Functional Dyspepsia and Food: Immune Overlap with Food Sensitivity Disorders.

PURPOSE OF REVIEW: Functional dyspepsia (FD) is a chronic functional gastrointestinal disorder characterised by upper gastrointestinal symptoms. Here, we aimed to examine the evidence for immune responses to food in FD and overlap with food hypersensitivity conditions. RECENT FINDINGS: A feature of FD in a subset of patients is an increase in mucosal eosinophils, mast cells, intraepithelial cytotoxic T cells and systemic gut-homing T cells in the duodenum, suggesting that immune dysfunction is characteristic of this disease. Rates of self-reported non-celiac wheat/gluten sensitivity (NCW/GS) are higher in FD patients. FD patients commonly report worsening symptoms following consumption of wheat, fermentable oligosaccharides, disaccharides, monosaccharides, or polyols (FODMAPs), high-fat foods and spicy foods containing capsaicin. Particularly, wheat proteins and fructan in wheat may drive symptoms. Immune mechanisms that drive responses to food in FD are still poorly characterised but share key effector cells to common food hypersensitivities including non-IgE-mediated food allergy and eosinophilic oesophagitis.

Effects of pirfenidone on increased cough reflex sensitivity in guinea pigs.

Pirfenidone, an antifibrotic drug with anti-inflammatory and antioxidant effects, delays fibrosis in idiopathic pulmonary fibrosis (IPF). Patients with IPF have a greater cough reflex sensitivity to inhaled capsaicin than healthy people, and cough is an independent predictor of IPF disease progression; however, the effects of pirfenidone on cough reflex sensitivity are unknown. After challenge with an aerosolized antigen in actively sensitized guinea pigs, pirfenidone was administered intraperitoneally, and the cough reflex sensitivity was measured at 48 h after the challenge. Bronchoalveolar lavage (BAL) was performed, and the tracheal tissue was collected. Pirfenidone suppressed the capsaicin-induced increase in cough reflex sensitivity in a dose-dependent manner. Additionally, increased levels of prostaglandin E2, substance P, and leukotriene B4, but not histamine, in the BAL fluid were dose dependently suppressed by pirfenidone. The decrease in neutral endopeptidase activity in the tracheal tissue was also alleviated by pirfenidone treatment. The total number of cells and components in the BAL fluid was not influenced. These results suggest that pirfenidone ameliorates isolated cough based on increased cough reflex sensitivity associated with allergic airway diseases, and potentially relieve chronic cough in IPF patients who often have increased cough reflex sensitivity. Prospective studies on cough-relieving effects of pirfenidone in patients with IPF are therefore warranted.

COX-2 inhibition attenuates cough reflex sensitivity to inhaled capsaicin in patients with asthma.

BACKGROUND AND OBJECTIVE: Cyclooxygenase (COX) is an enzyme that converts arachidonic acid to prostanoids. There are two isoforms of COX, namely COX-1 and COX-2. COX-2 is highly inducible by several stimuli and is associated with inflammation. Recent studies have shown that COX-2 is upregulated in the airway epithelium of patients with asthma but little is known about the role it plays in cough, a common symptom of bronchial asthma. This study was designed to investigate the role of COX-2 in cough reflex sensitivity in patients with asthma. PATIENTS AND METHODS: The effect of etodolac, a potent COX-2 inhibitor, on cough response to inhaled capsaicin was examined in 17 patients with stable asthma in a randomized, placebo-controlled crossover study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting 5 or more coughs, was measured as an index of airway cough reflex sensitivity. RESULTS: The geometric mean (geometric SEM) cough threshold was significantly increased after a 2-week treatment program with oral etodolac (200 mg twice a day) compared with placebo (36.7 [1.2] vs 21.6 [1.2] gM, P<.02). CONCLUSIONS: These findings indicate that COX-2 may be a possible modulator augmenting airway cough reflex sensitivity in asthmatic airways.

Mechanisms of increased airway sensitivity to occupational chemicals and odors.

