Reduction In Mucosal Blood Flow Research Articles

Role of the Vanins-Myeloperoxidase Axis in Colorectal Carcinogenesis.

The presence of chronic inflammation in the colonic mucosa leads to an increased risk of cancer. Among proteins involved in the regulation of mucosal inflammation and that may contribute both to structural damage of the intestinal mucosa and to intestinal carcinogenesis, there are myeloperoxidase (MPO) and vanins. The infiltration of colonic mucosa by neutrophils may promote carcinogenesis through MPO, a key enzyme contained in the lysosomes of neutrophils that regulates local inflammation and the generation of reactive oxygen species (ROS) and mutagenic species. The human vanin gene family consists of three genes: vanin-1, vanin-2 and vanin-3. All vanin molecules are pantetheinases, that hydrolyze pantetheine into pantothenic acid (vitamin B5), and cysteamine, a sulfhydryl compound. Vanin-1 loss confers an increased resistance to stress and acute intestinal inflammation, while vanin-2 regulates adhesion and transmigration of activated neutrophils. The metabolic product of these enzymes has a prominent role in the inflammation processes by affecting glutathione levels, inducing ulcers through a reduction in mucosal blood flow and oxygenation, decreasing local defense mechanisms, and in carcinogenesis by damaging DNA and regulating pathways involved in cell apoptosis, metabolism and growth, as Nrf2 and HIF-1α.

Red Blood Cell Storage in Transfusion-Related Acute Gut Injury

Transfusion-related acute gut injury is defined as the occurrence of necrotizing enterocolitis 48 hours or less after a packed red blood cell (PRBC) transfusion for marked anemia in older, low-risk infants born at extremely low gestational ages (<28 weeks’ gestational age) who are no longer experiencing any historically associated risk factors except enteral feeding. As oxygen delivery decreases with advancing anemia, growing premature neonates compensate by redistribution of blood flow, increased cardiac output, and elevated oxygen extraction. Further adjustments to microvascular blood flow arise from nitric oxide–based hypoxic vasodilation, which eventually becomes limiting for sustaining oxygen consumption. Among many effects on red blood cells (RBC), storage lowers donor RBC nitric oxide content and increases free hemoglobin nitric oxide scavenging, whereas low oxygenation reduces nitric oxide production by endothelial nitric oxide synthase; these varied mechanisms collectively result in mitigation of hypoxic vasodilation. Because the adverse effect of packed RBCs on neonatal gut oxygenation appears primarily in association with extreme anemia, a sudden reduction in mucosal blood flow during periods of increased oxygen demand (enteral feeding) presumably results in injury to the physical barrier, enabling bacterial invasion and necrotizing enterocolitis. In infants born at extremely low gestational ages, PRBC transfusions for iatrogenic or developmentally acquired anemia are common and will persist even after all conservation techniques, microassay methods, and use of erythropoietin have been implemented. A fixed need for transfusions exists because of additional biologic restrictions imposed by normal rates of human somatic growth coupled with limits of RBC production to accommodate the need for an expanding RBC mass. Improved understanding of etiologic mechanisms of microvascular injury with transfusion should be instructive to clinicians in managing this dilemma.

Is intra-abdominal hypertension a missing factor that drives multiple organ dysfunction syndrome?

In a recent issue of Critical Care, Cheng and colleagues conducted a rabbit model study that demonstrated that intra-abdominal hypertension (IAH) may damage both gut anatomy and function. With only 6 hours of IAH at 25 mmHg, these authors observed an 80% reduction in mucosal blood flow, an exponential increase in mucosal permeability, and erosion and necrosis of the jejunal villi. Such dramatic findings should remind all caring for the critically ill that IAH may severely damage the normal gut barrier functions and thus may be reasonably expected to facilitate bacterial and mediator translocation. The potential contribution of IAH as a confounding factor in the efficacy of selective decontamination of the digestive tract should be considered.

