaphorase, and levels and distribution of HO1 protein were determined by histochemical and imaging analyses of the same tissues. RESULTS: Gastric emptying remained delayed in vehicletreated diabetic mice but returned to normal in mice given IL10 (n ¼ 10 mice; P < .05). In mice given IL10, normalization of gastric emptying was associated with a membrane potential difference between the proximal and distal stomach, and lower irregularity and higher frequency of slow-wave activity, particularly in the distal stomach. Levels of HO1 protein were higher in stomach tissues from mice given IL10, and ICC networks were more organized, better connected, and more evenly distributed compared with controls. CONCLUSIONS: IL10 increases gastric emptying in diabetic mice and has therapeutic potential for patients with diabetic gastroparesis. This response is associated with up-regulation of HO1 and repair of connectivity of ICC networks.

American journal of physiology. Gastrointestinal and liver physiology, Jan 6, 2015

Objective: Myocytes are non-hemopoietic in origin and functionally essential in generating gastro... more Objective: Myocytes are non-hemopoietic in origin and functionally essential in generating gastrointestinal motility. In endotoxemia, a rapid onset non-hemopoietic mechanism potently triggers early ileus in a TLR4/MyD88-dependent manner. Moreover, synergistically with hemopoietic cells, non-hemopoietic cells escalate late ileus via an IL-6 receptor-dependent inflammation-driven pathway. Herein, we therefore specifically investigated the role of myocytes in TLR4-triggered inflammation and ileus. Design: TLR4(+/+), TLR4(-/-), bmTLR4(+/+)/TLR4(-/-) chimera, SM22-Cre(-/-)TLR4(flox/flox) and selective myocyte TLR4-deficient (SM22-Cre(+/-)TLR4(flox/flox)) mice were injected intraperitoneally with purified lipopolysaccharide. SM22-driven Cre recombinase activity was selectively detected in cardiac, gastrointestinal and skeletal myocytes as well as vascular myocytes of small-sized vessels in a two-color fluorescent Cre reporter mouse. In contrast to non-hemopoietic TLR4-deficiency, deletion...

Shock, 2009

Understanding "two-hit" experimental models is crucial for the rational development of therapies ... more Understanding "two-hit" experimental models is crucial for the rational development of therapies for hemorrhagic shock (HS). We modeled the clinical scenario of HS followed by polymicrobial sepsis (cecal ligation and puncture [CLP]) to investigate the molecular and functional alterations that occur within the gastrointestinal tract. Control, HS, CLP, simultaneous HS + CLP, and HS + delayed CLP by 24 h groups of Sprague-Dawley rats were studied for gastrointestinal transit and in vitro colonic circular muscle contractility to bethanechol. Reverse transcription-polymerase chain reaction quantified IL-6, IL-10, and heme oxygenase 1 messenger RNA expression in the isolated colonic muscularis 6 h after insult. Myeloperoxidase-positive neutrophils were quantified in colonic muscularis whole mounts. Mortality at 24 h was significantly increased in simultaneous mild HS + CLP (88%) over control, mild HS, CLP alone, or HS + delayed CLP. Cecal ligation and puncture significantly delayed transit compared with controls and HS alone. Hemorrhagic shock + delayed CLP animals had normal transit. Colonic contractions were suppressed by 50% after CLP compared with controls and HS. In contrast, HS + delayed CLP displayed control levels of contractile responses to bethanechol. Cecal ligation and puncture and simultaneous HS + CLP caused significant inflammatory messenger RNA induction of IL-6, iNOS, IL-10, and heme oxygenase 1 compared with control and HS, and these responses were significantly suppressed in HS + delayed CLP colonic muscularis extracts. Neutrophils were significantly recruited into the colonic muscularis following CLP after 24 h compared with control and HS. This recruitment was significantly less in the HS + delayed CLP animals. These data demonstrate the ability of mild HS to precondition the animal and protect it against a delayed, but not simultaneous, polymicrobial event.

Digestive Diseases and Sciences - DIGEST DIS SCI, 2001

Recovery from hemorrhagic shock (HS) is frequently accompanied by bowel stasis. The aim of this s... more Recovery from hemorrhagic shock (HS) is frequently accompanied by bowel stasis. The aim of this study was to examine whether or not HS initiates an inflammatory response that includes production of cytokines, specifically G-CSF and interleukin-6 (IL-6), and recruitment of leukocytes within the intestinal muscularis which contribute to impaired muscle contractility. Sprague-Dawley rats were subjected to HS (MAP 40 mm Hg for 156 min) followed by resuscitation, and then they were killed at 4 hr. Shock animals demonstrated accumulation of PMNs in the jejunal muscularis and decreased spontaneous and bethanechol-stimulated muscle contractility. Semiquantitative RT-PCR demonstrated elevated levels of IL-6 and G-CSF mRNA in shock animals in full-thickness jejunum and in mucosa and muscularis layers compared to sham controls. Immunostaining demonstrated increased IL-6 protein production within the muscularis externa and submucosa. In situ hybridization studies localized G-CSF mRNA production...