PURPOSE OF REVIEW: Airway symptoms induced by chemicals and odors are common problems that are also reported after contact with substances normally regarded as nontoxic. This article reviews current findings and opinions regarding mechanisms of increased airway sensitivity to occupational chemicals and odors. RECENT FINDINGS: Individuals exposed to organic solvents during work had more nasal irritation and lower threshold to pyridine odor compared with a nonexposed control group. Six percentage of a general population in Sweden had pronounced airway chemical sensitivity and augmented capsaicin cough sensitivity, known to reflect the sensory nerve reactivity of the airways. The cough sensitivity was associated with changed levels of nerve growth factor in nasal lavage and such patients had longstanding symptoms influencing their working capacity. Positron emission tomography activation studies with several different odorants showed in patients with odor-associated symptoms an odorant-related increase in activation of the anterior cingulate cortex and cuneus-precuneus in comparison with a control group. SUMMARY: In subgroups of individuals with airway symptoms induced by chemicals and odors, there seems to be a sustainable physiological mechanism behind the reactions. An increased vulnerability to stress cannot be neglected as a confounding factor in some sensitive individuals.

Arvanil and anandamide up-regulate CD36 expression in human peripheral blood mononuclear cells.

In this study we analysed the regulation of gene expression by arvanil and anandamide in human peripheral blood mononuclear cells (PBMCs) to clarify their immunosuppressive properties. PBMCs were activated, leading to CD36 down regulation, that was normalized by arvanil and anandamide. We used microarray technology to identify a regulatory pattern associated with cell proliferation in the presence of both substances. CD3-CD28 stimulated PBMCs showed a pattern of up-regulated and down-regulated genes after treatment with these substances. We selected and analysed several genes chosen by their function in the regulation of cell proliferation. We showed a transcriptional control of the CD36 gene by arvanil and anandamide associated with an increased protein expression, thus suggesting a possible role of CD36 in anandamide and arvanil anti-inflammatory pattern.

Some like it hot: The emerging role of spicy food (capsaicin) in autoimmune diseases.

Autoimmune diseases refer to a spectrum of diseases characterized by an active immune response against the host, which frequently involves increased autoantibody production. The pathogenesis of autoimmune diseases is multifactorial and the exploitation of novel effective treatment is urgent. Capsaicin is a nutritional factor, the active component of chili peppers, which is responsible for the pungent component of chili pepper. As a stimuli, capsaicin selectively activate transient receptor potential vanilloid subfamily 1(TRPV1) and exert various biological effects. This review discusses the effect of capsaicin through its receptor on the development and modulation of autoimmune diseases, which may shed light upon potential therapies in capsaicin-targeted approaches.

Neuromodulation of synovitis: capsaicin effect on severity of experimental arthritis.

This study addresses the effect of capsaicin on the severity of inflammation in experimental arthritis in the cat. Animals were sensitized with methylated bovine serum albumin (mBSA) and sequential serum antibody levels measured by enzyme-linked immunosorbent assay (ELISA). Synovitis was induced by intra-articular injection of mBSA. Histopathology revealed marked inflammatory cell infiltration and synovial cell hypercellularity, in comparison with the saline-injected control joint which showed no synovitis. In animals given intra-articular capsaicin concurrently with mBSA, there was consistently a diminution in the severity of inflammation compared with contralateral joints receiving mBSA alone. In this experimental system capsaicin appears to moderate the severity of inflammation in feline antigen-induced arthritis.

Capsaicin-induced inhibition of mitogen and interleukin-2-stimulated T cell proliferation: its reversal by in vivo substance P administration.

The direct and indirect interaction between the nervous and the immune systems was evaluated in the rat using the neurotoxin capsaicin. Capsaicin treatment of neonatal rats (50 mg/kg at 2 days of age), results in a marked inhibition of mitogen and hrIL-2-induced cell proliferation both in the spleen and peripheral blood. Inhibition is already evident on day 15 after treatment and persists until day 90 in the spleen; at this time a return to control levels is observed in peripheral blood. The inhibition of proliferative response strongly correlates with a decreased number of CD5+ and CD4+ T cells as evaluated by immunofluorescence and FACS analysis. Moreover, continuous in vivo SP administration stimulates mitogen and hrIL-2-induced proliferative response and completely reverts the capsaicin-induced inhibition of lymphocyte proliferation in the spleen.