Interaction of Helicobacter pylori Infection and Nonsteroidal Anti‐Inflammatory Drugs in Gastric and Duodenal Ulcers

Gastric (GU) and duodenal ulcers (DU) are in most instances either induced by Helicobacter pylori infection or by nonsteroidal anti-inflammatory drugs (NSAIDs). Whether eradication of H. pylori is beneficial in NSAID users for preventing NSAID induced GU and DU has been the focus of different studies. Mechanisms shared by both H. pylori and NSAIDs for the induction of GU and DU were reviewed and randomized controlled trials on H. pylori eradication for prevention and healing of GU and DU in patients requiring NSAID therapy were identified by a PubMed search. Key factors in the induction of GU and DU for both H. pylori and NSAIDs are a decrease in pH, imbalance between apoptosis and proliferation, reduction in mucosal blood flow, and recruitment of polymorphonucleates in distinct compartments. For primary ulcer prevention, H. pylori eradication before starting an NSAID therapy reduces the risk of NSAID induced GU and virtually abolishes the risk of DU. H. pylori eradication alone is not sufficient for secondary prevention of NSAID induced GU and DU. H. pylori infection appears to further increase the protective effects of proton-pump inhibitors (PPI) to reduce the risk of ulcer relapse. H. pylori eradication does not influence the healing of both GU and DU if NSAID intake is discontinued. Duodenal ulcer is more closely related to H. pylori infection than GU in NSAID users. H. pylori eradication is recommended for primary prevention of GU and DU in patients requiring NSAID therapy. PPI therapy is mandatory for secondary prevention of gastroduodenal ulcers, and appears to further reduce the risk of ulcer relapse in the presence of H. pylori.

Aging Gastropathy—Novel Mechanisms: Hypoxia, Up-regulation of Multifunctional Phosphatase PTEN, and Proapoptotic Factors

Aging gastric mucosa has impaired mucosal defense and increased susceptibility to injury. Our aims were to determine the mechanisms responsible for above abnormalities. We used Fisher F-344 rats, 3 and 24 months of age. We measured gastric mucosal blood flow; visualized mucosal hypoxia; examined expression of early growth response-1 transcription factor and phosphatase and tensin homologue deleted on chromosome 10 (PTEN); assessed apoptosis; and determined expression of caspase-3, caspase-9, and survivin. We also examined susceptibility of gastric mucosa of young and aging rats to ethanol injury and whether down-regulation of PTEN affects susceptibility of aging gastric mucosa to injury. To determine human relevance, we examined expression of PTEN and survivin in human gastric specimens of young and aging individuals. Gastric mucosa of aging (vs young) rats has a 60% reduction in mucosal blood flow; prominent hypoxia; and increased early growth response-1 transcription factor and PTEN messenger RNAs, and proteins. It also has increased expression of proapoptotic proteins caspase-3 and capase-9, reduced survivin, and a 6-fold increased apoptosis vs mucosa of young rats. Ethanol-induced gastric mucosal injury in aging (vs young) rats was significantly increased. The down-regulation of PTEN in gastric mucosa of aging rats completely reversed its increased susceptibility to ethanol injury. In aging human gastric mucosa, PTEN expression was significantly increased, whereas survivin was significantly reduced. (1) Gastric mucosa of aging rats has significantly reduced blood flow, tissue hypoxia, activation of Egr-1, PTEN; increased caspases; and reduced survivin. (2) These changes increase susceptibility of aging gastric mucosa to injury.

Pressures Exerted by Endobronchial Devices

High endotracheal cuff pressures have been shown to cause high mucosal pressures and a reduction in mucosal blood flow, with the risk of mucosal ischemia. We aimed to directly measure the pressure exerted by the bronchial cuffs of double-lumen tubes (DLT) and by the cuffs of three new designs of endobronchial blocker (EBB). Using a validated in vitro model and a previously described technique, we measured the static pressures exerted by the cuff of DLTs and EBBs with 1 mL increments in cuff volume until maximum inflation was achieved. The study was repeated under dynamic conditions of simulated positive pressure ventilation. The pressures exerted by the cuffs of DLTs ranged from 16-155 mm Hg. Pressures exerted by the EBB cuffs ranged from 39-194 mm Hg. At intra-cuff volumes required to create a seal to 25 cm H2O positive pressure, the pressures exerted by the cuffs of all the devices were <30 mm Hg. A transmitted pressure <30 mm Hg has been recommended to avoid mucosal injury. Our study shows that at clinically relevant cuff volumes, the pressures exerted by the cuffs do not exceed the recommended safe limit.