Neurogastroenterology & Motility, 2010

Our bacterial residents are deadly Janus-faced indwellers which can lead to a septic-induced syst... more Our bacterial residents are deadly Janus-faced indwellers which can lead to a septic-induced systemic inflammatory response syndrome and multiple organ failure. Over half of ICU patients suffer from infections and sepsis remains among the top ten causes of death in the United States. Severe ileus frequently accompanies sepsis setting up an insidious cycle of gut-derived microbial translocation and the copious intestinal production of potent systemic inflammatory mediators. Few therapeutic advances have occurred to prevent/treat the sequelae of sepsis. Here, we selectively review studies on cellular membrane bound Toll-like receptor (TLR) mechanisms of ileus. Virtually no data exists on Gram-positive/TLR2 signaling mechanisms of ileus, however, TLR2 is highly inducible by numerous inflammatory mediators and studies using clinically relevant scenarios of Gram-positive sepsis are needed. Specific Gram-negative/TLR4 signaling pathways are being elucidated using a "reverse engineering" approach and have revealed that endotoxin induced ileus is dually mediated by classical leukocyte inflammatory signaling and by a MyD88-dependent non-bone marrow derived mechanism, but the specific roles of individual cell populations are still unknown. Like TLR2, little is also know of the role of flagellin/TLR5 signaling in ileus. But, much can be learned by understanding TLR signaling in other systems. Clearly, the use of polymicrobial models provide important clinical relevancy but simultaneous activation of virtually all pattern recognition receptors make it impossible to discretely study specific signaling pathways. We believe that dissection of individual TLR pathways, which can then be intelligently reassembled in a meaningful manner, will provide insight into treatments for sepsis induced ileus.

Neurogastroenterology and Motility, 2004

Complex circuits involving both local intrinsic neurones (i.e. enteric nervous system; ENS) and e... more Complex circuits involving both local intrinsic neurones (i.e. enteric nervous system; ENS) and extrinsic neurones achieve nervous control of digestive functions. The ENS is comprised of many functionally different types of neurons: sensory neurons, interneurons and secreto-motor neurons. Each neuronal population is required to manifest local reflex behavior and is central to the regulation of both motor and secretory activities. It must be emphasized, however, that not only muscle and secretory cells but also other intestinal cells are targeted by enteric neurones, i.e. endocrine cells, interstitial cells of Cajal, immune cells, blood vessels and enteric glia. In addition to the ENS the gastrointestinal tract receives an extrinsic innervation by sympathetic, parasympathetic and sensory fibres. Neuronal projections from the intestine to prevertebral ganglia also exist. Taken together, the picture of a complex nervous regulation of digestive functions highly integrated with the central nervous system and the rest of the autonomic nervous system has emerged. The ENS is adaptive and plastic, but also vulnerable, system and ENS disturbances may be of pathogenic importance in functional bowel disease. In particular the interplay between the enteric neurones and the immune cells is suggested to be of crucial importance. The review discusses possible roles of the mediators vasoactive intestinal peptide (VIP) and prostanoids in ENS plasticity in response to injury and inflammation.

Neurogastroenterology & Motility, 2012

Background-Early murine endotoxin-induced ileus at 6 hours is exclusively mediated by nonhemopoie... more Background-Early murine endotoxin-induced ileus at 6 hours is exclusively mediated by nonhemopoietic TLR4/MyD88 signaling despite molecular activation of hemopoietic cells which included a significant IL-6 mRNA induction. Our objective was to define the role of hemopoietic cells in LPS/TLR4-triggered ileus and inflammation over time, and identify mechanisms of ileus. Methods-CSF-1 −/− , TLR4 non-chimera and TLR4 chimera mice were single-shot injected with intraperitoneal ultrapure lipopolysaccharide (UP-LPS) and studied up to 4 days. Subgroups of TLR4 WT mice were additionally intravenously injected with exogenous recombinant IL-6 (rmIL-6) or murine soluble IL-6 receptor blocking antibody (anti-sIL-6R mAB). Key Results-Hemopoietic TLR4 signaling independently mediated UP-LPS-induced ileus at 24 hours, but chemotactic muscularis neutrophil extravasation was not causatively involved and mice lacking CSF-1-dependent macrophages died prematurely. Synergy of hemopoietic and nonhemopoietic cells determined ileus severity and mortality which correlated with synergistic cell lineage specific transcription of inflammatory mediators like IL-6 within the intestinal muscularis. Circulating IL-6 levels were LPS-dose dependent, but exogenous rmIL-6 did not spark off a selfperpetuating inflammatory response triggering ileus. Sustained therapeutic inhibition of functional IL-6 signaling efficiently ameliorated late ileus while preemptive antibody-mediated IL-6R blockade was marginally effective in mitigating ileus. However, IL-6R blockade did not prevent endotoxin-associated mortality nor did it alter circulating IL-6 levels. Conclusions and Inferences-A time-delayed bone marrow-driven mechanism of murine endotoxin-induced ileus exists, and hemopoietic cells synergize with non-hemopoietic cells 1 This study was supported in parts by grants from the National Institutes of Health (R01-GM58241, R01-DK068610, P50-GM-53789, and DK02488) and from the Deutsche Forschungsgemeinschaft Bu 2403/2-1 (B.M.B.).