Plasma extravasation through neuronal stimulation in human nasal mucosa in the setting of allergic rhinitis.

We have previously shown that capsaicin nasal challenge in subjects with allergic rhinitis produces a dose-dependent increase in the albumin content of nasal lavage fluids. In the present set of studies, we determined whether this observation represents plasma extravasation that is neuronally mediated. To evaluate whether glandular secretions contribute to the albumin increase in nasal lavage fluids, volunteers with allergic rhinitis were pretreated with atropine or placebo before capsaicin challenge. Atropine significantly reduced the volume of returned lavage fluids and their lysozyme content but increased their albumin and fibrinogen content. To assess the contribution of sensory nerve stimulation, subjects with allergic rhinitis were pretreated in a second study with lidocaine or placebo before capsaicin challenge. Lidocaine significantly attenuated the capsaicin-induced increases in the volume of nasal lavage fluids, as well as their lysozyme and albumin content. To rule out the possibility of a direct effect of lidocaine on blood vessels rather than on nerves, healthy subjects were pretreated in a third study with lidocaine or placebo before bradykinin nasal challenge. Lidocaine did not affect the bradykinin-induced increase in the albumin content of nasal fluids. We conclude that, in allergic rhinitis, high-dose capsaicin induces plasma extravasation in the human nose and that this effect is neuronally mediated. This provides more definitive evidence that neurogenic inflammation can occur in vivo in the human upper airway.

Effects of capsaicin desensitization on nasal allergy-like symptoms and histamine release in the nose induced by toluene diisocyanate in guinea pigs.

Intranasal application of toluene diisocyanate (TDI) induced nasal allergy-like symptoms of sneezing and watery rhinorrhea and decreased the histamine content of the nasal mucosa in guinea pigs. However, in the animals pretreated with capsaicin (capsaicin desensitization) before sensitization with TDI, nasal allergy-like symptoms were not induced. Capsaicin desensitization also inhibited histamine release in the nasal mucosa induced by TDI. These findings suggest that antidromic impulses of capsaicin-sensitive sensory nerves stimulated by TDI cause histamine release from mast cells in the nasal mucosa, resulting in nasal discharge and sneezing in guinea pigs. Thus neurogenic inflammation via an axon reflex in the nose may contribute to the pathogenesis of vasomotor rhinitis.

[Capsaicin-induced mouse ear edema and its management]. / Kapszaicinnel elöidézett egérfül-ödéma és befolyásolása.

Oedema was induced in one ear of male mice of the CFLP strain with capsaicin solution (10 microliters/40 micrograms/ear). The development in time and the extent of the oedema were determined by the oedema-disk gravimetric technique. The maximum oedema was attained after 1 hour, and there was subsequently a gradual decrease. The extent of the mouse ear oedema induced in this way and measured after 60 minutes was inhibited to a statistically significant degree and in a dose-dependent manner by the antihistamine chloropyramine, the antihistamine-antiserotonin cyproheptadine, the non-steroidal antiinflammatory agent pyroxicam, the prostaglandin antagonist di-4-phloretin phosphate, and the lipoxygenase inhibitor nordihydroguaiaretic acid. The method proved suitable for the detection and biologically quantitative determination of the state of desensitization induced with capsaicin.

Role of transient receptor potential ion channels and evoked levels of neuropeptides in a formaldehyde-induced model of asthma in BALB/c mice.

