Table of Contents

Gastro-Intestinal Cyto-Protective System^tm (GICPS^tm)

This GICPS™ model is our depiction of the supra-mucosal, mucosal and sub-mucosal elements of the gut involeve in defensive and protective functions within the GI tract.  The gastro-intestinal cyto-protection system™, or GICPS™, as conceptualized by us, is composed of  two main interdependently operating sections. Section  1 contains the widely recognized,  “physio-chemical mucus gel barrier” with its lesser known inherent “neuro-immune” effector pathways.  Section 2 is  the “immuno-enteric cell mucosa” with its own immuno-neuronal effector pathways.  

Elements of  Section 1 include (a) salivary mucin,  (b) epithelial gland mucin [ which is  5% glycoprotein solution containing phospholipids, glycolipids, neutral lipids and fatty acids], (c) bicarbonate, (d) EGF [epithelial growth factor], (e) FGF [fibroblast growth factor], (f) TGF-alpha & TGF-beta [transforming growth factors], (g) PGE2 [protaglandin E2],  (h) IgA and (i) the tandem of cells involved in the neuro-immune response in the gut.

Elements of Section 2 include  (a) two types of intra-epithelial T-lymphocytes (Alpha-Beta [ abIEL] intra-epithelial lymphocytes and the Gamma-Delta [gdIEL] intra-epithelial lymphocytes), (b) enteroendocrine chromaffin cells [EEC] , (c) epithelial mucosa cell [EPI],  (d) paneth cells,  (e) neuronal cells, (f) mast cells, (g) neutrophils, (h) submucosal T-lymphocytes [T-Lympho], (i ) monocytes and  (j) macrophages, all of which are responsible for both defensive and digestive roles of the GI tract.

Disruption of the physio-chemical mucus gel barrier, Section 1, results in mucosal irritation, erosion and ulceration an activation of the neuro-immune pathway of cyto-protection as well as an activation of Section 2.  Activation of Section 2, either by disruption of the physio-chemical mucus gel barrier, or by direct stimulus from antigens, toxins, viral agents or microbials, lead to the upregulation of a immuno-neuronal cascade.  Upregulation of the immuno-neuronal cascade can occur either by activated of intraepithelial alpha beta T-lymphocytes  abIEL]  or by  stimulation of enteroendocrine chromaffin cells [EEC].

Disturbance of these elements are reported as “molecular markers” in individuals who suffer from  functional bowel syndrome. And among those with the functional bowel syndrome, functional dyspepsia occurs in over  three out of four persons with symptomatic IBS, irritable bowel syndrome.

Table 4. Gastro-Intestinal Cyto-Protection System™ (GICPS™) UPREGULATED

Copyright © Mueller Medical International LLC 1995, 2001, 2006

Molecular Markers for Functional Bowel Syndromes

Patients with functional dyspepsia share many of the  common molecular defects of seen in functional bowel syndrome.

In some there appears to be a genetic pre-disposition to low secretion of IL-10, a lymphokine responsible for oversight and down-regulatory modulation of inflammatory states brought about by cytokine release from lymphocytes activated by antigens.

Additionally,  nearly a two fold increase of intra-epithelial lymphocytes  in is present in the lamina propria.

There is a 35% increase in CD3+ lymphocytes and a 7 to 8 fold increase of CD25+,  both of which are inflammatory changes similar to those seen in the lungs of asthmatics.

There is an increase neutrophil count, well over 300%, in the lamina propria. These neutrophils are activated having released markers of acute inflammation, lipocalin and myeloperoxidase, each  being respectively elevated 260% and 380% above healthy controls.

Mastocytosis of the lamina propria occurs  in functional bowel syndrome.  Elevated tissue concentration of mast-cell derived mediators is common.