Neurogastroenterology & Motility, 2011

Background-Trauma is a leading cause of death and although the gut is recognized as the "motor" o... more Background-Trauma is a leading cause of death and although the gut is recognized as the "motor" of post-traumatic systemic inflammatory response syndrome and multiple organ failure, studies on the gastrointestinal tract are few. Our objectives were to create a precisely controllable tissue injury model in which gastrointestinal motility, systemic inflammation and wound fluid can be analyzed. Methods-A non-narcotic murine trauma model was developed by the subcutaneous dorsal trans-implantation of a devitalized donor syngeneic harvested tissue-bone matrix (TBX), which was precisely adjusted to % total body weight and studied after 21 hrs. Gastrointestinal transit histograms were plotted after the oral administration of non-digestible FITC-dextran and geometric centers calculated. Organ bath evaluated jejunal circular muscle contractility. Multiplex

Journal of Pharmacology and Experimental Therapeutics, 2006

Treatment with inhaled carbon monoxide (CO) has been shown to ameliorate bowel dysmotility caused... more Treatment with inhaled carbon monoxide (CO) has been shown to ameliorate bowel dysmotility caused by surgical manipulation of the gut in experimental animals. We hypothesized that administration of CO dissolved in lactated Ringer's solution (CO-LR) might provide similar protection to that observed with the inhaled gas while obviating some its inherent problems. Post-operative gut dysmotility (ileus) was induced in mice by surgical manipulation of the small intestine. Some mice were treated with a single intraperitoneal dose of CO-LR immediately after the surgical procedure, whereas other mice received only the LR vehicle. Twenty-four h later, intestinal transit of a nonabsorbable marker (70 kDa FITC-labeled dextran) was delayed in mice subjected to intestinal manipulation but not the sham procedure. Gut manipulation also was associated with increased expression within the muscularis propria of transcripts for IL-1β, cyclooxygenase-2, inducible nitric oxide synthase, intracellular adhesion molecule-1 and Toll-like receptor-4, as well as infiltration of the muscularis propria with polymorphonuclear leukocytes and activation of mitogen-activated protein kinases and nuclear factor-κB. All of these effects were attenuated by treatment with CO-LR. The salutary effect of CO-LR on gut motility as well as many of the anti-inflammatory effects of CO-LR was diminished by treatment with a soluble guanylyl cyclase (sGC) inhibitor, suggesting that the effects of CO are mediated via activation of sGC. These data support the view that a single intraperitoneal dose of CO-LR ameliorates post-operative ileus in mice, by inhibiting the inflammatory response in the gut wall induced by surgical manipulation, possibly in a sGCdependent fashion.

The Journal of Physiology, 1985

With 7 text-figures

The Journal of Physiology, 1985

Slow waves decay in amplitude as they propagate through the thickness of circular muscle of the c... more Slow waves decay in amplitude as they propagate through the thickness of circular muscle of the canine antrum. Slow waves are the excitable events that initiate contractions in the antrum. Excitation-contraction coupling occurs if slow wave depolarizations surpass a 'mechanical threshold'. 2. The amplitude of slow waves recorded from circular muscle cells near the submucosa was insufficient to reach the mechanical threshold previously determined for muscle near the myenteric plexus, suggesting that either submucosal cells are normally mechanically quiescent, or that contractions of submucosal cells are initiated at more polarized levels. 3. Experiments were performed to determine the voltage-tension relationships in adjacent 'myenteric' and 'submucosal' circular muscles. Membrane potentials of the muscles were depolarized by elevated concentrations of potassium. 4. Submucosal muscles were stimulated to contract at lower potassium concentrations than were myenteric muscles. Contractions of submucosal muscles at each potassium concentration studied were more forceful than contractions of myenteric muscles. 5. Plots of membrane potential vs. potassium concentration on a logarithmic scale showed that the membrane potential of myenteric cells was more dependent upon the potassium gradient than the membrane potential of submucosal cells. The potassium permeability of both groups of cells increased when depolarized, and the slopes of these plots approached Nernstian levels when depolarized below-55 mV. 6. Force developed in submucosal strips at more polarized levels than in myenteric muscles. The 'mechanical threshold' of submucosal muscles was 5-10 mV above resting potential, whereas myenteric muscles had to be depolarized by 25-30 mV before contraction was initiated. 7. The mechanisms responsible for the difference in mechanical thresholds are not known, but differences in the voltage dependence of calcium channels, in calcium release mechanisms, or in the sensitivity of the contractile proteins to calcium could be involved.