OBJECTIVE: Asthma is a complex pulmonary inflammatory disease characterized by the hyper-responsiveness, remodeling and inflammation of airways. Formaldehyde is a common indoor air pollutant that can cause asthma in people experiencing long-term exposure. The irritant effect and adjuvant effect are the two possible pathways of formaldehyde promoted asthma. METHODOLOGY/PRINCIPAL FINDINGS: To explore the neural mechanisms and adjuvant effect of formaldehyde, 48 Balb/c mice in six experimental groups were exposed to (a) vehicle control; (b) ovalbumin; (c) formaldehyde (3.0 mg/m(3)); (d) ovalbumin+formaldehyde (3.0 mg/m(3)); (e) ovalbumin+formaldehyde (3.0 mg/m(3))+HC-030031 (transient receptor potential ankyrin 1 antagonist); (f) ovalbumin+formaldehyde (3.0 mg/m(3))+ capsazepine (transient receptor potential vanilloid 1 antagonist). Experiments were conducted after 4 weeks of combined exposure and 1-week challenge with aerosolized ovalbumin. Airway hyper-responsiveness, pulmonary tissue damage, eosinophil infiltration, and increased levels of interleukin-4, interleukin-6, interleukin-1ß, immunoglobulin E, substance P and calcitonin gene-related peptide in lung tissues were found in the ovalbumin+formaldehyde (3.0 mg/m(3)) group compared with the values seen in ovalbumin -only immunized mice. Except for interleukin-1ß levels, other changes in the levels of biomarker could be inhibited by HC-030031 and capsazepine. CONCLUSIONS/SIGNIFICANCE: Formaldehyde might be a key risk factor for the rise in asthma cases. Transient receptor potential ion channels and neuropeptides have important roles in formaldehyde promoted-asthma.

Effect of mucosal TRPV1 inhibition in allergic rhinitis.

Transient receptor potential vanilloid-1 (TRPV1) has been implicated as a mediator of itch in allergic rhinitis. To address this possibility, we synthesized a TRPV1 blocker (SB-705498) for nasal administration in patients with seasonal allergic rhinitis. The pharmacological activity of SB-705498 was confirmed on human TRPV1-expressing HEK293 cells, using fluorometric calcium imaging, and in patients with allergic rhinitis subjected to nasal capsaicin challenges. The effect of SB-705498 was studied in patients with seasonal allergic rhinitis subjected to daily allergen challenges for 7 days, using a double-blind, placebo-controlled, randomized and cross-over design. SB-705498 was delivered by nasal lavage 2 min. before each allergen challenge. Primary end-point was total nasal symptom score on days 5-7. Nasal peak inspiratory flow (nPIF) and eosinophil cationic protein (ECP) content in nasal lavages were also monitored. Daily topical applications of SB-705498 at a concentration that inhibited capsaicin-induced nasal symptoms had no effect on total symptom score, nPIF and ECP levels in allergen-challenged patients with seasonal allergic rhinitis. The individual symptoms, nasal itch or sneezes, were also not affected. These findings may indicate that TRPV1 is not a key mediator of the symptoms in allergic rhinitis. However, additional studies, using drug formulations with a prolonged duration of action, should be conducted before TRPV1 is ruled out as a drug target in allergic rhinitis.

Tumor macrophages as a target for Capsaicin mediated immunotherapy.

Tumor microenvironment contributes to a large extent for failure of immunological destruction of antigenic tumors. Most solid tumors adapt to the microenvironment and escape the host immune system. The dramatic and systemic effectiveness of neuro-immune ligand Capsaicin (CP) in regression of established solid tumors led us to investigate its immunomodulatory role in tumor microenvironment. In this report we demonstrate that CP induced tumor cell apoptosis leads to increased sensitization of the surrounding stroma manifested by enhanced antigen presentation by stromal macrophages and its destruction by tumor specific T-cells. Further, CP injection alters the tumor microenvironment with regards to tumor-infiltrating Treg cells as well as the cytokine milieu at the tumor site. Our data collectively demonstrates that injection of CP sets in motion, a cascade of several independent innate and adaptive immunological events initiated at the tumor environment.

The distribution of sensory fibers immunoreactive for the TRPV1 (capsaicin) receptor in the human prostate.

