Cyclical upregulated iNOS and long-term downregulated nNOS are the bases for relapse and quiescent phases in a rat model of IBD

We previously reported that indomethacin induces a chronic intestinal inflammation in the rat where the cyclical characteristic phases of Crohn's disease are manifested with a few days' interval and lasting for several months: active phase (high inflammation, hypomotility, bacterial translocation) and reactive phase (low inflammation, hypermotility, no bacterial translocation). In this study, we investigated the possible role of both constitutive and inducible isoforms of nitric oxide (NO) synthase (NOS) and cyclooxygenase (COX) in the cyclicity of active and reactive phases in rats with chronic intestinal inflammation. Rats selected at either active or reactive phases and from 2 to 60 days after indomethacin treatment were used. mRNA expression of both constitutive and inducible NOS and COX isoforms in each phase was evaluated by RT-PCR and cellular enzyme localization by immunohistochemistry. The effects of different COX and NOS inhibitors on the intestinal motor activity were tested. mRNA expression of COX-1 was not modified by inflammation, whereas mRNA expression of neuronal NOS was reduced in all indomethacin-treated rats. In contrast, NOS and COX inducible forms showed a cyclical oscillation. mRNA expression and protein of both iNOS and COX-2 increased only during active phases. The intestinal hypomotility associated with active phases was turned into hypermotility after the administration of selective iNOS inhibitors. Sustained downregulation of constitutive NOS caused hypermotility, possibly as a defense mechanism. However, this reaction was masked during the active phases due to the inhibitory effects of NO resulting from the increased levels of the inducible NOS isoform.     

Protection by constitutively formed nitric oxide of intestinal damage induced by indomethacin in rats.

In the present study, we investigated a protective role of constitutively occurred nitric oxide (NO) against indomethacin-induced intestinal lesions in rats. Indomethacin (10 mg/kg) was given s.c. to animals without fasting, and the intestinal mucosa was examined for lesions 24 h later. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) was given s.c. 0.5 h before or 6 hr after indomethacin, while the NO donor (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexnamine (NOR-3) was given s.c. 0.5 h before indomethacin. Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility and bacterial translocation. These lesions were markedly prevented or worsened, respectively, by later or prior administration of L-NAME (20 mg/kg), in a L-arginine-sensitive manner. The worsening effect of L-NAME (5-20 mg/kg) on these lesions was dose-dependently observed in association with further enhancement of the bacterial translocation and intestinal hypermotility following indomethacin. By contrast, prior administration of NOR-3 (1-6 mg/kg) dose-dependently prevented the development of intestinal lesions, together with suppression of the bacterial translocation and intestinal hypermotility in response to indomethacin. On the other hand, both indomethacin and L-NAME decreased intestinal mucus and fluid (water) secretion in the small intestine, while NOR-3 increased these secretions. These results suggest that (1) NO occurred constitutively exerts a protective action against indomethacin-induced intestinal ulceration, and (2) this effect is related with prevention of bacterial translocation, the process functionally associated with increase of mucus and fluid secretions as well as inhibition of intestinal hypermotility.     

益生菌对炎症性肠病幼鼠 Th17细胞的调节作用

目的观察鼠李糖乳杆菌(LGG)对炎症性肠病(IBD)幼鼠结肠白细胞介素-17A (IL-17A)水平的影响,探讨益生菌对Th17细胞的调节作用。方法 36只健康雄性SD幼鼠随机分4组:空白对照组、LGG对照组各8只,IBD组、IBD-LGG组各10只。利用2,4,6-三硝基苯磺酸(TNBS)诱导幼鼠IBD模型,观察一般状况、IBD疾病活动指数评分。第8天处死所有幼鼠,留取结肠标本,观察病理改变并采用免疫组织化学法测定结肠组织IL-17A的表达。结果相比两对照组,IBD组、IBD-LGG组幼鼠一般状态差,IBD-LGG组便性状及隐血较IBD组缓解;IBD组、IBD-LGG组幼鼠结肠组织均见炎症改变,但IBD-LGG组较轻。IBD-LGG组DAI评分、IL-17A水平均低于IBD组,差异有统计学意义(Ps0.05)。结论益生菌可减轻IBD幼鼠肠道炎症,其机制可能与益生菌调节Th17细胞进而调控IL-17A表达有关。     

Protection by aspirin of indomethacin-induced small intestinal damage in rats: mediation by salicylic acid.

