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Biomedical subjects

M H Perdue

Publications and source records attributed to M H Perdue.

At least 91 records · Page 5Linked to original sources
PubMed1989

Intestinal mucosal injury is associated with mast cell activation and leukotriene generation during Nippostrongylus-induced inflammation in the rat.

We examined mucosal injury in the jejunum of the rat during infection with the nematode parasite, Nippostrongylus brasiliensis (Nb). Injury was documented morphologically (increase in crypt length with or without villus atrophy) and biochemically (activities of digestive or proliferative enzymes) and related to mast cell activation and leukotriene generation. At day 4 crypt length and thymidine kinase activity were increased; no changes in villus parameters were recorded. No evidence of mast cell activation was found and leukotriene levels in the mucosa were normal. At day 7, the gut was acutely inflamed and edema was present at the tips of the villi. This progressed to enterocyte detachment, resulting in villus atrophy with decreased activities of brush border enzymes. At this stage mucosal histamine was decreased and rat mast cell protease II (RMCP II) was increased in serum, indicating mast cell activation. In addition, mucosal leukotrienes (LTB4, LTC4, LTE4) were present in significant quantities. Following worm expulsion, the villus abnormalities resolved and serum RMCP II returned to normal. However, the crypt hyperplasia persisted. Our results suggest that during Nb infection at least two components of injury can be identified. One component, epithelial injury at the villus tips, may be related to activation of mucosal mast cells.

Animals↗
PubMed1989

Novel cellular interactions and networks involving the intestinal immune system and its microenvironment.

The interactions we have described enable the intestine to respond appropriately to antigenic challenge in an effective and coordinated way. This is of vital importance when one considers the dual role of the intestine as a first line of defence against harmful microorganisms and as the route by which the animal obtains nutrition. Under normal circumstances, these interactions select for an appropriate cell phenotype by providing a network of interactions that contribute to intestinal homeostasis. If there is dysfunction of any component, then other cells will be affected. For example, if down-regulation of the mucosal immune response is not effective, damage to the epithelium, nerves and muscle may occur during an inflammatory response. Similarly, if the integrity of the epithelium is disrupted, damage to the elements of the mucosal immune system may occur. This model would suggest that these interactions must be considered if one wishes to adequately explain diseases such as IBD and design innovative therapeutic regimens. Future interdisciplinary research will shed light on the web of interactions occurring in the intestinal environment and provide a novel view of the respective contributions of the immune system and its local environment to cell differentiation, function and regulation.

Animals↗
PubMed1989

Effects of platelet-activating factor on ion transport in isolated rat jejunum.

In isolated normal rat jejunum, platelet-activating factor (PAF) induced a dose-dependent increase in short-circuit current (Isc) that was reduced in chloride-free buffer and inhibited by the Cl- channel blocker, diphenylamine-2-carboxylate. An immediate rise in Isc (early phase) occurred that fell to a new elevated base line by 15 min (late phase). These responses to PAF occurred only when experiments were conducted at or before approximately 9 A.M. Early phase responses were blocked by the specific PAF antagonists, BN52021 and WEB2086, and were inhibited by the neurotoxin, tetrodotoxin. Early and late phases were also reduced by cyclooxygenase inhibitors and by doxantrazole, a mast cell stabilizing drug. However, histamine and serotonin antagonists were ineffective. We conclude that PAF causes changes in ion transport that include Cl- secretion and acts on the epithelium possibly via an intermediate cell and enteric nerves. In addition, known PAF receptors are involved in one component of the response that appears to follow a circadian rhythm.

Animals↗
PubMed1988

Role of nonspecific cytotoxic cells in intestinal epithelial cell injury in Nippostrongylus brasiliensis infection.

We have employed a cultured crypt-like intestinal epithelial rat cell line (IEC-18) to assess whether killing by nonspecific cytotoxic cells contributes to epithelial cell destruction in Nippostrongylus brasiliensis (N.b.) infection. Spleen cells from N.b.-infected Sprague-Dawley rats, 11-13 days postinfection when villus atrophy and crypt hyperplasia were evident, killed IEC-18 in a 4-hr 51Cr-release assay. In contrast, intraepithelial leukocytes (IEL) from N.b.-infected rats showed decreased killing of IEC-18 compared to controls in a 16-hr assay. Spleen NK activity was increased in N.b.-infected rats whereas IEL NK activity was decreased. We conclude that direct cytotoxicity of crypt-like intestinal epithelial cells by nonspecific cytotoxic cells appears to play no significant role in intestinal injury in N.b. infection.

