Epithelial Secretory Response to Inflammation MAE J. CIANCIO AND EUGENE B. CHANG" Department of Medicine Section of Gastroenterology The University of Chicago Chicago, Illinois 60637

INTRODUCTION Diarrhea is reported in 66-92% of the patients with inflammatory bowel disease (IBD),' the severity of which is dependent on the degree of intestinal inflammation. The positive correlation between degree of inflammation and severity of diarrhea suggests that the local immune response elicited in the intestines may directly alter epithelial cell transport, resulting in increased secretion, decreased absorption, or a combination of the two. Histological examination of the intestinal wall reveals an epithelial cell monolayer, beneath which are infiltrating fibroblasts, polymorphonuclear cells, macrophages, mast cells, eosinophils and lymphocytes. The physical closeness of these cells suggests a close interplay between the local immune system and the intestinal tract. During a diseased state, such as IBD, the intensity of immunoregulation is enhanced, resulting in acute and chronic changes in the intestinal wall. Acutely, the number of inflammatory cells in the lamina propria increases significantly as a result of mediator-induced chemotaxis and increased vascular permeability. Secondly, the production of inflammatory mediators by these cells, such as histamine, serotonin, platelet activating factor, reactive oxygen metabolites, cytokines, prostaglandins, leukotrienes, bradykinin and nitric oxide, is elevated. The acute effects of these immune and inflammatory mediators on epithelial cell secretion is listed in TABLE 1. The inflammatory response can elicit more chronic changes in the intestinal tract as well, as listed in TABLE2. With repeated mucosal injury, the number of crypt-like, regenerative cells increases and the number of well-differentiated absorptive cells decreases, resulting in a leakier, dysfunctional state in the colon. Enhanced mucosal permeability to electrolytes and intestinal bacteria has been reported in patients with IBD,*-' though whether this is a result of genetic predisposition or a consequence of the inflammatory response remains unclear. And the responsiveness of the epithelial cells to normal intestinal agents, in many cases, is altered after preexposure to some of the inflammatory agents indicated above. As a result of the complexity of interactions between the enterocyte and the underlying immune cells, a direct cause and effect relationship between these cells during an inflammatory state has been difficult to assess. Much work has been done using specific inhibitors in vivo in order to evaluate the role of these inflamma-

To whom correspondence should be addressed: Eugene B. Chang, M.D., The University of Chicago, Department of Medicine, Section of Gastroenterology, Box 400, 5841 South Maryland Ave., Chicago, IL 60637. 210

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TABLE 1. Acute Effects of Immune and Inflammatory Mediators on Intestinal

Epithelial Cell Secretion 1. Direct stimulation of net enteric secretions ( e . g . , BK, PGE,). 2. Activation of enteric neurons (e.g., PGI,). 3. Activation of arachidonic acid metabolism (e.g., IL-1, f-MLP). 4. Alteration of blood flow (e.g., PGs, histamine). 5 . Increased mucosal permeability (e.g., LPS, IGF-1)

tory agents in IBD. I n uitro studies conducted on isolated intestinal tissues mounted in Ussing chambers or on a human colonic carcinoma cell line, T84, have been performed to evaluate more directly the role of these mediators on intestinal secretion. The purpose of this paper is to provide an overview of the effects of inflammation, more specifically inflammatory mediators, on intestinal epithelial cell secretion. Their mode of action, either direct or indirect via stimulation of enteric nerves, production of other mediators, or modifications in the normal secretory/ absorption response 'to intestinal hormones, will be discussed. Additionally, the cellular changes which are responsible for the net increase in intestinal secretion, i.e., second messenger involvement or alterations in epithelial cell barrier function, will be addressed. Arachidonic Acid Metabolites

Perhaps the most extensively studied of all the intestinal inflammatory agents in the inflammation and diarrhea associated with IBD have been the arachidonic acid metabolites. These agents directly affect intestinal secretion8-I0 as well as acting as secondary agents for many of the other inflammatory mediators released in the lamina propria, such as bradykinin,"-14 interleukins 1 and 3,I5-I8the chemotactic peptide formyl-methionyl-leucyl-phenylalanine(fh4LP),'9*20 and certain reactive oxygen metabolites.21 As shown in FIGURE 1, two of the key enzymes involved in arachidonic acid metabolism are cyclooxygenase and 5-lipoxygena~e.~~ Cyclooxygenase converts arachidonic acid into prostacyclin (PG12),thromboxane (TxA,), and prostaglandins E, , D2, and F2alpha. The 5-lipoxygenase enzyme converts arachidonic acid to 5hydroperoxyeicosatetraenoic acid (5-HPETE), which is subsequently converted to leukotriene A4, the peptidoleukotrienes C, , D, , and E4, and leukotriene B,. These agents are thought to be synthesized in the intestinal tract by the cells in the lamina propria underlying the epithelium, namely fibroblasts, macrophages, neutrophils, eosinophils and mast cells.23There is some information, however,