Most of non-steroidal anti-inflammatory drugs (NSAIDs) except aspirin (ASA) produce intestinal damage in rats. In the present study, we re-examined the intestinal toxic effect of ASA in rats, in comparison with various NSAIDs, and investigated why ASA does not cause damage in the small intestine, in relation to its metabolite salicylic acid (SA). Various NSAIDs (indomethacin; 10 mg/kg; flurbiprofen; 20 mg/kg; naproxen; 40 mg/kg; dicrofenac; 40 mg/kg; ASA; 20-200 mg/kg) were administered s.c., and the small intestinal mucosa was examined macroscopically 24 h later. All NSAIDs tested, except ASA, caused hemorrhagic lesions in the small intestine, with a decrease of mucosal PGE(2) contents. ASA did not provoke any damage, despite inhibiting (prostaglandin) PG production, and prevented the occurrence of intestinal lesions induced by indomethacin, in a dose-related manner. This protective action of ASA was mimicked by the equimolar doses of SA (17.8-178 mg/kg). Indomethacin caused intestinal hypermotility, in preceding to the occurrence of lesion, and this event was followed by increases of enterobacterial translocation in the mucosa. Both ASA and SA prevented both the intestinal hypermotility and the bacterial translocation seen after indomethacin treatment. In addition, the protective effect of SA was not significantly influenced by either the adenosine deaminase or the adenosine receptor antagonists. Following administration of ASA, the blood SA levels reached a peak within 30 min and remained elevated for more than 7 h. These results suggest that SA has a cytoprotective action against indomethacin-induced small intestinal lesions, and this action may be associated with inhibition of the intestinal hypermotility and the bacterial translocation, but not mediated by endogenous adenosine. Failure of ASA to induce intestinal damage may be explained, at least partly, by a protective action of SA, the metabolite of ASA.     

骶神经电刺激对脊髓损伤大鼠肠黏膜机械屏障的保护作用

目的：观察骶神经电刺激对脊髓损伤大鼠肠黏膜机械屏障的保护作用。方法：56只Wistar大鼠分7组（n=8）：正常组、急性完全性脊髓损伤（SCI）组和骶神经电刺激组（按24、48、72h各8只）。进行内毒素测定;肠系膜淋巴结、肝脏、脾脏菌培养;肠道形态学观察;紧密连接蛋白zo-1的蛋白表达测定。结果：对照组肠黏膜不同程度损伤;肠道上皮细胞及细胞间连接破坏;内毒素血症和细菌移位明显。实验组肠黏膜得到改善,内毒素水平下降且细菌移位减少。ZO-1蛋白表达无统计学差异。对照组ZO-1的分布出现不同程度的散乱、排列不规则,实验组分布得到改善。结论：骶神经电刺激可促肠蠕动、排肠内容物、减少肠道菌群数量,保护肠黏膜上皮细胞及紧密连接的机械屏障,减少细菌移位和内毒素血症。     