Animals↗
PubMed1988

Changes in intestinal permeability and epithelial differentiation during inflammation in the rat.

We examined changes in gut permeability in a controlled model of inflammation produced in rats after infection with the nematode parasite, Nippostrongylus brasiliensis. The probe, 51Cr-EDTA, was injected into ligated loops of jejunum in vivo and recovery of radioactivity was measured in urine, kidney, and intact loop at five hours. Urinary recovery was significantly increased during the early (day 7) and acute (day 10) stages of the infection compared with values in control rats but subsequently returned to normal. Urinary clearance of the probe after iv injection was unaltered during infection. Villus atrophy occurred only at the stage, whereas crypt hyperplasia was evident at both the early and acute stages. The terminal ileum appeared normal and showed normal permeability when compared with controls. We conclude that permeability changes are local to the site of inflammation, are reversible after healing and may be related to an increase in the proportion of relatively undifferentiated epithelium.

Animals↗
PubMed1988

Altered regulation of intestinal ion transport by enteric nerves in diabetic rats.

We compared ion transport parameters in isolated ileal mucosa from diabetic rats (8 wk after streptozotocin injection) and littermate controls under basal conditions and in response to electrical transmural stimulation (TS). Stripped ileal mucosa (submucosal plexus intact) was mounted in Ussing flux chambers modified to include stimulating electrodes on opposite sides of the tissue. Under basal conditions unidirectional fluxes of Na+ and Cl- were decreased across mucosa from diabetic rats compared with controls, whereas net fluxes were not significantly different. TS caused a tetrodotoxin (TTX)-sensitive transient increase in short-circuit current (Isc) that was significantly less in tissue from diabetic than control rats. The muscarinic cholinergic receptor antagonist, atropine, significantly reduced the Isc response to TS in ileum from control but not diabetic rats. In addition, the noncholinergic component of the response was smaller. The muscarinic agonist, Urecholine chloride (bethanechol chloride), caused an increase in Isc that was unaffected by pretreatment with TTX and was the same in tissue from control and diabetic rats. Our results suggest that the intestinal abnormalities that occur in diabetes may include a defect in the regulation of ion transport by enteric nerves resulting in an abnormal ability to respond to luminal and other stimuli.

Animals↗
PubMed1988

Effect of immunologic reactions on rat intestinal epithelium. Correlation of increased permeability to chromium 51-labeled ethylenediaminetetraacetic acid and ovalbumin during acute inflammation and anaphylaxis.

In these studies we compared jejunal permeability to two probes--chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) (mol wt, 360) and ovalbumin (mol wt, 45,000)--under control conditions, during acute intestinal inflammation, and in response to systemic anaphylaxis. Acute inflammation was produced after infection with Nippostrongylus brasiliensis and rats were studied at day 0 (control), day 4 (early), day 10 (acute), and day 35 (postinfection). At the latter stage, immune rats were also studied during anaphylaxis induced by i.v. N. brasiliensis antigen. In each study, blood and urine were sampled over 5 h after the probes were simultaneously injected into ligated loops in anesthetized rats. In controls, small quantities (less than 0.04% and 0.002% of the administered dose for 51Cr-EDTA and ovalbumin, respectively) appeared in the circulation and plateaued at 1 h. During acute inflammation, the appearance of both probes continued to increase with time. Compared with controls, 5-h values for 51Cr-EDTA and ovalbumin were (a) significantly elevated at day 4 (p less than 0.005), (b) increased approximately 20-fold at day 10 (p less than 0.005 and less than 0.01, respectively), and (c) normal at day 35. Urinary recovery of 51Cr-EDTA followed the same pattern. During anaphylaxis, appearance of the probes in the circulation increased at 1 h to values approximately 10-fold those in controls (p less than 0.001 and less than 0.01, for 51Cr-EDTA and ovalbumin, respectively), and then declined. Urinary recovery of 51Cr-EDTA over 5 h was also significantly increased. We conclude that epithelial barrier function becomes impaired during both acute inflammation and anaphylaxis. In this rat model, gut permeability changes to 51Cr-EDTA reflect gut permeability changes to macromolecular antigens. If similar conditions exist in humans, urinary recovery of 51Cr-EDTA may be useful in monitoring intestinal abnormalities associated with inflammation.