Gastrointestinal: Bleeding from ischemic colitis

Ischemic colitis is a relatively common disorder caused by a reduction in mucosal blood flow in the colon. The typical patient is an elderly person who presents with abdominal pain, diarrhea and rectal bleeding. This may occur spontaneously or may follow a hypotensive episode associated with severe illness, cardiac disease or surgery. The diagnosis is usually established by colonoscopy or a barium enema study within 2 or 3 days of the onset of symptoms. Typical findings at colonoscopy include hemorrhagic nodules, areas of inflammation and superficial ulceration. Barium enema studies usually show ‘thumbprinting’ due to submucosal hemorrhages. Ischemic changes can occur in any part of the colon but are most common in the region of the splenic flexure, descending colon and sigmoid colon. Longer-term complications such as colonic strictures and relapses of ischemic colitis are rare. Occasionally, ischemic colitis can occur in younger individuals. This is usually due to vasculitis, coagulation disorders or to use of various medications. The images shown below were from a 36-year-old woman who was referred for evaluation because of prominent rectal bleeding. Seven days previously, she had an emergency hysterectomy because of uterine atony after a cesarian section. This was complicated by probable amniotic fluid pulmonary embolism and by disseminated intravascular coagulation. Colonoscopy revealed superficial ulcers in the sigmoid colon and persistent bleeding from two blood vessels in the distal sigmoid colon (Fig. 1). The bleeding vessels were treated by the application of bands using a gastroduodenoscope. The appearance after application of one of the bands is shown in Figure 2. Treatment was followed by cessation of bleeding, but whether banding is superior to other methods for achieving hemostasis remains unclear.

Impact of antithrombin III on hepatic and intestinal microcirculation in experimental liver cirrhosis and bowel inflammation: Anin vivoanalysis

To analyze the hepatic and intestinal microcirculation in an animal model of liver cirrhosis and inflammatory bowel disease (IBD) and to characterize the anti-inflammatory action of antithrombin III (ATIII) on leukocyte kinetics and liver damage. Hepatic and intestinal microcirculation was investigated by intravital videomicroscopy. Standardized models of experimental chronic liver cirrhosis and bowel inflammation were employed. Animals were divided into four groups (n = 6/group): controls, animals with cirrhosis, animals with cirrhosis and IBD, animals with cirrhosis and IBD treated with ATIII. Cirrhosis facilitated leukocyte rolling and sticking in hepatic sinusoids (1.91+/-0.28 sticker/microm vs 0.5+/-0.5 sticker/microm in controls, P<0.05). The effect enhanced in animals with cirrhosis and IBD (5.4+/-1.65 sticker/microm), but reversed after ATIII application (3.97+/-1.04 sticker/microm, P<0.05). Mucosal blood flow showed no differences in cirrhotic animals and controls (5.3+/-0.31 nL/min vs 5.4+/-0.25 nL/min) and was attenuated in animals with cirrhosis and IBD significantly (3.49+/-0.6 nL/min). This effect was normalized in the treatment group (5.13+/-0.4 nL/min, P<0.05). Enzyme values rose during development of cirrhosis and bowel inflammation, and reduced after ATIII application (P<0.05). Liver cirrhosis in the presence of IBD leads to a significant reduction in mucosal blood flow and an increase in hepatic leukocyte adherence with consecutive liver injury, which can be prevented by administration of ATIII.

Physiopathologie des lésions gastro-duodénales induites par les anti-inflammatoires non stéroïdiens

The pathogenesis of the gastroduodenal lesions induced by non-steroidal anti-inflammatory drugs and aspirin is primarily caused by a reduction in mucosal blood flow, which is the consequence of inhibition of cyclooxygenase-producing vasodilator prostaglandins. The subsequent phase is adherence of leukocytes to the endothelium, which may depend on cyclooxygenase-2. Endothelial lesions accentuate the fall of mucosal blood flow and promote the inflammatory process in the gastric mucosa. The inflammatory process is amplified by expression of TNFalpha in polymorphonuclears induced by non-steroidal anti-inflammatory drugs. A few days after starting treatment, epithelial proliferation and increased mucosal blood flow, partly dependent on cyclooxygenase-2 and nitric oxide expression, compensates for the damaging process. Selective inhibitors of inducible cyclooxygenase-2 have reduced gastrointestinal toxicity, which could partially be explained by the protection effect of cyclooxygenase-2 on the gastrointestinal mucosa during inflammation or epithelial repair. Selective inhibitors may worsen inflammatory bowel disease. Non-steroidal inflammatory drugs and aspirin, but perhaps not selective inhibitors, increase the mucosal lesions associated with Helicobacter pylori-induced gastritis. Co-administration of selective inhibitors and aspirin leads to gastrointestinal toxicity equivalent to that of non-specific anti-inflammatory drugs.