大承气汤对MODS时肠道细菌微生态学影响的实验研究

目的探讨多器官功能不全综合征(MODS)大鼠肠道细菌微生态的变化及其与肠源性内毒素血症和细菌易位的关系,并观察大承气汤的影响。方法32只SD大鼠随机分成4组,对照组、模型组、大承气组和氨苄青霉素组。腹腔注射无菌酵母多糖A制备大鼠MODS模型。各组动物于造模后48 h无菌操作抽取外周静脉血和门静脉血进行内毒素含量测定;取肠系膜淋巴结进行细菌定量培养,取回肠和盲肠内容物进行肠腔内游离内毒素测定;取盲肠内容物进行肠道细菌微生态学分析。结果模型组外周血和门静脉血内毒素水平以及肠腔内游离内毒素含量均明显高于对照组(P<0.05);与对照组相比,模型组肠道菌群出现明显变化。肠球菌、肠杆菌数量明显增加,而双歧杆菌和乳酸杆菌数量出现显著下降,类杆菌数量亦出现明显下降(P<0.05)。模型组厌氧菌总数明显下降而需氧菌总数明显增加,同时厌氧菌总数/需氧菌总数的比值和B/E比值呈相应下降,发生倒置(P<0.05);正常对照组未发现肠道细菌向肠系膜淋巴结的易位,而模型组细菌易位阳性率是83.33%(P<0.05)。与模型组相比,大承气汤组上述各指标均出现明显变化(P<0.05);抗生素组作用不明显(P>0.05)。结论MODS时大鼠肠道细菌微生态出现明显变化,发生肠源性内毒素血症和细菌易位。大承气汤可以调整肠道菌群,恢复肠道微生态平衡,增加机体定植抗力,防治细菌易位和内毒素血症。     

Semi-stochastic cell-level computational modeling of the immune system response to bacterial infections and the effects of antibiotics

A mathematical model for the immune system response to bacterial infections is proposed. The formalism is based on modeling the chemokine-determined transmigration of leukocytes from a venule through the venule walls and the subsequent in-tissue migration and engulfment of the pathogens that are responsible for the infection. The model is based on basic principles, such as Poiseuille blood flow through the venule, fundamental solutions of the diffusion–reaction equation for the concentration field of pathogen-released chemokines, linear chemotaxis of the leukocytes, random walk of pathogens, and stochastic processes for the death and division of pathogens. Thereby, a computationally tractable and, as far as we know, original framework has been obtained, which is used to incorporate the interaction of a substantial number of leukocytes and thereby to unravel the significance of biological processes and parameters regarding the immune system response. The developed model provides a neat way for visualization of the biophysical mechanism of the immune system response. The simulations indicate a weak correlation between the immune system response in terms of bacterial clearing time and the leukocyte stiffness, and a significant decrease in the clearing time with increasing in-blood leukocyte density, decreasing pathogen motility, and increasing venule wall transmissivity. Finally, the increase in the pathogen death rate and decrease in pathogen motility induce a decrease in the clearing time of the infection. The adjustment of the latter two quantities mimic the administration of antibiotics.     

GPR65 (TDAG8) inhibits intestinal inflammation and colitis-associated colorectal cancer development in experimental mouse models

GPR65 (TDAG8) is a proton-sensing G protein-coupled receptor predominantly expressed in immune cells. Genome-wide association studies (GWAS) have identified GPR65 gene polymorphisms as an emerging risk factor for the development of inflammatory bowel disease (IBD). Patients with IBD have an elevated risk of developing colorectal cancer when compared to the general population. To study the role of GPR65 in intestinal inflammation and colitis-associated colorectal cancer (CAC), colitis and CAC were induced in GPR65 knockout (KO) and wild-type (WT) mice using dextran sulfate sodium (DSS) and azoxymethane (AOM)/DSS, respectively. Disease severity parameters such as fecal score, colon shortening, histopathology, and mesenteric lymph node enlargement were aggravated in GPR65 KO mice compared to WT mice treated with DSS. Elevated leukocyte infiltration and fibrosis were observed in the inflamed colon of GPR65 KO when compared to WT mice which may represent a cellular mechanism for the observed exacerbation of intestinal inflammation. In line with high expression of GPR65 in infiltrated leukocytes, GPR65 gene expression was increased in inflamed intestinal tissue samples of IBD patients compared to normal intestinal tissues. Moreover, colitis-associated colorectal cancer development was higher in GPR65 KO mice than WT mice when treated with AOM/DSS. Altogether, our data demonstrate that GPR65 suppresses intestinal inflammation and colitis-associated tumor development in murine colitis and CAC models, suggesting potentiation of GPR65 with agonists may have an anti-inflammatory therapeutic effect in IBD and reduce the risk of developing colitis-associated colorectal cancer.     