OBJECTIVES: To determine the distribution of sensory fibers immunoreactive to the pain receptor TRPV1 in the human prostate. METHODS: Eight prostates were harvested from cadaver transplant donors and immediately immersion fixed. Longitudinal and transverse 20 microm sections were cut on a cryostat and immunoreacted with two anti-human TPRV1 antibodies. RESULTS: TRPV1-immunoreactive nerve fibers were distributed throughout the prostatic urethral mucosa, verumontanum, ejaculatory ducts and periurethral prostatic acini. In the urethral mucosa, TRPV1-immunoreactive fibers penetrated the epithelial layer up to its surface. In the transitional and peripheral zones of the gland no TRPV1-immunoreactive nerve fibers were detected. CONCLUSIONS: The existence of a rich TRPV1 sensory innervation in the human prostate may open new therapeutic perspectives for the treatment of pain in patients with chronic prostatitis (Chronic Pelvic Pain Syndrome).

Characterization of increased cough sensitivity after antigen challenge in guinea pigs.

Increased sensitivity of cough reflex is a fundamental feature of bronchodilator resistant non-productive cough associated with eosinophilic tracheobronchitis. Our hypothesis is that cough sensitivity is increased by airway allergic reaction characterized by airway eosinophilic inflammation. The aim of this study was to elucidate the hypothesis and clarify the characteristics of the increased cough sensitivity. Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an aerosolized antigen or saline in actively sensitized or non-sensitized (naive) conscious guinea pigs and then bronchoalveolar lavage was performed. The cough response was also measured 1 day before and 1, 2, 3, 5 and 7 days after an aerosolized antigen challenge in sensitized or naive animals. In addition, effect of procaterol (0.1 mg/kg), atropine (1 or 10 mg/kg), phosphoramidon (2.5 mg/kg) given intraperitoneally 30 min before the capsaicin challenge or capsaicin desensitization on the cough response was examined. Furthermore, the thromboxane A2 (TXA2) receptor antagonist S-1452 in a dose of 0.01 or 0.1 mg/kg or vehicle (saline) was given intraperitoneally at 24 and 1 h before the measurement of cough response. Number of coughs caused by capsaicin was extremely increased 24 h after an antigen challenge in sensitized guinea pigs compared with a saline or an antigen challenge in naive animals or a saline challenge in sensitized animals. The increased cough response disappeared at 3-7 days after the antigen challenge. Eosinophils in bronchoalveolar lavage fluid obtained after the measurement of capsaicin-induced coughs, which was performed 24 h after the antigen challenge, were significantly increased in sensitized guinea pigs. The eosinophil count was significantly correlated to the number of capsaicin-induced coughs. Procaterol or atropine did not alter the antigen-induced increase of cough sensitivity, whereas atropine did reduce the cough response in naive animals. Phosphoramidon increased the number of capsaicin-induced coughs in naive guinea pigs but not in sensitized and antigen-challenged animals. Capsaicin desensitization decreased the cough response in both antigen-challenged sensitized guinea pigs and naive animals. S-1452 reduced the antigen-induced increase of cough response in sensitized guinea pigs, but not in naive animals. Airway allergy accompanied with airway eosinophilia induces transient increase in cough sensitivity, which is not mediated by bronchoconstriction. The increased cough sensitivity may result in part from inactivation of neutral endopeptidase and TXA2, one of the inflammatory mediators.

Role of capsaicin-sensitive sensory nerve reflexes in guinea pig model of nasal allergy.