Acute Disease↗
PubMed1987

Evidence for substance P as a functional neurotransmitter in guinea pig small intestinal mucosa.

We showed previously that electrical transmural stimulation (TS) of guinea pig jejunal mucosa in vitro released neurotransmitters from submucosal plexus neurons which caused alterations in ion transport. The present studies were performed to obtain information regarding the identity of the neurotransmitters. The addition of exogenous substance P (SP) to the serosal side of the tissue caused a transient increase in short-circuit current (Isc) which closely mimicked the response to TS. Both TS and SP caused net secretion of Cl- ions by stimulating movement toward the luminal side. Tetrodotoxin abolished the response to TS, inhibited approximately 70% of the response to SP but did not affect the response to urecholine, a cholinergic muscarinic agonist. In the presence of the muscarinic antagonist, atropine, Isc responses to both TS and SP were reduced suggesting that a portion of both responses was due to action on enteric nerves causing release of acetylcholine. Following desensitization of the tissue with supramaximal doses of SP the response to TS was significantly reduced but the response to urecholine was unchanged. In the presence of atropine, SP desensitization reduced the nerve-stimulated response by approximately 65%; treatment of tissue with SP antibodies reduced the response by approximately 55%. Under the same conditions Isc responses to histamine were unaltered. Our results suggest that both SP (or a structurally analogous neurotransmitter) and acetylcholine as well as additional unidentified neurotransmitter(s) are functionally important in the regulation of intestinal ion transport in guinea pig jejunum.

Animals↗
PubMed1986

Rat jejunal mucosal response to histamine and anti-histamines in vitro. Comparison with antigen-induced changes during intestinal anaphylaxis.

We previously showed that rats sensitized to egg albumin (EA) respond in vivo intraluminal antigen-challenge with decreased net absorption of water and electrolytes and depletion of mucosal histamine. However, administration of anti-histamines did not prevent the transport abnormalities. The present in vitro studies examined the effect of histamine to alter net ion transport and the ability of diphenhydramine (DPH) and cimetidine (CIM) to block the responses to both histamine and antigen. Control rat jejunum was mounted in Ussing chambers and histamine was added to the serosal side either in the absence or presence of DPH or CIM. In control tissues histamine caused a transient increase in short-circuit current (Isc) in a dose-dependent manner between 10(-5) and 10(-4) M which was blocked by 10(-5) M DPH but was unaffected by CIM in concentrations up to 10(-4) M. There was no response to EA. Jejunum from sensitized rats exposed to EA demonstrated a biphasic Isc response: a rapid transient rise followed by a somewhat less elevated but sustained component. In tissues pre-treated with DPH the initial peak was unaffected but the sustained component was reduced. Our results indicate that H1-receptors mediated the effects of histamine in rat jejunal mucosa but that during intestinal anaphylaxis histamine is responsible for only a portion of the antigen-induced transport abnormalities. Our data also suggest that IgE-mediated reactions in the intestine may involve an interaction between mast cell mediators and enteric nerves.

Animals↗
PubMed1986

Intestinal anaphylaxis in the rat: jejunal response to in vitro antigen exposure.

In previous studies we showed that rats sensitized to egg albumin respond to in vivo intraluminal antigen with decreased net absorption of Na+, Cl-, and water. These abnormalities are associated with high serum levels of immunoglobulin E (IgE) antibodies and mucosal mast cell degranulation. In the present in vitro study electrical parameters, unidirectional fluxes of Na+ and Cl-, and levels of cAMP were determined in jejunum from sensitized and control rats during a basal period and after antigen addition. In Ussing chambers potential difference and short-circuit current increased significantly in tissue from sensitized rats after addition of 100 micrograms/ml of egg albumin to both mucosal and serosal surfaces. These changes were accompanied by a reversal of net Cl- absorption to net Cl- secretion. The presence of doxantrazole, a mast cell-stabilizing agent, in the buffer prevented these abnormalities. No changes occurred in response to antigen challenge in tissue from controls. In a further series of experiments the antigen was added only to the mucosal side of the tissue in Ussing chambers. In these studies short-circuit current increased after a lag period of approximately 25 min and was significantly increased (P less than 0.025) at 35 min. cAMP levels increased significantly in jejunal slices from sensitized rats exposed to antigen for 2 min. Our findings suggest that the in vivo transport abnormalities induced by IgE-mediated mucosal reactions to a food protein are related to antigen stimulation of a Cl- secretory process.