Alterations of intestinal motor responsiveness in a model of mild mesenteric ischemia/reperfusion in rats

In this study we investigate the changes in intestinal motor responsiveness after mild mesenteric ischemia/reperfusion in anaesthetized rats. Motor responsiveness to pharmacological/electrical stimulation was studied in isolated ileum excised from sham-operated rats or animals which underwent occlusion of superior mesenteric artery (1 h) plus interruption of collateral blood flow and reperfusion for 0, 24, 72 h. Only 24 h reperfusion resulted in a significant suppression in acetylcholine induced contractile response and in indomethacin induced relaxation. In the presence of adrenergic and cholinergic blockade a greater relaxant response to field stimulation (trains 10 s every min, 120 mA, 1 ms and 10 Hz) was unmasked in all groups except 24 h reperfused rats. Such effect was sensitive to N(G)-Nitro-L-arginine methyl ester (NOS unselective inhibitor) and the proteolytic enzyme alpha-chymotrypsin but resistant to aminoguanidine (iNOS selective inhibitor). In conclusion, in this rat model, intestinal mild ischemia/24 h reperfusion induces reversible changes in enteric motility attributable to a decrease in eicosanoids, nitric oxide and neuropeptides availability.     

Role of intercellular adhesion molecule 1 in indomethacin-induced ileitis

Adhesion molecules have been implicated in the pathogenesis of inflammatory bowel diseases. We investigated their expression and contribution to leukocyte recruitment in experimental intestinal inflammation. Ileitis was induced in Sprague-Dawley rats by two injections of indomethacin (7.5 mg/kg), given 24 h apart. Endothelial intercellular adhesion molecule-1 (ICAM-1) expression was quantified using the dual radiolabeled monoclonal antibody technique and Mac-1 (CD11b/CD18) expression on leukocytes by flow cytometry. Leukocyte infiltration was monitored by tissue myeloperoxidase (MPO) activity. The first indomethacin injection induced a time- and site-dependent increase of ICAM-1 expression in ileal mucosa and muscularis. The second injection resulted in a reduction of ICAM-1 expression below constitutive levels whereas Mac-1 was upregulated. MPO changes paralleled lesion development over 48 h. ICAM-1 and MPO values were correlated for the first 24 h. Immunoneutralization of either ICAM-1 or Mac-1 attenuated mucosal injury. We conclude that (i) indomethacin-induced ileitis is associated with a temporally disassociated upregulation of ICAM-1 and (ii) despite a reduction in ICAM-1 after 24 h, ICAM-1, in concert with Mac-1, contributes to mucosal injury and leukocyte infiltration elicited by indomethacin.     

Green Fluorescent Protein Labeling Escherichia coli TG1 Confirms Intestinal Bacterial Translocation in a Rat Model of Chemotherapy

It has been reported that treatment with methotrexate (MTX) induces intestinal bacterial translocation; however, the definitive evidence of intestinal bacterial translocation induced by MTX has been lacking. The aim of this study was to confirm the intestinal bacterial translocation caused by MTX and to evaluate the preventive effect of granulocyte colony-stimulating factor (G-CSF) on intestinal bacterial translocation caused by MTX. Sprague-Dawley rats were treated with MTX (3.5 mg/kg) for 3 days to induce intestinal bacterial translocation; with gavaged Escherichia coli TG1 labeled with green fluorescent protein (GFP) for 2 days to track intestinal bacterial translocation; and with G-CSF (10 μg/kg) for 4 days to prevent intestinal bacterial translocation. Representative tissue specimens from the mesenteric lymph nodes, spleen, liver, and kidney were aseptically harvested for bacteria culture in ampicillin-supplemented medium. The bacteria labeled with GFP were detected in tissue specimens harvested from the rats treated with MTX but not detected in the rats that were not treated with MTX. G-CSF significantly ameliorated the situation of intestinal bacterial translocation.     