Elevation of serum and tissue concentration of neuro-peptides released from activated, upregulated neuronal afferents is also seen.  Substance P, vasoactive intestinal peptide, and neuro-peptide Y are all elevated while neuropeptide YY is markedly decreased in those with functional bowel syndromes.  Collectively these neuropeptides cause  hyperalgesia, local tissue pain, secretomotor diarrhea, muscular ileus and the urge to vomit with associated loss of appetite. This observation of gut-based focal secretion of symptom-generating neuropeptides from neuronal dendrites that have be upregulated raises the question as to the etiology of upregulation.  The answer could reside in the fact that nerve growth factor, NGF,  the principal agent for trophic changes in submucosal neuronal endings  is elaborated, stored and released by activated tissue mast cells and that in functional bowel disorders there is mastocytosis of the lamina propria and submucosa.  Notably, these activated mast cells are in close proximity to dendritic nerve endings.  Mast cell activation lead to the production and release of NGF which in turn act on dendritic nerve endings leading to the synthesis and release of neuropeptides, such as Substance P, Vasoactive Intestinal Peptide, and neuro-peptide Y and the depletion of neuro-peptide YY.  Subsequent clinical symptoms include, hyperalgesia of the gut, ileus, nausea, cramps and diarrhea.

Finally those with upper and lower functional bowel syndrome possess only 35% expression of serotonin reuptake protein, SERT-P.  Although, there is an increase epithelial representation of EEC , enteric chromatoffin cells  in those with functional bowel syndrome compared to healthy controls there is 75% reduction in overall SERT-P activity.  SERT-P activity is required for coordinated peristalsis.   This result in an over-representaion of enterochromaffin cells, EEC. These cells contain 95% of the body’s total serotonin, using, serotonin as the unique means  enteric neuro-signal communications. The same EEC cells are tasked with the burden to remove serotonin from the tissue once released; therefore, it is surprising that the overall expression of SERT-P in those with functional bowel disease is only 35% of that in healthy controls.

Mucosal Mediation of GI Symptoms

Symptoms and signs of disease in the GI tract are mediated through the actions of the epithelial mucosal lining.  Stimuli to mucosal elements of the GI lining lead to predictable responses of nausea, pain, cramps, vomiting, diarrhea and bloating. These responses result directly from the stimuli-mediated release of cytokines, neuromediators, and humoral substances.

Just as the lung uses a common mode of symptom and signs (cough, sputum production, wheezing, hypoxia or hypercapnia ) to express many divergent disorders, so too, the GI tract has a common subset of symptoms and signs generated from many divergent disorders. Nausea, pain, cramps, vomiting, diarrhea and bloating are responses originating from the mucosal lining interaction with specific stimuli.

Transduction of various forms of stimuli from the mucosal epithelium through an elaborate network of sentinnel cells equipped with specialized sensors and the associated receptor-mediator cascades of these sensors result in the common symptom and signs of the GI tract.  In veterinary medicine, the sponsor refers to this mucosal mediation of symptom/sign complex as “functional mucosal syndrome” or FMS. Whether, nausea, vomiting, diarrhea in dogs and cats, anorexia, abdominal pain, excessive salivation, bruxism and colitis in horses or food avoidance and post-surgical reflux and ileus in both, all GI symptom/sign complexes, for the most part, result from the same sequence of processes mediated by elements of the mucosa.  Likewise, in human, mucosally mediated events are responsible for symptom/sign complexes observed by physicians who evaluate patients with functional dyspepsia,  irritable bowel syndrome, small bowel motility disturbances, GERD, ulcer disease, inflammatory bowel disease or GI neoplasm.

As seen in Table 4, and discussed in detail later, these symptom/sign complexes are the consequence of breaching the defenses provided by the mucus gel layer of Section I of the GICPS™ and/or  the independent activation of the immuno-neuronal pathway within Section II of the GICPS™.

GICPS™ activation involves immuno-upregulation of intra-epithelial T-cells, enterochromaffin cells and epithelial enterocytes; these upregulated elements subsequently  upregulate submucosal neurons, hypersensitizing them in the process, activating submucosal T-lymphocytes, neutrophils and mast cells. Activated submucosal T-lymphocytes, neutrophils and mast cells in turn target other tissues and cellular elements via chemo-mediator and cytokine cascades through their own elaborate network of receptor-mediators pairings.  Breaching defensive elements and molecular factors of Section I result in neuronal hypersensitization with resultant neuro-chemotaxis of submucosal immune and inflammatory cells (see Table 4). The overall outcome are secreto-motility disruptions that give rise to most GI symptoms and signs that define clinical syndromes.

