Indomethacin-induced intestinal inflammation

Indomethacin induces inflammation of the small-intestinal mucosa leading to ulceration in patients. In rats we examined this untoward drug effect by measuring changes inde novo macromolecular synthesis and morphology during exposure to indomethacin given as a single oral dose of 15 mg/kg. Indomethacin alone induced diffuse jejunoileal mucosal inflammation accompanied by spotty ulceration. These lesions were not observed at 2 and 6 hr after administering the drug but were apparent by 24 hr. By 72 hr the intestinal inflammation had intensified, and there were multiple perforating ulcers, extensive adhesions, and peritonitis in the moribund animals.De novo DNA synthesis was increased approximately fourfold by 24 hr and ninefold by 72 hr; RNA synthesis was nearly doubled by 24 hr and nearly trebled by 72 hr; protein synthesis increased about fourfold at 24 hr and eightfold at 72 hr. Both the histological lesions and the macromolecular synthetic changes induced by indomethacin were prevented by 16,16-dimethyl prostaglandin E ₂ and by broad-spectrum antibiotics but not by dexamethasone, prednisolone, or colchicine. Neither ligation of a mesenteric arterial branch nor administration of vasopressin induced the intestinal inflammatory lesions seen with indomethacin. The predominant mechanism involved in indomethacin ulceration of the gut appears to be acute inflammation rather than ischemia.This research was supported by NIH grant #AM-15997 and by a gift from The Upjohn Company.     

Radiation-induced intestinal inflammation

Radiation induces an important inflammatory response in the irradiated organs, characterized by leukocyte infiltration and vascular changes that are the main limiting factor in the application of this therapeutic modality for the treatment of cancer. Recently, a considerable investigative effort has been directed at determining the molecular mechanisms by which radiation induces leukocyte recruitment, in order to create strategies to prevent intestinal inflammatory damage. In these review, we consider current available evidence on the factors governing the process of leukocyte recruitment in irradiated organs, mainly derived from experimental studies, with special attention to adhesion molecules, and their value as therapeutic targets.     

Helminth infections and intestinal inflammation

Evidence from epidemiological studies indicates an inverse correlation between the incidence of certain immune-mediated diseases, including inflammatory bowel diseases （IBD）, and exposure to helminths. Helminth parasites are the classic inducers of Th2 responses. The Th2-polarized T cell response driven by helminth infection has been linked to the attenuation of some damaging Th1 driven inflammatory responses, preventing some Th1-mediated autoimmune diseases in the host, including experimentally induced colitis. Helminth parasites （the porcine whipworm, Trichuris suis ） have been tested for treating IBD patients, resulting in clinical amelioration of the disease. As a result, there is a great deal of interest in the research community in exploring the therapeutic use of helminth parasites for the control of immune-mediated diseases, including IBD. However, recent studies have provided evidence indicating the exacerbating effects of helminths on bacterial as well as non-infectious colitis in animal models. Therefore, a better understanding of mechanisms by which helminths modulate host immune responses in the gut may reveal novel, more effective and safer approaches to helminth-based therapy of IBD.     

Nitric oxide and intestinal inflammation

Inflammation of the intestinal tract remains a very serious concern in the clinical setting. Unfortunately, to date, the mechanisms underlying many inflammatory conditions such as sepsis or inflammatory bowel diseases are poorly understood and our therapeutic interventions are less than ideal. Over the past decade, an abundance of research has been directed toward the role of nitric oxide (NO) in intestinal inflammation. It has become apparent that NO might have a dichotomous role as both a beneficial and detrimental molecule. Nitric oxide is a weak radical produced from L-arginine via the enzyme nitric oxide synthase (NOS). NOS exists in three distinct isoforms; constitutively (cNOS) expressed neuronal NOS (NOS1 or nNOS) and endothelial NOS (NOS3 or eNOS) or an inducible isoform (NOS2 or iNOS) capable of high production output of NO during inflammation. Constitutively expressed NOS has been shown to be critical to normal physiology and inhibition of these enzymes (nNOS or eNOS) caused damage. It has been proposed that the high output production of NO from iNOS causes injury, perhaps through the generation of potent radicals such as peroxynitrite and hence may explain the apparent dichotomous role of NO. However, recent studies have challenged this simple paradigm providing evidence that iNOS may have some protective role in some inflammatory models. Moreover, the importance of peroxynitrite has been questioned. In this review we discuss the role of cNOS and iNOS in intestinal inflammation and provide an overview of peroxynitrite in intestinal inflammation, highlighting some of the controversy that exists.     