The predominant contribution of platelets to baseline and ascorbate-stimulated increments in cyclic GMP in human mononuclear leukocyte preparations.

In nine consecutive experiments with Ficoll-Hypaque-purified human mononuclear leukocytes containing 2.8 (range 1.1–4.3) platelets per leukocyte, 2–5 mM sodium ascorbate produced a 14-fold (range, 7- to 18-fold) rise in guanosine 3′: 5′-cyclic monophosphate (cyclic GMP) from baseline levels of 0.103 ± 0.056 pmol/10⁷ mononuclear leukocytes. In five experiments with mononuclear leukocytes prepared by the Ficoll-Hypaque method from human blood depleted of platelets by defibrination, 2–5 mM sodium ascorbate produced a twofold (range, one- to fourfold) rise in cyclic GMP from baseline levels of 0.030 ± 0.012 pmol/10⁷ mononuclear leukocytes. Thus, platelets contribute substantially to baseline and ascorbate-stimulated levels of cyclic GMP in standard Ficoll-Hypaque preparations of mononuclear leukocytes. The rise in cyclic GMP concentration in mononuclear leukocyte preparations elicited by ascorbate was independent of a calcium requirement, persisted for up to 3 hr in the presence of ascorbate, and was prevented by the introduction of nonsteroidal anti-inflammatory agents such as aspirin and indomethacin (ID₅₀ = 105 and 23.5 μM, respectively).     

大鼠失血性休克后肠道微生态的改变

本研究对无特殊致病菌大鼠失血性休克后肠道微生态的改变及肠道细菌易位进行了动态观察。结果表明,失血性休克复苏后5小时,肠道微生态即发生改变,表现为回肠内肠杆菌菌量增多,肠道内类杆菌与肠杆菌菌量比值下降,而后这一改变随时间推移逐渐恢复;肠道细菌易位率也有类似变化,易位细菌以肠杆菌为主。结果提示,大鼠失血性休克后肠道细菌易位与肠道微生态的改变有密切关系。     

PECAM-1 (CD 31) mediates transendothelial leukocyte migration in experimental colitis

Transendothelial migration of circulating leukocytes into the colonic wall is a key step in the development of the inflammatory infiltrate in inflammatory bowel disease (IBD). The platelet-endothelial cell adhesion molecule-1 PECAM-1 (CD31) is expressed in the tight junction area of endothelial cells, where it is supposed to support the transmigration process. The aim of this study was to determine the role of PECAM-1 in experimental IBD and to show whether blockade of PECAM-1 has therapeutic effects. Chronic colitis was induced in female BALB/c mice by cyclic oral administration of dextran sodium sulfate (DSS) 3% (wt/vol). Expression of PECAM-1 was visualized by immunohistochemistry. In the treatment group animals received 1 mg/kg anti-PECAM-1 (2H8) ip daily starting on day 26. On day 30 leukocyte adhesion and migration was measured during N(2)O-isoflurane anesthesia in the distal colon by intravital microscopy. Disease activity index (DAI), histology, and MPO levels were compared with healthy and diseased controls. PECAM-1 was expressed in colitic mice. Chronic DSS colitis was characterized by a marked increase in rolling, adherent, and transmigrated leukocytes compared with healthy controls. Immunoblockade of PECAM-1 reduced leukocyte transmigration significantly and also diminished leukocyte rolling and sticking in an indirect manner. It also resulted in a significantly diminished DAI and MPO levels, as well as an amelioration of the histological inflammation score. PECAM-1 plays an important role in transendothelial leukocyte migration in DSS colitis. PECAM-1 could be a novel target for antibody-based treatment in IBD.     