Gastrafate has been designed with the view that, it is the focal release of chemo-mediators which, for the most part, causes the symptoms experienced in dyspepsia, both functional and erosive reflux type. Since normal GI function depends on the structural and functional integrity of the “barrier processes” of the GICPS™ operating as a first and second line of defense, then it follows that their disruption lead to the common and predictable signs and symptoms of disease: nausea,  pain, food avoidance, colicky discomfort, vomiting and diarrhea.

Whether disruption of the GICPS™, “the stimulus”,  results from viral infection, parasitic invasion or bacterial assault, the GI tract responds predictably in the same way with pain, nausea, vomiting and diarrhea all of which resulting from the relay of mediator-receptor effector actions.  Even if GICPS™ disruption is caused by toxins, or by digestive irritants or by unintended side-effects of iatrogenic agents, the GI tract, once offended, will respond with nausea, pain, vomiting, and diarrhea; and again these symptoms issuing directly from the cascading effects of reactions of mediator-receptor pairings that are under the direct control of the mucosal epithelium

The Enteric Nervous System (ENS) & The Network of Receptor-Mediator Pairings

The receptor-mediator networks vary in type and in distribution along the entire length of the GI tract, from the oro-pharynx to the rectal colon.

The receptor-mediator networks vary in type and in distribution throughout the entire width of the wall of the GI tract from the single cell epithelial lining of the lumen to the serosa.

Extensive research has identified and characterized these receptor-mediator pairings, and Table 3 organizes their inputs according to tissue location and expected function.  The elements of the GICPS™ are functionalized by an elaborate network of receptor-mediator pairings distributed along two axes, one transmurally from lumen to serosa, and the other longitunidally from the oral cavity to sigmoid colon.

Table 3, below, lists by function and by mucosal wall position, the GI mediators and receptors involved in both digestive and defensive functions.  Activation of these mediator-receptor pairings lead to clinical symptoms commonly experienced by patients.

Physiochemical characteristics of luminal contents of the gut stimulate to the mucosa, thereby activating both peristalsis and/or disease symptoms. Receptor-mediator pairings exist for digestion and peristalsis as well as for nociception.  Receptors are distributed on epithelial and subepithelial structures and depending on the type of physiochemical stimuli, receptor activation results in either a digestive or a defensive set of physical actions.  And these actions, peristalsis, nutrient absorption, hyperalgesia, disordered motility, nausea and psychosomatic behaviors all result from chemo-mediator cascades originating from mucosal signals of stimulated receptors.

The focal changes in mucosal integrity result (a) in the stimulation or inhibition (or both) of motility in the circular, longitudinal & muscularis mucosal myofibers, (b) in the secretion of bicarbonate, mucin, and fluid, (c) in the dilataion of arterioles, (d) in the increase permeability of venules, (e) in the degranulation of activated mast cells and (f) in the subsequent activation of other sub-mucosal immune cells.

Physical disruption of the mucosal lining  causes a backdiffusion of acid into the lamina propria. This in turn stimulate extrinsic afferents of both vagal and spinal origin. Vagal afferents respond to produces the sensation of nausea and pain.  Spinal afferents are prompted to increase mucosal blood flow. The hyperemia buffers the intruding acid, prevents deepening of the erosion or ulcer and assists in mitogen-mediated healing (via FGF, EGF, TGF) of the mucosal lesions. This protective increase of blood flow is inhibited by surgical interruption of pathways through the celiac ganglion and requires the independent generation and secretion,of calcitonin-related gene protein, CRGP,  and nitric oxide, NO,  by up-regulated enteric nerve-endings.  This rapid-acting neuro-immuno system is found in the human stomach and in the esophagus, small intestine and colon of veterinary mammals.

Acid-sensors and capsaicin-afferents in the mucosal can give rise to dyspeptic discomfort of functional dyspepsia through epithelial enterocytes and enterochromaffin cells.  Noxious elements within luminal content lead to signals generated from chemosensors in epithelial enterocytes and enterochromaffin cells.  These signals   pass through afferent nociceptors into both the intrinsic neurons to elicit immediate GI-based responses, and into the extrinsic neurons to elicit responses from dorsal spine and responses from the brainstem.  Extrinsic afferents conduct acid-elicited signals from the mucosa to all gastric dorsal root ganglia, to 55% of vagally-mediated nodose ganglion, with the remaining 45% of the nodose ganglion input arising from capsaicin vanilloid subtype I epithelial receptors.