Dual COX inhibition and upper gastrointestinal damage.

Aspirin and non-aspirin NSAIDs injure the gastrointestinal tract principally as a result of their inhibition of prostaglandin synthesis. This is mediated via abrogation of the secretion of mucus and bicarbonate and by reduction in mucosal blood flow. Topical injury and inhibition of platelet thromboxane may also contribute respectively to damage and ulcer bleeding. Recognition of a second cyclooxygenase, COX-2, enabled drugs to be developed that selectively target this enzyme which is expressed in inflamed joints. These have proved to be effective treatments whilst causing little or no acute gastroduodenal injury and reduced ulcers and their complications. Future strategies may capitalise upon the phenomenon of substrate diversion of lipoxygenase products. Balanced cyclooxygenase/lipoxygenase inhibition maybe less harmful than cyclooxygenase inhibition. Also, nitric oxide can subserve many of the protective effects of prostaglandins and NO-donating NSAIDs are under evaluation.

The effect of sympathetic nerve stimulation on ventilation and upper airway resistance in the anaesthetized rat.

We have previously demonstrated that moderate cooling of the isolated upper airway (UA) causes a substantial fall in UA resistance in anaesthetized rats (O’Halloran et al, 1994). This effect is partly of reflex origin but a large fall in resistance still persists following elimination of reflex effects. We have proposed that this residual effect is due to a direct effect of cooling on the UA mucosal vasculature, causing a reduction in mucosal blood flow, a thinning of the mucosa and therefore, an increase in UA cross-sectional area and a fall in resistance. If such a mechanism were responsible for the fall in resistance, then we might expect that activation of sympathetic vasoconstrictor fibres in the cervical sympathetic trunk would also reduce UA resistance in the same preparation. The present experiments examine the effects of electrical stimulation of the cervical sympathetic trunk on the airflow resistance of the isolated UA in anaesthetized rats breathing spontaneously through a low-cervical tracheostomy. Spontaneously breathing animals were used because we also wished to examine the effects of sympathetic stimulation on ventilation. The influence of the cervical sympathetic nerves on ventilation are complex and controversial and very little is known about their effects in the rat.

Nitric oxide regulates basal but not capsaicin-, CGRP-, or bile salt-stimulated rabbit esophageal mucosal blood flow.

Esophageal mucosal blood flow is a dynamic phenomenon that is altered by luminal content that probably represents an important intrinsic method of defense. This study investigated the role played by endogenous nitric oxide in the regulation of esophageal mucosal blood flow at rest and in response to luminal capsaicin, a specific stimulant for visceral afferent nerves, as well as calcitonin gene-related peptide, and the bile salt deoxycholate. The L-arginine analog L-NAME was used to block nitric oxide synthesis. Radiolabeled microspheres were used to measure blood flow in a well-characterized rabbit model. Phenylephrine was used to mimic the hemodynamic effects of L-NAME to show the specificity of positive findings. Administration of L-NAME led to a significant reduction in mucosal blood flow at rest, an effect that was not shared by phenylephrine. The blood flow responses to luminal capsaicin, intra-arterial calcitonin gene-related peptide (CGRP), and luminal deoxycholate, however, were not diminished in the presence of L-NAME. Although nitric oxide may play a role in the maintenance of normal resting esophageal mucosal blood flow, the reactive responses to luminal capsaicin, luminal deoxycholate, and intra-arterial CGRP are not nitric oxide dependent.

Role of leukotrienes in indomethacin-induced mucosal damage in rats.