The Journal of Physiology, 1991

1. Experiments were designed to determine in circular muscle of the canine jejunum whether exogen... more 1. Experiments were designed to determine in circular muscle of the canine jejunum whether exogenous nitric oxide (NO) mimics the non-adrenergic, noncholinergic inhibitory junction potential (NANC IJP), and whether changes in the availability of endogenous NO affects IJP amplitude. 2. Mechanical and intracellular electrical activity were recorded simultaneously from circular muscle of the canine jejunum. Electrical field stimulation evoked NANC IJPs and inhibited spontaneous contractions. 3. Infusions of NO solutions evoked immediate dose-dependent and transient hyperpolarizations and transiently inhibited spontaneous contractions. NO-evoked hyperpolarizations were unaffected by atropine, propranolol, phentolamine and tetrodotoxin. 4. The maximum IJP amplitude and the maximum amplitude of NO-evoked hyperpolarization were similar. 5. NG-Mono-methyl-L-arginine (L-NMMA), which inhibits synthesis of NO from Larginine, reduced IJP amplitudes but did not reduce the response to exogenous NO. L-Arginine, but not D-arginine, reversed the effect of L-NMMA on IJP amplitude. 6. Oxyhaemoglobin, which binds and inactivates NO, reduced IJP amplitude and abolished the response to exogenous NO. 7. Exogenous NO mimicked the effects of NANC inhibitory input. Reducing the availability of endogenous NO reduced NANC inhibitory input. 8. It was concluded that NO mediates NANC neural inhibition and may act as a NANC inhibitory neurotransmitter in the canine jejunum.

The Journal of Physiology, 1991

The effects of opioid peptides on inhibitory transmission in the circular muscle layer of canine ... more The effects of opioid peptides on inhibitory transmission in the circular muscle layer of canine duodenum were investigated in vitro using simultaneous mechanical and intracellular electrical recording techniques. 2. Exogenously added [Met5]enkephalin, [Leu5]enkephalin and dynorphin (1-13) decreased the amplitude of non-adrenergic, non-cholinergic inhibitory junction potentials (IJPs) evoked by transmural nerve stimulation. 3. A selective d-receptor agonist, DPDPE ([D-Pen2, D-Pen5]enkephalin), and a selective ,u-receptor agonist, PLO17 (Try-Pro-NMePhe-D-Pro-NH2), decreased the amplitude of IJPs whereas a selective K-receptor agonist, U-50,488H ([trans-3,4dichloro-N-methyl-N-(2-91-pyrolidinyl)-cyclohexyl]-benzeneacetamide methanesulphonate), in large doses (1 /UM) produced only a small reduction. 4. A selective 8-receptor antagonist, ICI-174,864, blocked the effect of DPDPE but not that of PLO17 suggesting the presence of distinct d-and ,u-opioid receptors on inhibitory motor nerves. 5. Exogenously added dynorphin (1-13) decreased the amplitude of IJPs. 8-Opioid receptors appeared to be involved because ICI-174,864, a selective 8-antagonist, blocked the inhibitory effect of exogenously added dynorphin (1-13). 6. The inhibitory effect of the opioid peptides was still observed in preparations of circular muscle devoid of myenteric and submucosal plexuses, indicating that the site of action was on inhibitory motor nerve fibres located within the circular muscle layer and not on neuronal cell bodies in the enteric plexuses. 7. It was concluded that in the canine small intestine, opioid peptides could modulate release of inhibitory transmitter(s) at or near nerve terminals of inhibitory motor nerves innervating circular muscle cells.

Transplantation, 1997

IgG antibodies present in newborn sera are primarily directed against ex Gal epitopes and may be ... more IgG antibodies present in newborn sera are primarily directed against ex Gal epitopes and may be implicated in the pathogenesis of the xenograft rejection process. In order to permit prolonged xenograft survival in newborn primates, therapeutic strategies may need to be developed that incorporate techniques to deplete IgG antibodies pretransplant, such as plasmapheresis, together with those which prevent induction of antibody production posttransplant, such as the use of anti-B cell chemotherapeutic agents. REFERENCES 1. Good AH, Cooper DKC, Malcolm, AJ, et al. Identification of carbohydrate structures that bind human anti-pig antibodies: implications for discordant xenografting in humans. Transplant Proc 1992: 24: 559. 2. Galili U. Evolution and pathophysiology of the human natural anti-alpha-galactosyl IgG (anti-Gal) antibody. Springer Semin Immunopathol 1993; 15: 155. 3. Xu H, Edwards NM, Dong X, et al. Age-related development of human preformed anti-porcine endothelial cell xenoantibody.