Dyspeptic symptoms in non-ulcer dyspepsia is believed to be mediated through visceral nociceptive C-type fibers.  Using capsaicin to desensitize gastric nociceptive C-fibers, functional dyspepsia can be decreased by 60% compared to 30% in the placebo treated group. GastrafateRx  brand of Sucralfate relieves dyspeptic symptoms via both receptor-pathways.

Regarding vomition,  there exist a centrally located “chemoreceptor trigger zone” that respond to humoral input  from emetic drugs, uremia, hypoxia and ketoacidosis. This chemoreceptor trigger zone also respond to neuronal or visceral inputs. Visceral inputs can be gastrointestinal (mucosal erosion, luminal distention),  cardiovascular, hepatopancreatobiliary, nephro-uretero-cystic or immediate-extramedullary in the brain (from psychic stimuli of odors or fear, vestibular stimulus of motion sickness, or cerebral trauma/injury).  GI-based nausea with subsequent vomiting is mediated from the epithelial mucosa by both vagal and spinal afferents.

Upregulated Gastro-Intestinal Cyto-Protective System

In accordance to our model, upregulation may occur in either Section of the GICPS™. This upregulation, depicted in Table 4,  of GICPS elements (shown in Table 2) occurs in response to either direct assault on the mucosa or by activation of epithelial sensors without breach of mucosal integrity.   Regardless of the pathway of upregulation, (whether  [a] from breaching the mucus gel barrier with subsequent activation of exposed neurons, and activation of FGF, EGF, or TGF, or [b] from direct stimulation of intra-epithelial lymphocytes, enterocytes, or enterochrommafin cells to switch on the immuno-neuronal cascade) the result of upregulation is the same:  production and focal release of of chemo-mediators, cytokines, nerve growth factors with responses from targeted  cells (lymphocyte, neutrophils, macrophages, basophils ) and targeted tissues (capillary vessels, muscles fibers and other neuronal endings).

In Section I of the GICPS™, simple breach of  the physio-chemical mucus gel barrier is sufficient to upregulate the system.  Upregulation will occur with physical breach of the mucus gel barrier and the underlying enteric epithelium; assault of the barrier can occur with digestive or chemical irritants, microbes, or toxins.  Once effaced of its mucus gel, enteric epithelium of the upper GI tract lies vunerable to acid, bile, pepsin or infection leading to irritation, erosions and ulceration.  The back diffusion of acid into epithelial layers sets off immediate and emergent neuronal signals, [“Q”] in both spinal and vagal afferents that then (i) hypersensitize surrounding nerve endings [“Q”], and (ii) stimulate the intracellular elaboration and focal release of mediators targeting immune cells, [“S’],(namely mast cells), arterioles, venules [“R”] and all three layers of muscles [“T”], depending on the severity of breach.  Neuronally activated mast cells then elaborate chemomediators to modulate responses of vasculature [“W”], musculature [“U”] and other pro-inflammatory actions [“V”].   Besides this neuronal-immune response issuing from acid-backdiffusion, cellular disruption lead to the release and activation of heparin-bound mitogen, FGF,which regulate tissue repair and healing.