TABLE 2. Potential Chronic Effects of Immune and Inflammatory Mediators on

Intestinal Epithelial Cell Secretion 1. "Priming" of epithelialhnesenchymal cell responses (?IL-1, TNF-alpha). 2. Increase in proportion of crypt cells. 3. "Sick cell" syndrome. 4. Increase in mucosal permeability (IFN-gamma).

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which suggests that arachidonic acid metabolites are also made by intestinal entero~ytes.,~-,’ Prostaglandins, especially PGE, ,are potent inflammatory mediators as well as diarrhea-inducing agents. They can directly and indirectly stimulate intestinal secretion. Prostaglandin E2 stimulates active anion secretion and inhibits neutral Na+ and C1- absorption primarily by activating adenylate cyclase and increasing intracellular cyclic AMP in mucosal e n t e r o ~ y t e s . ’ ~However, , ~ ~ , ~ ~ when submicromolar doses of PGE are present, the changes in ion transport are dependent on f Prostaglandin I,, however, stimulates intestinal secretion cytosolic calcium.30indirectly, by stimulating enteric neurons to release the neurotransmitter acetylcholine, which in turn, stimulates intestinal s e ~ r e t i o n . ~ ~ - ~ ~ Less well defined has been the role of prostaglandin D2on intestinal secretion.

FIGURE 1. Arachidonic acid is released from membrane phospholipids and metabolized by cyclooxygenase and 5-lipoxygenase.

As reported by Keenan and R a t ~ g a c h a r i , ~the ~ ~effects ~’ of PGD, on the canine epithelium is dependent upon the state of activation of the tissue. Under stimulated conditions following agents such as PGE, , forskolin and carbachol, PGD, acts as an antisecretory agent, thereby preventing an increase in short circuit current (Isc), a reflection of active anion secretion. In rat colon as well, PGD, has an antisecretory effect, reducing both basal Isc as well as the neurally-mediated secretory response.38 However, as reported by R a n g a ~ h a r i the , ~ ~response observed to PGD, is dose-related, with higher doses of PGD, eliciting a secretory response. These various effects of PGD, actually depend on its conversion into the metabolites 11-~-prostaglandin-F,alphaand 13,14-dihydro-15-ketoprostaglandin D, . The metabolite 1l-~-prostaglandin-F,alphadose-dependently increases D2 decreases Isc. Thus, the net Isc, whereas 13,14-dihydro-15-ketoprostagland1n

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secretory response to PGD, is dependent on which metabolite predominates in the intestinal response. A more detailed discussion of this subject is provided by the paper written by P. K. Rangachari. The role of leukotrienes in the inflammation and diarrhea of IBD has been examined as well. The metabolites 5-HPETE and 5-HETE and the leukotrienes C4 (LTC,), D4 (LTD,), and E4 (LTE,) have been reported to alter intestinal ion t r a n ~ p o r t . ~ Peptidoleukotrienes ~p~-~~ LTC, , LTD, , and LTE, stimulate intestinal secretion when added serosally to isolated rat and rabbit in uitro. The Isc increased and the transepithelial conductance (Gt) de~reased.~’ The elevation in Isc was the net result of an increase in CI- secretion and a decrease in Na+ and C1- absorption. The mechanism of action of these agents is reported to be through cyclooxygenase-dependent and independent pathways. The increase in Isc is reported to be via a cyclooxygenase-dependent p a t h ~ a y . In ~ ~rabbit . ~ ~ ileum, LTD, elevated PGE, levels without a change in PGI, or TxA, c ~ n c e n t r a t i o nIn . ~ the ~ rat ileum, however, LTD, increased TxA, without altering PGE, or PGI, levels.44However, the decrease in Gt as well as the decrease in Na+ and C1- absorption in the rat ileum is mediated through a cyclooxygenase-independent pathway,,’ thus suggesting a direct cellular effect of these agents on intestinal ion transport. In addition to the secretory and antiabsorptive effects of LTC4, LTD, , and LTE4, these agents also stimulate intestinal smooth muscle contraction, thereby contributing further to the diarrhea of IBD by decreasing intestinal transit times. A more detailed discussion of the intestinal effects of peptidoleukotrienes on intestinal ion transport is provided in the paper by P. L. Smith. Unlike peptidoleukotrienes, LTB, does not appear to have a direct role in mediating the ion transport changes which accompany inflammatory diarrhea, although elevated levels have been reported in the mucosa of patients with IBD.45 This agent acts instead as a potent chemoattractant, stimulating neutrophil migration into the submucosa of the intestinal tract.46Moreover, LTB4 induces neutrophi1 aggregation and degran~lation,4’*~~ thereby exacerbating the inflammatory response and increasing the contributory role of the neutrophils to the inflammatory process. Histamine