Clinical cancer research : an official journal of the American Association for Cancer Research, 2002

The development of colon cancer markers that can detect liver metastases early and predict which ... more The development of colon cancer markers that can detect liver metastases early and predict which patients are at risk to develop liver metastases would have a major impact on this disease. We have previously identified G. Brunagel, et al., Cancer Research, 62:2437-2442, 2002, nuclear matrix proteins (NMPs), which are associated with colon cancer. The objective of this study is to identify the existence of a specific NMP "fingerprint" for human liver metastasis from colon cancer. Using high-resolution two-dimensional gel electrophoresis, we analyzed the NMP expression of 12 matched liver metastases and adjacent normal samples and three normal donor liver samples. These were compared with colon cancer NMP patterns, along with several primary cell systems and lines. Analysis of multiple gels for each sample revealed three proteins present in all liver metastases, which are not present in normal liver tissue and normal hepatocytes. These three proteins were also present in col...

Journal of the American College of Surgeons, 2007

cancer cell lines. This combination may have important clinical therapeutic implications.

Gastroenterology, 2010

Background & Aims-Gastroparesis is a well-recognized complication of diabetes. In diabetics, up-r... more Background & Aims-Gastroparesis is a well-recognized complication of diabetes. In diabetics, up-regulation of heme oxygenase-1 (HO1) in gastric macrophages protects against oxidative stressinduced damage. Loss of up-regulation of HO1, the subsequent increase in oxidative stress, and loss of Kit delays gastric emptying; this effect is reversed by induction of HO1. Macrophages have proand anti-inflammatory activities, depending on their phenotype. We investigated the number and phenotype of gastric macrophages in NOD/ShiLtJ (NOD) mice after onset of diabetes, when delayed gastric emptying develops, and after induction of HO1 to reverse delay. Methods-Four groups of NOD and db/db mice were studied: non-diabetic, diabetic with normal emptying, diabetic with delayed gastric emptying, and diabetic with delayed gastric emptying reversed by the HO1 inducer hemin. Whole-mount samples from stomach were labeled in triplicate with antisera against F4/80, HO1, and CD206 and macrophages were quantified in stacked confocal images. Markers for macrophage subtypes were measured by quantitative PCR.

Cytokine, 2009

In hemorrhagic shock and trauma, patients are prone to develop systemic inflammation with remote ... more In hemorrhagic shock and trauma, patients are prone to develop systemic inflammation with remote organ dysfunction, which is thought to be caused by pro-inflammatory mediators. This study investigates the role of the immuno-modulatory cytokine IL-10 in the development of organ dysfunction following hemorrhagic shock. Male C57/BL6 and IL-10 KO mice were subjected to volume controlled hemorrhagic shock for 3h followed by resuscitation. Animals were either sacrificed 3 or 24h after resuscitation. To assess systemic inflammation, serum IL-6, IL-10, KC, and MCP-1 concentrations were measured with the Luminex multiplexing platform; acute lung injury (ALI) was assessed by pulmonary myeloperoxidase (MPO) activity and lung histology and acute liver injury was assessed by hepatic MPO activity, hepatic IL-6 levels, and serum ALT levels. There was a trend towards increased IL-6 and KC serum levels 3h after resuscitation in IL-10 KO as compared to C57/BL6 mice; however this did not reach statistical significance. Serum MCP-1 levels were significantly increased in IL-10 KO mice 3 and 24 h following resuscitation as compared to C57/BL6 mice. In IL-10 KO mice, pulmonary MPO activity was significantly increased 3 h following resuscitation and after 24 h histological signs of acute lung injury were more apparent than in C57/BL6 mice. In contrast, no significant differences in any liver parameters were detected between IL-10 KO and C57/BL6 mice. Our data indicate that an endogenous IL-10 deficiency augments acute lung but not liver injury following hemorrhagic shock.

American Journal of Physiology-Heart and Circulatory Physiology, 2004

The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-α r... more The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-α receptor-1 (TNFR1)-mediated pathways in a murine model of myocardial infarction and remodeling. One hundred and ninety-four wild-type (WT) and TNFR1 gene-deleted (TNFR1KO) mice underwent left coronary artery ligation to induce myocardial infarction. On days 1, 3, 7, and 42, mice underwent transesophageal echocardiography. Hearts were weighed, and the left ventricle (LV) was assayed for matrix metalloproteinase (MMP)-2 and -9 activity and for tissue inhibitor of MMP (TIMP)-1 and -2 expression. Deletion of the TNFR1 gene substantially improved survival because no deaths were observed in TNFR1KO mice versus 56.4% and 18.2% in WT males and females, respectively ( P < 0.002). At 42 days, LV remodeling, assessed by LV function (fractional area change of 31.9 ± 7.9%, 32.2 ± 7.7%, and 21.6 ± 7.1% in TNFR1KO males, TNFR1KO females, and WT females, respectively, P < 0.04), and hypertrophy (he...