The role of leukotriene (LT) in the pathogenesis of indomethacin-induced gastric mucosal damage was investigated in rats. After administration of indomethacin, LTB4 and sulfidopeptide LT (SPLT) content in gastric mucosa were assessed by radioimmunoassay and mucosal blood flow was measured by laser-Doppler flowmetry. Indomethacin (20 mg/kg) caused visible gastric mucosal damage. Indomethacin at this dose caused marked reduction of gastric mucosal blood flow but did not affect gastric mucosal content of LTB4 and SPLT. AA-861, a selective 5-lipoxygenase, and DS-4575 and YM-683, two different SPLT receptor antagonists, inhibited both mucosal damage and reduction of mucosal blood flow. These results suggested that endogenous LT, especially SPLT, may be involved in the indomethacin-induced mucosal damage via the reduction of gastric mucosal blood flow.

Necrotizing Tracheobronchitis (NTB) Following High Frequency Ventilation: Role of an Angiotensin Converting Enzyme Inhibitor

The purpose of this investigation was to study the effect of an angiotensin converting enzyme inhibitor (enalaprilat) on the morphologic manifestations of experimentally induced necrotizing tracheobronchitis (NTB). Twenty piglets were anesthetized before saline lung lavage. High frequency flow interrupter (HFFI) ventilation was used with a strategy known to produce NTB. Animals were randomly assigned to receive IV enalaprilat 0.1 mg/kg (ENP-Hi), enalaprilat 0.01 mg/kg (ENP-Lo), or saline (C). After 8 hours of ventilation, the piglets were sacrificed. Total airway injury scores (mean +/- S.D.) were 1.2 +/- 0.7 for ENP-Hi, 0.2 +/- 0.2 for ENP-Lo, and 21.3 +/- 16 for group C. Enalaprilat minimizes NTB lesions in neonatal piglets exposed to high frequency oscillatory ventilation. Although the origin of NTB is multifactorial, airway mucosa ischemia may play an important role. Enalaprilat may compensate for the reduction of mucosal blood flow by limiting formation of angiotensin II and/or preventing degradation of bradykinin.

The mucoid cap over superficial gastric damage in the rat: A high-pH microenvironment dissipated by nonsteroidal antiinflammatory drugs and endothelin

The ability of the “mucoid cap” of mucus, fibrin, and cellular debris that forms over sites of superficial gastric damage to provide a relatively high-pH microenvironment was investigated in the rat. Furthermore, the effects of administration of nonsteroidal antiinflammatory drugs or reduction of mucosal blood flow on this microenvironment were investigated. Superficial mucosal damage induced by a 2-minute exposure to Hypertonic saline produces a mucoid cap that has a pH of 4–6 despite the presence in the lumen of a solution of acid with a pH of less than 1. This relatively high-pH microenvironment remained even when the exposure to 0.15-mol/L HCl was continued for as long as 1 hour. Intraperitoneal administration of indomethacin (5 mg/kg) or naproxen (10 mg/kg) resulted, within 10–25 minutes, in complete dissipation of this high-pH microenvironment, with the subsequent development of hemorrhagic erosions. These effects of indomethacin and naproxen occurred subsequent to significant inhibition of gastric prostaglandin synthesis by these agents. Rapid dissipation of the pH gradient could also be produced by brief (30-second) clamping of the arterial blood supply to the chambered mucosa or by systemic administration of a vasoconstrictor (endothelin-1), in both cases resulting in the development of hemorrhagic erosions. These results show that the mucoid cap over sites of superficial damage provides a relatively high-pH microenvironment and that dissipation of this microenvironment by inhibitors of prostaglandin synthesis or by reduction of mucosal blood flow can convert sites of superficial mucosal injury to hemorrhagic erosions. Such inhibitory effects might contribute to the ulcerogenic actions of nonsteroidal antiinflammatory drugs.

Impairment of gastric microcirculation in stress.

Gastric mucosal blood flow and microvascular patterns were studied in normal and stressed rats. In addition, various regulating factors of gastric mucosal blood flow, such as autonomic nervous system and biogenic amines, were investigated by histochemical procedures. Gastric mucosal blood flow was determined by the hydrogen gas clearance method as well as the hydrogen gas electrolytic method, and the microvascular structure was observed by the infusion method with two-colored silicon rubber. The gastric mucosal blood flow decreased significantly in the early period after induction of burn stress. The incidence of acute gastric mucosal lesions had a highly correlative relation with the decrease in mucosal blood flow. Reduction of mucosal blood flow was consequently due to opening of an arteriovenous shunt and hyperpermeability of true capillaries. This hemodynamic change, regulated by biogenic amines and autonomic nerves, was followed by ischemia and congestion of the gastric mucosa. The results of these studies demonstrated the importance of defensive factors; that reduction of mucosal blood flow resulted in the sequence of events that led to formation of acute gastric mucosal lesions.