Histamine and mast cell mediators contribute to the diarrhea associated with systemic anaphylaxis, food allergy, systemic mastocytosis, rejection of helminth parasites, and more recently, IBD.,’ Histamine has been shown to induce diarrhea by increasing intestinal chloride secretion. Both direct and indirect effects of histamine on epithelial cell ion transport have been reported. Using the human colonic cell line, T84, histamine directly stimulated chloride secretion by a calcium dependent process.s0 Histamine bound directly to the enterocyte via HI receptors, thus stimulating an increase in cytosolic calcium via activation of phosphoinositol turnover. Histamine has been reported to indirectly stimulate chloride secretion in intestinal segments from guinea pig and rat via stimulation of arachidonic acid metabolism and enteric nerve s t i m u l a t i ~ n . ~ ~ ~ ~ ~ Histamine also has been reported to have acute as well as chronic effects on the secretory capacity of intestinal e n t e r o c y t e ~As . ~just ~ described, acute exposure to histamine or activated mast cell lysates or supernatants stimulates chloride secretion. However, chronic exposure to mast cell lysates alters the enterocytes’ subsequent response to further stimulation. Intestinal tissue from sensitized rats

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were more responsive to the chloride secretory effects of histamine and substance P.54 Exposure of T84 cells to mast cell lysates containing preformed mast cell mediators for 1 week increased the cells response to further stimulation with the potent secretagogues vasoactive intestinal peptide, carbachol and heat stable enterotoxin of Escherichia coli without altering the electrical properties of the monolayer, such as resistance and potential differen~e.’~ However, when these cells were exposed to supernatants from activated mast cells which contained stored as well as newly made mediators for 1 week, the resistance of the T84 cell monolayers was significantly reduced, suggesting an alteration in the paracellular transport process of these cells.55Thus, histamine and other mast cell mediators have significant effects on epithelial cell transport, both as immediate inducers of intestinal secretion and as long-term modifiers of epithelial cell function and permeability. A more detailed discussion is provided in the paper by K. E. Barrett.

Bradykinin While the physiological role for this nonapeptide is unclear, this agent has a significant role in the inflammation and diarrhea of IBD. Bradykinin has been reported to stimulate C1- secretion in guinea pig and rabbit ileum, rabbit colon and rat colon as well as monolayers of HCA-7 and T84 cell^.'^.^^ This effect is mediated by both direct and indirect action on epithelial transp01-t.~~ Intracellular Ca++ is believed to be important in mediating the direct effect of bradykinin on intestinal enterocytes via activation of the bradykinin B, receptor.56The bradykinin-induced change in intracellular Ca+ is believed to be responsible also for the change in epithelial cell cytoskeletal structure observed during the C1- secretory response. Bradykinin indirectly stimulates intestinal secretion through the production of prostaglandins as well as l e ~ k o t r i e n e s .Elevated ~ ~ * ~ ~ levels of PGE2, PGI, and TxAz have been found in animals with experimental colitis. Monolayers of T84 cells stimulatedwith bradykinin demonstrated an increased secretory response in the presence of intestinal fibroblasts compared to T84 monolayers a10ne.I~This enhanced secretory effect was the result of bradykinin-stimulatedarachidonicacid metabolite production by the underlying fibroblasts. +

Serotonin Serotonin, or 5-hydroxytryptamine,is present in mast cells, platelets, mucosal enterochromaffincells, and a subset of myenteric neurons.23Serotonin contributes to the diarrhea associated with inflammation by altering intestinal epithelial transport in two ways. First, serotonin causes a transient increase in chloride secretion. Second, serotonin causes a prolonged inhibition of neutral Na+ and CI- absorption. The direct effect of serotonin is a Ca++-dependent p r o c e s ~ . ~ Indirectly, ’.~~ serotonin alters intestinal transport through stimulation of prostaglandin production and enteric nerves. The neural component of serotonin’s actions has been demonstrated in guinea pigs but not in rats, whereas the prostaglandin dependency has been demonstrated in both animal^.^^.^'.'^ Serotonin, through its actions on vascular permeability and production of neutrophil attractants,” contributes further to the inflammatory response reported with IBD.