Cellular and Molecular Gastroenterology and Hepatology, 2016

Interleukin 10 reversed delayed gastric emptying in diabetic mice. It increased heme oxygenase 1 ... more Interleukin 10 reversed delayed gastric emptying in diabetic mice. It increased heme oxygenase 1 expression and normalized electrical activity and networks of interstitial cells of Cajal in the stomach. Thus, interleukin 10 is a potential therapy for diabetic gastroparesis. BACKGROUND & AIMS: Gastroparesis is a complication of diabetes characterized by delayed emptying of stomach contents and accompanied by early satiety, nausea, vomiting, and pain. No safe and reliable treatments are available. Interleukin 10 (IL10) activates the M2 cytoprotective phenotype of macrophages and induces expression of heme oxygenase 1 (HO1) protein. We investigated whether IL10 administration could improve gastric emptying and reverse the associated cellular and electrical abnormalities in diabetic mice. METHODS: Nonobese diabetic mice with delayed gastric emptying were given either IL10 (0.1-1 mg, twice/day) or vehicle (controls). Stomach tissues were isolated, and sharp microelectrode recordings were made of the electrical activity in the gastric muscle layers. Changes to interstitial cells of Cajal (ICC), reduced nicotinamide adenine dinucleotide phosphate diaphorase, and levels and distribution of HO1 protein were determined by histochemical and imaging analyses of the same tissues. RESULTS: Gastric emptying remained delayed in vehicletreated diabetic mice but returned to normal in mice given IL10 (n ¼ 10 mice; P < .05). In mice given IL10, normalization of gastric emptying was associated with a membrane potential difference between the proximal and distal stomach, and lower irregularity and higher frequency of slow-wave activity, particularly in the distal stomach. Levels of HO1 protein were higher in stomach tissues from mice given IL10, and ICC networks were more organized, better connected, and more evenly distributed compared with controls. CONCLUSIONS: IL10 increases gastric emptying in diabetic mice and has therapeutic potential for patients with diabetic gastroparesis. This response is associated with up-regulation of HO1 and repair of connectivity of ICC networks.

American journal of physiology. Gastrointestinal and liver physiology, Jan 6, 2015

Objective: Myocytes are non-hemopoietic in origin and functionally essential in generating gastro... more Objective: Myocytes are non-hemopoietic in origin and functionally essential in generating gastrointestinal motility. In endotoxemia, a rapid onset non-hemopoietic mechanism potently triggers early ileus in a TLR4/MyD88-dependent manner. Moreover, synergistically with hemopoietic cells, non-hemopoietic cells escalate late ileus via an IL-6 receptor-dependent inflammation-driven pathway. Herein, we therefore specifically investigated the role of myocytes in TLR4-triggered inflammation and ileus. Design: TLR4(+/+), TLR4(-/-), bmTLR4(+/+)/TLR4(-/-) chimera, SM22-Cre(-/-)TLR4(flox/flox) and selective myocyte TLR4-deficient (SM22-Cre(+/-)TLR4(flox/flox)) mice were injected intraperitoneally with purified lipopolysaccharide. SM22-driven Cre recombinase activity was selectively detected in cardiac, gastrointestinal and skeletal myocytes as well as vascular myocytes of small-sized vessels in a two-color fluorescent Cre reporter mouse. In contrast to non-hemopoietic TLR4-deficiency, deletion...

Shock, 2009

Understanding "two-hit" experimental models is crucial for the rational development of therapies ... more Understanding "two-hit" experimental models is crucial for the rational development of therapies for hemorrhagic shock (HS). We modeled the clinical scenario of HS followed by polymicrobial sepsis (cecal ligation and puncture [CLP]) to investigate the molecular and functional alterations that occur within the gastrointestinal tract. Control, HS, CLP, simultaneous HS + CLP, and HS + delayed CLP by 24 h groups of Sprague-Dawley rats were studied for gastrointestinal transit and in vitro colonic circular muscle contractility to bethanechol. Reverse transcription-polymerase chain reaction quantified IL-6, IL-10, and heme oxygenase 1 messenger RNA expression in the isolated colonic muscularis 6 h after insult. Myeloperoxidase-positive neutrophils were quantified in colonic muscularis whole mounts. Mortality at 24 h was significantly increased in simultaneous mild HS + CLP (88%) over control, mild HS, CLP alone, or HS + delayed CLP. Cecal ligation and puncture significantly delayed transit compared with controls and HS alone. Hemorrhagic shock + delayed CLP animals had normal transit. Colonic contractions were suppressed by 50% after CLP compared with controls and HS. In contrast, HS + delayed CLP displayed control levels of contractile responses to bethanechol. Cecal ligation and puncture and simultaneous HS + CLP caused significant inflammatory messenger RNA induction of IL-6, iNOS, IL-10, and heme oxygenase 1 compared with control and HS, and these responses were significantly suppressed in HS + delayed CLP colonic muscularis extracts. Neutrophils were significantly recruited into the colonic muscularis following CLP after 24 h compared with control and HS. This recruitment was significantly less in the HS + delayed CLP animals. These data demonstrate the ability of mild HS to precondition the animal and protect it against a delayed, but not simultaneous, polymicrobial event.