Endocannabinoid overactivity and intestinal inflammation

Cannabinoid receptors of type 1 and 2 (CB(1) and CB(2)), endogenous ligands that activate them (endocannabinoids), and mechanisms for endocannabinoid biosynthesis and inactivation have been identified in the gastrointestinal system. Activation of CB(1 )receptors by endocannabinoids produces relaxation of the lower oesophageal sphincter and inhibition of gastric acid secretion, intestinal motility, and fluid stimulated secretion. However, stimulation of cannabinoid receptors impacts on gastrointestinal functions in several other ways. Recent data indicate that the endocannabinoid system in the small intestine and colon becomes over stimulated during inflammation in both animal models and human inflammatory disorders. The pathological significance of this "endocannabinoid overactivity" and its possible exploitation for therapeutic purposes are discussed here.     

Prebiotics in chronic intestinal inflammation

Prebiotics are nondigestible fermentable fibers that are reported to have health benefits for the host. Older as well as more recent studies show beneficial effects in experimental colitis and lately also in human inflammatory bowel diseases (IBD), such as Crohn's disease, ulcerative colitis, and chronic pouchitis. In this review we give an overview of the benefits of prebiotics in rodent IBD models and in IBD patients and discuss their possible protective mechanisms. Commensal intestinal bacteria induce and perpetuate chronic intestinal inflammation, whereas others are protective. However, most of the current medications are directed against the exaggerated proinflammatory immune response of the host, some of them toxic and costly. Feeding prebiotics changes the composition of the intestinal microflora toward more protective intestinal bacteria and alters systemic and mucosal immune responses of the host. Therapy for IBD targeting intestinal bacteria and their function is just emerging. Prebiotics have the promise to be relatively safe, inexpensive, and easy to administer. Unraveling their protective mechanisms will help to develop rational applications of prebiotics. However, the initial promising results with dietary prebiotics in preclinical trials as well as small studies in human IBD will need to be confirmed in large randomized controlled clinical trials.     

Oxysterols in intestinal immunity and inflammation

Cholesterol is an essential molecule for life. It is a component of the cell membrane, and it is a precursor molecule for bile acids, vitamin D and steroid hormones. Cholesterol is actively metabolized, but the impact of endogenous cholesterol metabolites on immune function, especially in the intestine, is poorly understood. In this review, I focus on oxysterols, hydroxylated forms of cholesterol, and their specialized functions in intestinal immunity. Oxysterols act through various intracellular and extracellular receptors and serve as key metabolic signals, coordinating immune activity and inflammation. Our recent work has identified an unexpected link between cholesterol metabolism, innate lymphoid cell function and intestinal homeostasis. We discovered that oxysterol sensing through the G protein‐coupled receptor 183 (GPR183) directs the migration of innate lymphoid cells, which is essential for the formation of lymphoid tissue in the colon. Moreover, we found that the interaction of GPR183 with oxysterols regulates intestinal inflammation. I will discuss the therapeutic potential of oxysterols and future possibilities of treating inflammatory bowel disease through the modulation of cholesterol metabolism.     

Inflammasomes in intestinal inflammation and cancer

Inflammasomes are multi-protein complexes that mediate activation of caspase-1, which promotes secretion of the proinflammatory cytokines interleukin-1β and interleukin-18 and pyroptosis, a form of phagocyte cell death induced by bacterial pathogens. Members of the Nod-like receptor family (including Nlrp1, Nlrp3, and Nlrc4), the DNA sensor Aim2, the adaptor apoptosis-associated speck-like protein (ASC), and pro-caspase-1 are important components of inflammasomes. Stimulation with specific microbial and endogenous molecules leads to inflammasome assembly and caspase-1 activation. Inflammasomes are believed to mediate host defense against microbial pathogens and tissue homeostasis within the intestine, and their dysregulation might contribute to inflammatory diseases and intestinal cancer. Improving our understanding of inflammasome signaling pathways could provide insights into the pathogenesis of many gastrointestinal disorders and the development of therapeutic targets and approaches to treat diseases such as inflammatory bowel diseases and gastrointestinal cancers.     