Anaphylaxis↗
PubMed1986

Response of jejunal mucosa to electrical transmural stimulation and two neurotoxins.

We examined the mucosal response to endogenous neurotransmitters released from enteric nerves of guinea pig jejunum in vitro by 5 s of electrical transmural stimulation (TS). After TS, a rise in short-circuit current (Isc) occurred that peaked by 60 s and returned to base line by 3-6 min. The Isc response was associated with Cl- movement toward the luminal side of the tissue. The use of adrenergic and muscarinic cholinergic antagonists revealed that there was no adrenergic component but that the cholinergic component comprised up to 50% of the total response. Therefore, more than 50% of the response was due to the action of nonadrenergic, noncholinergic transmitter(s). The addition of the neurotoxin, tetrodotoxin (TTX), produced two effects: 1) an early fall in the base-line Isc and increased net absorption of Na+ and Cl-, and 2) a delayed inhibition of the response to TS. The former effect occurred at lower concentrations of TTX than the latter. Another neurotoxin, aconitine, blocked the response to TS without decreasing the base-line Isc or altering net ion transport. After aconitine, TTX still caused the Isc base line to fall. Because both neurotoxins prevented the Isc response to TS, we conclude that the response is due to the action of released endogenous neurotransmitters. Our results also suggest that TTX has an additional effect that is different from that of aconitine, acting either on the epithelium to enhance absorption or on a population of nerves that are relatively more TTX sensitive to block ongoing release of secretion-stimulating transmitter(s).

Aconitine↗
PubMed1985

Transport abnormalities during intestinal anaphylaxis in the rat: effect of antiallergic agents.

Our previous studies demonstrated that rats sensitized to egg albumin had reduced intestinal absorption of water and electrolytes in response to intraluminal antigen. The rapid onset of this effect and reduction in mucosal histamine and numbers of granulated mast cells in the lamina propria suggested a reaginic (IgE) mechanism involving mast cell mediators. In this study we examined the effect of antiallergic agents on the intestinal transport abnormalities in our model. Sensitized rats, 14 days after intraperitoneal injection of 10 micrograms of egg albumin plus alum had specific IgE serum titers greater than or equal to 1:64; control rats had no measurable IgE antibodies. Net fluxes of Na+, Cl-, and H2O were determined by in vivo perfusion during a 1-hour antigen-free period and then a 1-hour antigen period. Sodium cromoglycate, administered intravenously (20 mg/kg) or in the perfusate (5 X 10(-4) mol/L) failed to prevent mucosal mast cell degranulation as evidenced by histamine release or the decrease in absorption of H2O, Na+, and Cl- induced by antigen exposure. In contrast, 10(-3) mol/L of doxantrazole in the perfusate completely inhibited these changes. Histamine receptor antagonists, H1, diphenhydramine, or H2, cimetidine, in perfusates had no effect on the transport abnormalities. Our findings support a role for intestinal mucosal mast cells, but not connective tissue mast cells, in the pathogenesis of the intestinal dysfunction associated with mucosal IgE-mediated reactions to food proteins and suggest that mast cell mediators other than histamine are involved.

Animals↗
PubMed1985

D-Glucose transport in piglet jejunal brush-border membranes: insights from a disease model.

We measured glucose transport in jejunal brush-border membrane vesicles isolated from piglets with acute viral diarrhea, comparing our results with those from control animals. Characterization of membranes from both study groups demonstrated comparable purity and integrity. In the presence of an inwardly directed Na SCN gradient, D-glucose accumulated in control vesicles to a concentration several times the 60-min equilibrium level. "Overshooting" uptake was much lower and more gradual in vesicles from 40-h transmissible gastroenteritis (TGE)-infected pigs compared with control pigs. Equilibrium kinetic studies, in which gramicidin was used to clamp membrane potential at zero, demonstrated a pattern of Na-dependent D-glucose transport in 40-h TGE-infected membranes that differed greatly from the control pattern. From an Eadie-Hofstee plot of stereospecific Na-dependent D-glucose uptake into control vesicles, a pattern suggesting two carrier populations emerged: one with a low-affinity, apparent Km equaling 52.63 +/- 13.81 mM and the other a high-affinity apparent Km equaling 3.92 +/- 0.24 mM for D-glucose. In 40-h TGE-infected membranes, the pattern conformed to a single line, suggesting a homogeneous population of low-affinity carriers, (Km = 37.03 +/- 1.92 mM), which did not differ from the low-affinity carriers seen in control animals. We conclude that the absence of the high-affinity D-glucose carriers in jejunal brush-border membrane is an important determinant of the defective glucose transport that characterizes viral diarrhea. Because previous studies have strongly suggested that in acute TGE diarrhea the epithelium is composed of relatively undifferentiated crypt-type cells, we speculate that high-affinity D-glucose carriers are lacking in normal crypt epithelial cells and that they are incorporated into brush-border membranes of jejunal enterocytes as the cells differentiate in the course of their migration from crypt to villus.