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Platelet Activating Factor Platelet activating factor (PAF), or acetyl glyceryl ether phosphorylcholine, is the name given to designate a group of biologically active phosphoglycerides made by phagocytes, platelets, mast cells and vascular endothelium in the gastrointestinal t r a ~ t . PAF ~ ~ , is~ not ~ stored intracellularly, but rather is synthesized from membrane phospholipids. PAF has been reported to stimulate intestinal C1- secretion in the small intestines and colon.20*62 However, micromolar concentrations of PAF are required to elicit the secretory response. A plausible explanation for this is the finding that the gut elaborates an endogenous lipid antagonist to PAF (see paper by D. W. Powell). The presence of this antagonist thus decreases the tissue sensitivity to PAF, hence accounting for the variability in tissue response.63Using T84 cell monolayerst4as well as specific PAF a n t a g o n i ~ t sit, ~appears ~ that PAF has a direct effect on epithelial cell transport. The mechanism for this action is unclear, although PAF has been reported to increase intracellular C a + + in macrophages. However, most of PAF's intestinal effects are mediated through the production of prostaglandins (PGE2, PG12) and stimulation of enteric nerve activity.20*62 In addition to the secretory effects of PAF, PAF further contributes to the inflammatory response through its potent chemoattractant effects and synergistic interactions with various leukotrienes released during inflammation.a PAF also is an important mediator of the secretory response induced by anti-IgE and ~

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Reactive Oxygen Metabolites Reactive oxygen metabolites (ROM) are produced by the respiratory burst xanthinelxanthine oxidase reaction in phagocytic cells. These metabolites include the superoxide anion (OT), hydroxyl radical (OH-), hydrogen peroxide (H,O2) and the long-lived ROM monochloramine. ROMs have been reported to increase Isc in the rat colon by stimulation of C1- secretion.20This secretory response to ROM appeared to result from the stimulatory effect of H202,since the response was not inhibited by preincubation with desferoxamine or thiourea, but was inhibited by catalase and diethyldithiocarbamate (see paper by D. W. Powell). The secretory effect of H202resulted from a small direct effect of H202on epithelial cell transport and a more substantial effect through the release of prostaglandins (PG12and PGE2),PAF, and stimulation of enteric nerves.2' In uitro studies using T84 monolayers demonstrated a direct stimulatory effect as well as no direct effect of H202 on cell tran~port.'~.~' In the latter instance, H202stimulated T84 C1secretion only in the presence of intestinal fibroblasts, as a result of H202-stimulated prostaglandin prod~ction.'~ More recently, however, it has been shown that monochloramine stimulated T84 CI - secretion directly by increasing intracellular Ca+ .@ +

Cytokines Cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF), are inflammatory proteins produced primarily by activated macrophages. These potent inflammatory mediators are believed to have a substantial role in the intestinal alterations which are prevalent in IBD. Interleukins 1 and 3 have been reported to stimulate intestinal C1- secretion in the chicken through the

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production of prostaglandins.lSStudies employing the T84 cell line demonstrated that fibroblasts pretreated with IL-1 beta induced a greater secretory response in the T84 cells in response to stimulation with bradykinin, histamine and Hz02 than the control fibroblasts, most likely as a result of enhanced prostaglandin prod~ction.~’ TNF and IL-I also may contribute to the diarrhea associated with inflammation by increasing the number of less differentiated crypt-like cells in the intestinal m u c o ~ a . ~ Both ~ - ~TNF ~ and IL-1 have been reported to increase colonocyte proliferation in the cell line IEC-6 as well as in cultures of rabbit distal colon enterocytes. While these agents are not cytokines by the above definition, insulin-like growth factor 1 and interferon gamma may induce diarrhea through their actions on tight junctional i~~tegrity.’~,~’ Both agents have been reported to lower resistance in T84 monolayers, thus altering the passive electrolyte transport. TNF, on the other hand, was reported to have no effect on tight junctional integrity.