Helicobacter pylori and nonspecific intestinal inflammation

In 50 subjects with non-specific inflammations of the gut the total prevalence of Helicobacter pylori positive antibodies was 28%, while in the control group of blood donors its was 54% Patients with ulcerative colitis had lower antibodies--18%, in Crohn's disease the serum positivity was 33%. The lowest value of antibodies was found in patients taking Sulfasalazine--11%. The serum positivity was substantially higher in inactive ulcerative colitis and Crohn's disease--35% than in patients with signs of high activity--13%. In 28 patients with non-specific inflammations of the gut endoscopy was performed, in 60% with a pathological outcome. Histologically confirmed gastritis was in the majority Helicobacter pylori negative. It may be stated that in patients with non-specific inflammations of the gut there is a lower incidence of Helicobacter pylori than in the general population, in particular those subjects who were or are treated with Sulfasalazine. The explanation of this fact is however only speculative.     

Chronic pancreatitis： Maldigestion, intestinal ecology and intestinal inflammation

Exocrine pancreatic insufficiency caused by chronic pancreatitis results from various factors which regulate digestion and absorption of nutrients. Pancreatic function has been extensively studied over the last 40 years, even if some aspects of secretion and gastrointestinal adaptation are not completely understood. The main clinical manifestations of exocrine pancreatic insufficiency are fat malabsorption, known as steatorrhea, which consists of fecal excretion of more than 6 g of fat per day, weight loss, abdominal discomfort and abdominal swelling sensation. Fat malabsorption also results in a deficit of fat-soluble vitamins （A, D, E and K） with consequent clinical manifestations. The relationships between pancreatic maldigestion, intestinal ecology and intestinal inflammation have not received particular attention, even if in clinical practice these mechanisms may be responsible for the low efficacy of pancreatic extracts in abolishing steatorrhea in some patients. The best treatments for pancreatic maldigestion should be re-evaluated, taking into account not only the correction of pancreatic insufficiency using pancreatic extracts and the best duodenal pH to permit optimal efficacy of these extracts, but we also need to consider other therapeutic approaches including the decontamination of intestinal lumen, supplementation of bile acids and, probably, the use of probiotics which may attenuate intestinal inflammation in chronic pancreatitis patients.     

Antisecretory factor suppresses intestinal inflammation and hypersecretion

Background—Antisecretory factor (AF) is a recentlyidentified regulatory protein which inhibits the intestinal fluidsecretion induced by cholera toxin.
Aims—To test the effect of AF on: (a)inflammation and hypersecretion induced by toxin A fromClostridium difficile; and (b) morphologicalchanges and hypersecretion induced by okadaic acid (the blue musseltoxin) in rat intestinal mucosa.
Methods—Morphological changes and fluidaccumulation were observed in intestinal loops challenged with 1 µgof toxin A or 3 µg of okadaic acid administered beforeor after injection of 0.1 µg of recombinant AF (rAF).
Results—The cytotoxic and inflammatory reactioncaused by toxin A was abolished after treatment with rAF given eitherintraveneously or intraluminally prior to the toxin or one hour afterthe toxin. The intestinal fluid response induced by toxin A and okadaicacid was reduced 55-80% by rAF. However, the characteristic increase in goblet cells at the tips of villi in the okadaic acid treated mucosawas not inhibited by rAF.
Conclusion—Results suggest that AF might beinvolved in protection against inflammation and in counteractingdehydration caused by enterotoxins. Both effects are probably mediatedvia the enteric nervous system.