Alkaline Phosphatase↗
PubMed1984

Epithelial response to intestinal anaphylaxis in rats: goblet cell secretion and enterocyte damage.

The effects of immunoglobulin E (IgE)-mediated reactions on the intestinal epithelium were examined during intestinal anaphylaxis in the rat. Rats sensitized by intraperitoneal injection of egg albumin (EA) plus alum developed high serum titers of IgE anti-EA antibodies after 14 days; sham-treated littermate controls had no anti-EA antibodies. Two isolated loops of jejunum were prepared in vivo in anesthetized rats. The loops were injected with EA in saline or saline alone, and intraluminal contents of each loop were examined after 4 h. Mucosal histamine decreased in sensitized rat intestine exposed to EA. Luminal mucin, measured by radioimmunoassay, was not increased by antigen challenge. In contrast, DNA, protein, and sucrase activities were elevated in contents from the isolated segments exposed to EA in sensitized rats. Histology revealed that periodic acid-Schiff-stained material was contained in goblet cells in sections prepared from these segments after antigen exposure. Cellular debris was present over the tips of the villi. These findings suggest that IgE-mediated reactions in the intestine cause epithelial damage and loss of material from cells other than goblet cells. The results indicate that release of goblet cell mucus is not a feature of intestinal anaphylaxis.

Albumins↗
PubMed1984

Effect of intestinal anaphylaxis on gut function in the rat.

We examined the effect of intraluminal antigen on intestinal function in an animal model of anaphylaxis using Hooded-Lister rats sensitized to ovalbumin. Older rats were more difficult to sensitize than younger ones; younger rats more consistently developed antiovalbumin titers of greater than or equal to 1:64 as measured by passive cutaneous anaphylaxis. That these immunoglobulins were of the immunoglobulin E class was suggested by the fact that heating of the sera to 56 degrees C for 3 h eliminated the response. Net fluxes of water and electrolytes were measured in sensitized rats with serum titers greater than or equal to 1:64 and compared with nonsensitized sham-treated controls during two periods: when the perfusate was antigen-free and after the addition of antigen. Intraluminal antigen challenge had no effect in controls but caused a rapid and dramatic reduction in water, Na+, Cl-, and K+ absorption in experimental animals (greater than or equal to 1:64). There was no evidence of recovery after antigen withdrawal, and the response was antigen-specific. Mucosal homogenates prepared after antigen challenge in sensitized animals contained significantly less histamine than homogenates prepared from controls, and granulated mucosal mast cell numbers were reduced. Light microscopy did not reveal any alteration of villus height or crypt depth, but mucosal edema was apparent in sections from sensitized animals. The findings suggest that anaphylactic reactions to food proteins in the intestine lead to abnormalities of water and electrolyte absorption and that histamine, or other mast cell mediators, or both, may be responsible.

Anaphylaxis↗
PubMedDate not supplied

Effect of psychoneural factors on intestinal epithelial function.

Stress has been associated with abnormal gastrointestinal function, including diarrhea and abdominal pain, and stress-associated gastric ulceration has frequently been documented. Stress can also exacerbate ongoing pathophysiology and often precedes relapses in patients with inflammatory bowel disease or irritable bowel syndrome. The relatively new field of psychoneuroimmunology is involved with the elucidation of mechanisms that explain the link between the central nervous system and immune-mediated pathophysiology. Recent progress examining the interaction among the nervous system, the immune system and the epithelium of the intestine is discussed, and the evidence for central nervous system control of this interaction is examined.

Central Nervous System↗