The Role of Smoking in Peptic Ulcer Disease

Cigarette smoking appears to be a risk factor for the development, maintenance, and recurrence of peptic ulcer disease. Smoking has an inconsistent effect on gastric acid secretion, but it does have other effects on upper gastrointestinal function that could contribute to the pathogenesis of peptic ulcer disease. These include (a) interference with the action of histamine-2 antagonists, (b) acceleration of gastric emptying of liquids, (c) promotion of duodenogastric reflux, (d) inhibition of pancreatic bicarbonate secretion, (e) reduction in mucosal blood flow, and (f) inhibition of mucosal prostaglandin production. Because these effects are related directly to the act of smoking and cessation of smoking is associated with the prompt recovery of the respective functions, smokers will benefit immediately by stopping or reducing cigarette consumption.

Blood flow limitation of stimulated gastric acid secretion in the rat.

Secretagogue-stimulated gastric acid output is reduced when gastric mucosal blood flow is below normal. We tested the hypothesis that the reduction in acid secretion associated with reduced mucosal blood flow was due to a decrease in the delivery of the secretagogue. Gastric acid output was determined by continuous gastric lavage with 0.15 M NaCl, and gastric corpus mucosal blood flow was measured by hydrogen gas clearance in anesthetized, pylorus-ligated rats before and during a period of hypovolemia-induced reduction in mucosal blood flow. A linear correlation between pentagastrin- and histamine-stimulated gastric acid output and gastric corpus mucosal blood flow during hypotension over a range of mucosal blood flow rates was found, and each was expressed as a percentage of the plateau values before hemorrhage. When the dose of pentagastrin was doubled or tripled, or when the stimulation of gastric acid secretion was vagus nerve stimulation, a stimulant of acid secretion that is independent of blood flow for secretatogue delivery, the reduction in gastric acid output by hypotension was not reversed. We conclude that stimulated gastric acid secretion during hemorrhagic hypotension is blood flow-limited and not related to inadequate delivery of secretagogue to parietal cells.

Effect of platelet activating factor on the human nasal mucosa.

In order to determine the effect of PAF-acether on the vascular bed in the human nose, 11 healthy volunteers were studied. Rhinomanometry was performed to determine the effect on the capacitance vessels, and the 133Xe wash-out method enabled determination of the mucosal blood flow, regulated mainly by the resistance vessels. These measurements were made before and after topical administration of PAF-acether in three different doses; 0.26 micrograms, 2.6 micrograms and 26 micrograms per nostril. The results indicate that PAF-acether induces a dose-dependent vasoconstriction of the capacitance vessels and a reduction in mucosal blood flow. That PAF-acether should be a principal mediator in the allergic reaction in the human nose is not supported by these findings.

Action of somatostatin on stomach, pancreas, gastric mucosal blood flow, and hormones.

In dogs gastric secretion induced by tetragastrin and pancreatic secretion induced by secretin and/or cholecystokinin were inhibited by somatostatin at doses of 0.06-1 microgram X kg-1 X h-1 and 0.06-1 microgram X kg-1 X 0.5 h-1, respectively. Inhibition was a linear function of the logarithm of dose. Basal and 2-deoxy-D-glucose-induced gastric acid secretion was also significantly inhibited by low doses of somatostatin. Results in this study differ from those reported previously by clarifying the action of somatostatin as follows. 1) The inhibitory effect of somatostatin on pancreatic protein secretion was significantly greater than that on water and bicarbonate production. Somatostatin was more effective on cholecystokinin- than secretin-induced pancreatic secretion. 2) Although gastric mucosal blood flow (MBF) was affected by somatostatin, the reduction of MBF was not the primary mechanism responsible for its inhibitory action. 3) The low doses of somatostatin used in this study significantly inhibited gastric and pancreatic secretion without affecting the basal plasma concentrations of insulin, glucagon, growth hormone, gastrin, or secretin in the dogs, suggesting that the inhibitory action was not mediated by changes or reduction in plasma concentration of these hormones.