Progressive myelopathy in older German shepherd dogs. II. Presence of circulating suppressor cells

Progressive myelopathy in the German shepherd dog is a degenerative neurologic disease of unknown etiology. Results presented in a previous study indicated a depression in the response to thymus-dependent mitogens by peripheral blood leukocytes obtained from dogs with progressive myelopathy. Data presented here indicate that this depressed response to mitogens was associated with the presence of peripheral blood suppressor cells. Suppressor cell activity was detected in dogs that were severely affected with PM, but was not apparent in dogs that were mildly affected. Peripheral blood leukocytes obtained from dogs with progressive myelopathy suppressed the mitogenic response to autologous lymph node cells as well as allogeneic normal canine peripheral blood cells. The suppressor cells had the capacity to suppress mixed leukocyte reactions. Suppressor cell activity was radioresistant. Both nylon wool-adherent and -nonadherent peripheral blood leukocyte populations contained suppressor activity. Suppressive activity diminished after incubation of the suppressor cells with indomethacin, suggesting that suppression may be mediated by the release of prostaglandins. Although a role for peripheral blood suppressor cells in the disease process has not yet been established, it is possible that this abnormal regulatory activity reflects an attempt by the host to control an autoimmune event.     

Gastric prostacyclin (PGI2) prevents stress-induced gastric mucosal injury in rats primarily by inhibiting leukocyte activation.

We investigated whether, in rats, gastric prostacyclin (PGI2) prevented gastric mucosal injury that was induced by water-immersion restraint stress by inhibiting leukocyte activation. Gastric levels of 6-keto-PGF1alpha, a stable metabolite of PGI2, increased transiently 30 min after stress, followed by a decrease to below the baseline 6-8 h after stress. Gastric mucosal blood flow decreased to approximately 40% of the baseline level 8 h after stress. Myeloperoxidase activity was significantly increased 8 h after stress. Treatment with indomethacin before stress inhibited the increase in 6-keto-PGF1alpha levels and markedly reduced mucosal blood flow. It also markedly increased leukocyte accumulation and mucosal lesion formation. Iloprost, a stable PGI2 analog, inhibited the indomethacin-induced decrease in mucosal blood flow, mucosal lesion exacerbation, and increase in leukocyte accumulation. Nitrogen mustard-induced leukocytopenia inhibited the indomethacin-associated lesion exacerbation and the increase in leukocyte accumulation, but not the decreases in mucosal blood flow. These observations indicate that gastric PGI2 decreases gastric mucosal lesion formation primarily by inhibiting leukocyte accumulation.     

Gut-associated lymphoid T cell suppression enhances bacterial translocation in alcohol and burn injury

The mechanism of alcohol-mediated increased infection in burn patients remains unknown. With the use of a rat model of acute alcohol and burn injury, the present study ascertained whether acute alcohol exposure before thermal injury enhances gut bacterial translocation. On day 2 postinjury, we found a severalfold increase in gut bacterial translocation in rats receiving both alcohol and burn injury compared with the animals receiving either injury alone. Whereas there were no demonstrable changes in intestinal morphology in any group of animals, a significant increase in intestinal permeability was observed in ethanol- and burn-injured rats compared with the rats receiving either injury alone. We further examined the role of intestinal immune defense by determining the gut-associated lymphoid (Peyer's patches and mesenteric lymph nodes) T cell effector responses 2 days after alcohol and burn injury. Although there was a decrease in the proliferation and interferon-gamma by gut lymphoid T cells after burn injury alone; the suppression was maximum in the group of rats receiving both alcohol and burn injuries. Furthermore, the depletion of CD3(+) cells in healthy rats resulted in bacterial accumulation in mesenteric lymph nodes; such CD3(+) cell depletion in alcohol- and burn-injured rats furthered the spread of bacteria to spleen and circulation. In conclusion, our data suggest that the increased intestinal permeability and a suppression of intestinal immune defense in rats receiving alcohol and burn injury may cause an increase in bacterial translocation and their spread to extraintestinal sites.     