Digestive Diseases and Sciences - DIGEST DIS SCI, 2001

Recovery from hemorrhagic shock (HS) is frequently accompanied by bowel stasis. The aim of this s... more Recovery from hemorrhagic shock (HS) is frequently accompanied by bowel stasis. The aim of this study was to examine whether or not HS initiates an inflammatory response that includes production of cytokines, specifically G-CSF and interleukin-6 (IL-6), and recruitment of leukocytes within the intestinal muscularis which contribute to impaired muscle contractility. Sprague-Dawley rats were subjected to HS (MAP 40 mm Hg for 156 min) followed by resuscitation, and then they were killed at 4 hr. Shock animals demonstrated accumulation of PMNs in the jejunal muscularis and decreased spontaneous and bethanechol-stimulated muscle contractility. Semiquantitative RT-PCR demonstrated elevated levels of IL-6 and G-CSF mRNA in shock animals in full-thickness jejunum and in mucosa and muscularis layers compared to sham controls. Immunostaining demonstrated increased IL-6 protein production within the muscularis externa and submucosa. In situ hybridization studies localized G-CSF mRNA production...

Neurogastroenterology & Motility, 2010

Our bacterial residents are deadly Janus-faced indwellers which can lead to a septic-induced syst... more Our bacterial residents are deadly Janus-faced indwellers which can lead to a septic-induced systemic inflammatory response syndrome and multiple organ failure. Over half of ICU patients suffer from infections and sepsis remains among the top ten causes of death in the United States. Severe ileus frequently accompanies sepsis setting up an insidious cycle of gut-derived microbial translocation and the copious intestinal production of potent systemic inflammatory mediators. Few therapeutic advances have occurred to prevent/treat the sequelae of sepsis. Here, we selectively review studies on cellular membrane bound Toll-like receptor (TLR) mechanisms of ileus. Virtually no data exists on Gram-positive/TLR2 signaling mechanisms of ileus, however, TLR2 is highly inducible by numerous inflammatory mediators and studies using clinically relevant scenarios of Gram-positive sepsis are needed. Specific Gram-negative/TLR4 signaling pathways are being elucidated using a "reverse engineering" approach and have revealed that endotoxin induced ileus is dually mediated by classical leukocyte inflammatory signaling and by a MyD88-dependent non-bone marrow derived mechanism, but the specific roles of individual cell populations are still unknown. Like TLR2, little is also know of the role of flagellin/TLR5 signaling in ileus. But, much can be learned by understanding TLR signaling in other systems. Clearly, the use of polymicrobial models provide important clinical relevancy but simultaneous activation of virtually all pattern recognition receptors make it impossible to discretely study specific signaling pathways. We believe that dissection of individual TLR pathways, which can then be intelligently reassembled in a meaningful manner, will provide insight into treatments for sepsis induced ileus.

Neurogastroenterology and Motility, 2004

Complex circuits involving both local intrinsic neurones (i.e. enteric nervous system; ENS) and e... more Complex circuits involving both local intrinsic neurones (i.e. enteric nervous system; ENS) and extrinsic neurones achieve nervous control of digestive functions. The ENS is comprised of many functionally different types of neurons: sensory neurons, interneurons and secreto-motor neurons. Each neuronal population is required to manifest local reflex behavior and is central to the regulation of both motor and secretory activities. It must be emphasized, however, that not only muscle and secretory cells but also other intestinal cells are targeted by enteric neurones, i.e. endocrine cells, interstitial cells of Cajal, immune cells, blood vessels and enteric glia. In addition to the ENS the gastrointestinal tract receives an extrinsic innervation by sympathetic, parasympathetic and sensory fibres. Neuronal projections from the intestine to prevertebral ganglia also exist. Taken together, the picture of a complex nervous regulation of digestive functions highly integrated with the central nervous system and the rest of the autonomic nervous system has emerged. The ENS is adaptive and plastic, but also vulnerable, system and ENS disturbances may be of pathogenic importance in functional bowel disease. In particular the interplay between the enteric neurones and the immune cells is suggested to be of crucial importance. The review discusses possible roles of the mediators vasoactive intestinal peptide (VIP) and prostanoids in ENS plasticity in response to injury and inflammation.