Neural Stimulation, Substance P and Neurotensin Stimulation of the enteric nerves in the gastrointestinal tract significantly influences electrolyte transport by intestinal epithelial cells. Substance P, neurotensin and vasoactive intestinal peptide have receptors on the enterocyte which are responsible for mediating the secretory effects of these agents.72Moreover, as indicated in the previous sections of this review, a significant proportion of the secretory response elicited by many inflammatory agents is mediated by enteric nerve stimulation. Most of the information implicating the role of neural stimulation in the secretory response to many inflammatory agents is obtained through the use of specific inhibitors, such as tetrodotoxin, hexamethonium, and atropine. Less information is available demonstrating a direct effect of various inflammatory agents on enteric nervous system ganglia. Histamine, for example, has been shown to elicit excitatory postsynaptic potentials in myenteric plexus.73The prostaglandins, PGE, and PG12,are reported to directly stimulate acetylcholine release from guinea pig myenteric plexus as well as suppress norepinephrine release from adrenergic neurons in the rat ~ o l o n . ~PAF ~ *has ~ ~been * ~demonstrated ~ to release norepinephrine in the rat intestine as well as stimulate Ca++-mediated neurotransmitter release in cultured rat enteric nervous system preparation^.^^.^^ In addition, ROM directly stimulate acetylcholine release from enteric nerves.77Evident from this discussion is the close interaction between the enteric nervous system and many of the immune cells present in the intestinal wall. The close proximity of these cells anatomically suggests a close network of interaction between nervous and immune control of intestinal secretion. In support of this, mast cells, lymphocytes and macrophages have been demonstrated to possess receptors for substance P and n e u r o t e n ~ i o n . ~ ~ - ~ ~

Adenosine and ATP Adenosine and ATP have been demonstrated to stimulate intestinal secretion. Adenosine can act directly on the enterocyte to stimulate intestinal CI- secretion.*’ The A, adenosine receptor is believed to be responsible for the intestinal effects of adenosine. The role of the other two adenosine receptors, A, and A,, in the intestinal response to this agent is unclear. Studies using the T84 intestinal cell

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line demonstrated that adenosine analogues stimulate C1- secretion when added serosally and mucosally.81The two responses are believed to be elicited through different cellular mechanisms, with serosal addition inducing a more potent response. Nitric Oxide

This neutrophil- and macrophage-released mediator, believed to be a major component of endothelium-derived relaxation factor, may have a significant role in the inflammation and diarrhea associated with IBD. Nitric oxide may stimulate intestinal secretion through its stimulatory effects on the iron-sulfur containing soluble form of guanylate cyclase. It has been demonstrated in rat distal colon that spontaneous generation of nitric oxide with nitroprusside stimulates secretioma2 This effect appeared to be mediated, in part, by prostaglandin production as well as enteric nerve stimulation, since piroxicam and tetrodotoxin inhibited the effect by 15% and SO%, respectively. Enteric Bacteria

The bacteria and bacterial by-products, such as endotoxin, normally present in the intestinal flora may have a significant contributory role to the diarrhea associated with IBD. Endotoxin, a lipopolysaccharide component of the cell wall of gram-negative bacteria, is a known diarrhea-inducing agent.83Circulating levels of endotoxin have been reported in patients with IBD.84-86In uivo intestinal loop studies demonstrated that endotoxin significantlyreduces colonic saline absorption by 50% without altering ileal or jejunal absorption rates.87 Unidirectional fluxes indicated that endotoxin treatment in uivo significantly reduced net Nat transport in virro, with a comparable decrease in C1- transport. Inulin flux studies, as well as the Nat and CI- fluxes, suggested an elevation in the serosal to mucosal flux for each of these agents, analogous to the previous findings which demonstrated increased serosal to mucosal leakiness for electrolytes in inflamed tissue.2 The bacterial chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMLP) has been shown to stimulate chloride secretion in colon and ileum in vitro.19*20 This well-known neutrophil activator stimulated intestinal secretion through stimulation of cyclooxygenase metabolism as well as enteric nerve stimulation.

SUMMARY As suggested by this and previous review^,*^*^^*^^ the neuroimmunoregulation of intestinal secretion is a complex series of endocrine, neurocrine, paracrine and autocrine interactions between the underlying cells in the mucosa and submucosa and the intestinal enterocyte. Under normal conditions, the balance of each of these systems is delicately controlled, thus allowing for normal, consistent intestinal function. However, when this finely-tuned system is altered, such as in a diseased state, the resultant effect is an amplification of the host defense response. Initially thought to be protective against further insult, this local immune response, if allowed to continue uncontrollably, can exacerbate the disease process.

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