Factor associated with neutral sphingomyelinase activity mediates navigational capacity of leukocytes responding to wounds and infection: live imaging studies in zebrafish larvae

Factor associated with neutral sphingomyelinase activity (FAN) is an adaptor protein that specifically binds to the p55 receptor for TNF (TNF-RI). Our previous investigations demonstrated that FAN plays a role in TNF-induced actin reorganization by connecting the plasma membrane with actin cytoskeleton, suggesting that FAN may impact on cellular motility in response to TNF and in the context of immune inflammatory conditions. In this study, we used the translucent zebrafish larvae for in vivo analysis of leukocyte migration after morpholino knockdown of FAN. FAN-deficient zebrafish leukocytes were impaired in their migration toward tail fin wounds, leading to a reduced number of cells reaching the wound. Furthermore, FAN-deficient leukocytes show an impaired response to bacterial infections, suggesting that FAN is generally required for the directed chemotactic response of immune cells independent of the nature of the stimulus. Cell-tracking analysis up to 3 h after injury revealed that the reduced number of leukocytes is not due to a reduction in random motility or speed of movement. Leukocytes from FAN-deficient embryos protrude pseudopodia in all directions instead of having one clear leading edge. Our results suggest that FAN-deficient leukocytes exhibit an impaired navigational capacity, leading to a disrupted chemotactic response.     

Circadian coupling between pancreatic secretion and intestinal motility in humans

Human interdigestive intestinal motility follows a circadian rhythm with reduced nocturnal activity, but circadian pancreatic exocrine secretion is unknown. To determine whether circadian changes in interdigestive pancreatic secretion occur and are associated with motor events, pancreatic enzyme outputs, proximal jejunal motility, and plasma pancreatic polypeptide concentrations were measured during consecutive daytime and nighttime periods (12 h each) in seven healthy volunteers using orojejunal multilumen intubation. Studies were randomly started in the morning or evening. Nocturnally, motility decreased (motor quiescence: 67 +/- 22 vs. 146 +/- 37 min; motility index: 3.59 +/- 0.33 vs. 2.78 +/- 0.40 mmHg/min; both P < 0.05) but amylase output increased (273 +/- 78 vs. 384 +/- 100 U/min; P < 0.05) and protease output remained unchanged (P > 0.05); consequently, enzyme/motility ratio increased. Amylase outputs were always lowest during phase I. Motor but not pancreatic circadian activities were associated with sleep. Pancreatic polypeptide plasma concentrations were unchanged. Consequently, intestinal motor and pancreatic exocrine functions may have different circadian rhythms, i.e., decreased motor and stable secretory activity during the night. However, the association between individual phases of interdigestive motor and secretory activity is preserved. The nocturnal increase in enzyme/motility ratio is probably not caused by increased cholinergic tone.     

Effects of leukocyte random motility and chemotaxis in tissue inflammatory response.

A rapidly growing body of experimental evidence indicates that defects in leukocyte motility and chemotactic response correlate with increased susceptibility to and severity of bacterial infection in tissue. While this is understandable in qualitative terms, the sensitivity of the correlation is remarkable.In the present study, a theoretical analysis has been developed to relate the dynamics of bacterial growth to the growth and transport parameters of bacteria and leukocytes in tissue. The model considers a local tissue region in the vicinity of a venule and applies continuum unsteady state species conservation equations to the bacterial population, the phagocytic leukocytes, and a chemotactically active chemical mediator assumed to be produced by the bacteria. The analysis quantifies the effects of key parameters, such as leukocyte random motility and chemotactic coefficients, phagocytic and growth rate constants, and leukocyte vessel wall permeability, upon host ability to eliminate the bacteria.As an example, the model's predictions are compared to experimental results correlating inhibition of leukocyte chemotaxis by hemoglobin with its adjuvant action in experimental peritoneal infection by E. coli.