Neurogastroenterology & Motility, 2012

Background-Early murine endotoxin-induced ileus at 6 hours is exclusively mediated by nonhemopoie... more Background-Early murine endotoxin-induced ileus at 6 hours is exclusively mediated by nonhemopoietic TLR4/MyD88 signaling despite molecular activation of hemopoietic cells which included a significant IL-6 mRNA induction. Our objective was to define the role of hemopoietic cells in LPS/TLR4-triggered ileus and inflammation over time, and identify mechanisms of ileus. Methods-CSF-1 −/− , TLR4 non-chimera and TLR4 chimera mice were single-shot injected with intraperitoneal ultrapure lipopolysaccharide (UP-LPS) and studied up to 4 days. Subgroups of TLR4 WT mice were additionally intravenously injected with exogenous recombinant IL-6 (rmIL-6) or murine soluble IL-6 receptor blocking antibody (anti-sIL-6R mAB). Key Results-Hemopoietic TLR4 signaling independently mediated UP-LPS-induced ileus at 24 hours, but chemotactic muscularis neutrophil extravasation was not causatively involved and mice lacking CSF-1-dependent macrophages died prematurely. Synergy of hemopoietic and nonhemopoietic cells determined ileus severity and mortality which correlated with synergistic cell lineage specific transcription of inflammatory mediators like IL-6 within the intestinal muscularis. Circulating IL-6 levels were LPS-dose dependent, but exogenous rmIL-6 did not spark off a selfperpetuating inflammatory response triggering ileus. Sustained therapeutic inhibition of functional IL-6 signaling efficiently ameliorated late ileus while preemptive antibody-mediated IL-6R blockade was marginally effective in mitigating ileus. However, IL-6R blockade did not prevent endotoxin-associated mortality nor did it alter circulating IL-6 levels. Conclusions and Inferences-A time-delayed bone marrow-driven mechanism of murine endotoxin-induced ileus exists, and hemopoietic cells synergize with non-hemopoietic cells 1 This study was supported in parts by grants from the National Institutes of Health (R01-GM58241, R01-DK068610, P50-GM-53789, and DK02488) and from the Deutsche Forschungsgemeinschaft Bu 2403/2-1 (B.M.B.).

Neurogastroenterology & Motility, 2011

Background-Trauma is a leading cause of death and although the gut is recognized as the "motor" o... more Background-Trauma is a leading cause of death and although the gut is recognized as the "motor" of post-traumatic systemic inflammatory response syndrome and multiple organ failure, studies on the gastrointestinal tract are few. Our objectives were to create a precisely controllable tissue injury model in which gastrointestinal motility, systemic inflammation and wound fluid can be analyzed. Methods-A non-narcotic murine trauma model was developed by the subcutaneous dorsal trans-implantation of a devitalized donor syngeneic harvested tissue-bone matrix (TBX), which was precisely adjusted to % total body weight and studied after 21 hrs. Gastrointestinal transit histograms were plotted after the oral administration of non-digestible FITC-dextran and geometric centers calculated. Organ bath evaluated jejunal circular muscle contractility. Multiplex

Journal of Pharmacology and Experimental Therapeutics, 2006

Treatment with inhaled carbon monoxide (CO) has been shown to ameliorate bowel dysmotility caused... more Treatment with inhaled carbon monoxide (CO) has been shown to ameliorate bowel dysmotility caused by surgical manipulation of the gut in experimental animals. We hypothesized that administration of CO dissolved in lactated Ringer's solution (CO-LR) might provide similar protection to that observed with the inhaled gas while obviating some its inherent problems. Post-operative gut dysmotility (ileus) was induced in mice by surgical manipulation of the small intestine. Some mice were treated with a single intraperitoneal dose of CO-LR immediately after the surgical procedure, whereas other mice received only the LR vehicle. Twenty-four h later, intestinal transit of a nonabsorbable marker (70 kDa FITC-labeled dextran) was delayed in mice subjected to intestinal manipulation but not the sham procedure. Gut manipulation also was associated with increased expression within the muscularis propria of transcripts for IL-1β, cyclooxygenase-2, inducible nitric oxide synthase, intracellular adhesion molecule-1 and Toll-like receptor-4, as well as infiltration of the muscularis propria with polymorphonuclear leukocytes and activation of mitogen-activated protein kinases and nuclear factor-κB. All of these effects were attenuated by treatment with CO-LR. The salutary effect of CO-LR on gut motility as well as many of the anti-inflammatory effects of CO-LR was diminished by treatment with a soluble guanylyl cyclase (sGC) inhibitor, suggesting that the effects of CO are mediated via activation of sGC. These data support the view that a single intraperitoneal dose of CO-LR ameliorates post-operative ileus in mice, by inhibiting the inflammatory response in the gut wall induced by surgical manipulation, possibly in a sGCdependent fashion.