In Section II of the GICPS™, upregulation can occur not from direct mucosal breachment, but  from receptor actIvation of one of at least three sentinel cell types acting as  “ on-switches” for the immuno-neuronal cascade.  In Section I there is a neuronal-immune cascade, while in Section II, there is an immuno-neuronal cascade of events that lead to the GI symptoms common to all mammalian species. These “on-switches” are specialized receptors on alpha-beta T-cells, on enterochromaffin and on enteric epithelial cells.    This initial tide of upregulation [depicted in Table 4 by solid arrows labeled “A, B, C,D, E”] of chemo-mediators, cytokines, nerve growth factors result in the following sequelae that detail the “immuno-neuronal cascade”.  [i] There is the hypersensitization of nerve endings at all tissue levels from specialized sensors in epithelial enterocytes of the lumen, to the endothelial cells of capillaries of the lamina propria and the myofibres of arterioles of the sub-mucosa, even, on to local motoneurons where neuropeptides, tachykinins,  some mitogenic substances are elaborated and released on targeted receptors distributed on circular, longitudinal and  muscularis mucosal  myofibers. [ii] The initial tide also acitvate sub-mucosal T-lymphocytes which in turn elaborate and secrete additional cytokines and growth factors [depicted in Table 4 by arrows labeled “F,G,H’] that are generally pro-inflammatory. [iii] The initial tide of mediators, cytokines and growth factors, result in the chemotaxis, activation and degranulation of sub-mucosal neutrophils and mast cells whose products of degranulation in turn  [depicted in Table 4 by arrow labeled “G,H’] targets blood vessels for either constriction, dilatation or changes in permeability, the latter occuring to facilatate focal edema and chemotaxis of other immune cells like monocytes, macrophages and eosinophils.  Products of neutrophil and mast cell degranulation  [depicted in Table 4 by arrow labeled “G,H’] also target neuro-muscular junctions to effect changes in muscular chronotropicity and inotropicity, to decrease or increase either the rate or strength of contraction, selecting either the longitudinal or the circular muscles of the GI tract by selective release of neuro-peptides.

Implied though not mention explicitly, the gut has its own nervous system, known as the “enteric nervous system”  comprised of [i] an intrinsic afferents (receiving input from various sources—epithelium, immune cells--for the purpose of targeting enteric vessels, enteric muscles and other enteric neurons) and of [ii]an extrinsic afferents (receiving input from various sources-epithelium, activated immune cells, sensitized neurons--for the purpose of acting on enteric targets, by way of either the brainstem and nodose ganglia, or the spinal cord and the dorsal root ganglion with re-distributed intersegmental outputs).  With breach of physio-chemical mucus gel layer, there are epithelially mediated cyto-protection via spinal afferents nerve fibers activated by epithelial injury to take efferent-type actions in a bid to provide quick local protective function. By releasing calcitonin gene-related peptide (CGRP), Substance-P (SP), neurokinin-a (NKA), nitric oxide (NO),  and adenosine triphosphate (ATP) from peripheral terminal endings.  These spinal afferent mediators target the ENS, epithelium and vasculature.

Sucralfate-Mediated Reversal of Neuro-Immune Reaction

Sucralfate-mediated reversal of the symptoms of non-ulcer functional dyspepsia and acid related dyspepsia is diagramed in Table 5, and is far beyond the concept of a “band-aid” effect.

Table 5. Gastro-Intestinal Cyto-Protection System™ (GICPS™) DOWNREGULATED

Copyright © Mueller Medical International LLC 1995, 2001, 2006

As a poly-anion, PA, in Table 5, sucralfate operates in several ways beyond that of a “band aid”.  The concept of polyanions and proteomic interactions driving many extra- and intra cellular reactions provides a unique way to view sucralfate.

Sucralfate works on contact by  driving mitogens, EGF or FGF, to (i) injured beds of irritation, erosion or ulceration, to (ii) surface membranes of enterochromaffin cells, EEC,  and to (iii) enteric epithelial cells resulting in repair and reversal of immuno-neuronal and neuro-immune mediated inflammation.

Sucralfate also works by direct contact to EEC cell membranes downregulating activated chemosensors, nociceptor sensors, and other receptors  responsible for hyerpalgesia, nausea, vomiting and diarrhea.

In addition to this, sucralfate work by direct contact with enteric epithelial cell membranes to repolarize activated vagal and spinal receptors with subsequent deactivation of stimulated afferents of the vagus nerve and stimulated afferent neurons of the spinal (sympathetic) dorsal root ganglion.

• GICPS^tm

• Molecular Markers of  Functional Bowel Disease

• Mucosal Mediation of GI Symptoms

• The Enteric Nervous System & the Network of Receptor Mediator Pairings

• Sucralfate-Mediated Reversal of Neuro-Immune Reaction