Keywords:okadaic acid; Clostridiumdifficile toxin A; diarrhoea; neuropeptide; S5a; rat

     

Healing of intestinal inflammation by IL-22

An interleukin (IL)-10 family cytokine, IL-22 is characterized by several unique biological properties, including 1) the target restricted to innate cells; 2) the distinct expression pattern between large and small intestines; 3) alteration of the cellular source depending on several factors; 4) the dual abilities to serve as protective versus proinflammatory mediators in inflammatory responses; and 5) the close association with some major inflammatory bowel disease (IBD) susceptibility genes. The major functions of IL-22 in the intestine are the stimulation of epithelial cells to produce a wide variety of antibacterial proteins, the reinforcement of mucus barrier through stimulation of mucin 1 production under intestinal inflammatory conditions, and the enhancement of epithelial regeneration with goblet cell restitution. Through these beneficial functions, IL-22 contributes to the improvement of some types of experimental chronic colitis, which are mediated by T helper (Th)1 or Th2 responses. Most important, studies using both loss-of-function and gain-of-function approaches have clearly demonstrated the ability of IL-22 to promote intestinal wound healing from acute intestinal injury. These findings highlight IL-22 as an attractive and promising target for future IBD therapy. Alternatively, the enormous progress in the field of IL-22 biology has also suggested more complicated mechanisms with the IL-22 pathway than previously predicted. This review article briefly summarizes previous and current knowledge on IL-22 particularly associated with intestinal inflammation.     

Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans

This study examines the effects of nonsteroidal antiinflammatory drugs on the small intestine in humans. Using an 111In-leukocyte technique in patients with rheumatoid arthritis (n = 90) and osteoarthritis (n = 7), it appears that nonsteroidal antiinflammatory drugs cause small intestinal inflammation in two-thirds of patients on long-term treatment and on discontinuation, the inflammation may persist for up to 16 mo. The prevalence and magnitude of the intestinal inflammation was unrelated to the type and dose of nonsteroidal drugs and previous or concomitant second-line drug treatment. There was a significant inverse correlation (r = -0.29, p less than 0.05) between fecal 111In excretion and hemoglobin levels in patients treated with nonsteroidal antiinflammatory drugs. The kinetics of fecal indium 111 excretion in patients treated with nonsteroidal antiinflammatory drugs was almost identical to that of patients with small bowel Crohn's disease. Eighteen patients on nonsteroidal antiinflammatory drugs underwent a radiologic examination of the small bowel and 3 were found to have asymptomatic ileal disease with ulceration and strictures. Nineteen patients on nonsteroidal antiinflammatory drugs, 20 healthy controls, and 13 patients with Crohn's ileitis underwent a dual radioisotopic ileal function test with tauro 23 (75Se) selena-25-homocholic acid and cobalt 58-labeled cyanocobalamine. On day 4, more than half of the patients with rheumatoid arthritis had evidence of bile acid malabsorption, but the ileal dysfunction was much milder than seen in patients with Crohn's ileitis.     

Cross-talk between iron homeostasis and intestinal inflammation

Recent publications from my laboratory have highlighted the important influence of altered iron homeostasis on the inflammatory response to intestinal bacteria. Here, I provide commentary on one of those papers, "Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice", which was published in the Journal of Clinical Investigation in October, 2009. It describes experiments that point to a previously unappreciated role for intracellular iron in the regulation of Toll-like receptor 4 signaling, and also demonstrates the potential therapeutic application of this information in a novel anti-inflammatory strategy based on manipulating iron balance. Our findings indicate that further investigation of the cross-talk between iron homeostasis and inflammation will yield new insights into the pathogenesis of chronic inflammatory diseases and may suggest new treatment approaches for these conditions.     

Cross-talk between iron homeostasis and intestinal inflammation

Recent publications from my laboratory have highlighted the important influence of altered iron homeostasis on the inflammatory response to intestinal bacteria. Here, I provide commentary on one of those papers, "Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice", which was published in the Journal of Clinical Investigation in November, 2009. It describes experiments that point to a previously unappreciated role for intracellular iron in the regulation of Toll-like receptor 4 signaling, and also demonstrates the potential therapeutic application of this information in a novel anti-inflammatory strategy based on manipulating iron balance. Our findings indicate that further investigation of the cross-talk between iron homeostasis and inflammation will yield new insights into the pathogenesis of chronic inflammatory diseases and may suggest new treatment approaches for these conditions.