The aim of this study was to examine the pathophysiological role of capsaicin-sensitive sensory nerves in an animal model of nasal allergy. In ovalbumin (OA)-sensitized guinea pigs, a significant increase in nasal total airway resistance (TAR) was noted for at least 180 min after topical antigen challenge. The TAR response to antigen challenge was significantly inhibited for 120 min by general capsaicin pretreatment (167 +/- 12.1 vs. 113 +/- 5.0%, p < 0.001, and 186 +/- 14.9 vs. 119 +/- 6.6%, p < 0.001, control vs. capsaicin pretreatment group at 20 and 90 min after challenge, respectively). However, TAR was significantly though slightly affected even after general capsaicin pretreatment. Following nasal capsaicin challenge, TAR increased for 90 min, and nasal secretion for 30 min. Both the TAR and secretory responses to nasal capsaicin challenge were significantly greater in OA-sensitized guinea pigs than in nonsensitized animals (171 +/- 12.1 vs. 137 +/- 7.4% at 30 min, p < 0.05, and 82.3 +/- 8.6 vs. 13.4 +/- 1.7 mg/10 min, p < 0.05, TAR and secretory response to 300 microM nasal capsaicin challenge, respectively). These results suggest that capsaicin-sensitive sensory nerve reflexes play an important role in the occurrence of early-phase nasal symptoms following topical antigen exposure and are accelerated in OA-sensitized guinea pigs.

Nerve growth factor-induced substance P in capsaicin-insensitive vagal neurons innervating the lower mouse airway.

BACKGROUND: Nerve growth factor (NGF) is elevated in allergic diseases such as bronchial asthma and can lead to an induction of substance P (SP) and related neuropeptides in guinea-pigs large-diameter, neurofilament-positive airway neurons. OBJECTIVE: In the present study, the effect of NGF on tyrosine kinase receptor trkA and the capsaicin receptor TRPV1 expression in airway-specific vagal sensory neurons located in the jugular-nodose ganglia complex (JNC) of mice was investigated. METHODS: Using retrograde neuronal tracing in combination with double-labelling immunohistochemistry, SP, trkA- and TRPV1-receptor expression was examined in airway-specific sensory neurons of BALB/c mice before and after NGF treatment. RESULTS: NGF injected into the lower airway was able to induce SP (13.0+/-2.03% vs. 5.9+/-0.33%) and trkA expression (78+/-2.66% vs. 60+/-2.11%) in larger diameter (>25 microm), capsaicin-insensitive and trkA-positive vagal sensory neurons that were retrograde-labelled with Fast Blue dye from the main stem bronchi. CONCLUSION: Based on the extent of SP and trkA co-expression in airway-specific neurons by NGF treatment, the present study suggests that, following a peripheral activation of trkA receptor on SP afferent by NGF which is elevated in allergic inflammation, there may be trkA-mediated SP induction to mediate neurogenic airway inflammation.

Endogenous tachykinins play a role in IL-1-induced neutrophil accumulation: involvement of NK-1 receptors.

Pretreatment of mice with capsaicin resulted in approximately 40% inhibition of the polymorphonuclear leucocyte (PMN) influx elicited by interleukin-1 (IL-1) injected into a murine air-pouch. This inhibition was mimicked by two selective antagonists of neurokinin-1 (NK-1) tachykinin (TK) receptors, i.e. CP-96,345 and RP-67,580, but not by the inactive enantiomer RP-68,651. A selective NK-2 antagonist, SR-48,968, was inactive. The natural peptide, substance P (SP), and a selective NK-1 agonist, (Sar9)SP, induced PMN infiltration into the murine air-pouch, whereas a selective NK-2 agonist, (beta Ala8)NK-A(4-10), was ineffective. Moreover, SP-induced PMN accumulation was prevented by co-administration of RP-67,580 and CP-96,345, but not by RP-68,651. These findings suggest that the release of an endogenous TK, possibly SP, may occur following IL-1 injection in vivo, indicating a contributory role for neuropeptides in the PMN migration elicited by this cytokine. The action of selective agonists and antagonists suggests the involvement of NK-1 receptors.

Effects of acute stress, relaxation, and a neurogenic inflammatory stimulus on interleukin-6 in humans.

Effects of three experimental manipulations: mental stress, relaxation, and a nociceptive inflammatory stimulus, capsaicin, on levels of interleukin-6 (IL-6) were examined. Fifty subjects were pre-trained in relaxation and then randomized to a stress (Stroop test), relaxation (tape), or control (video) manipulation. Subjects participated in an evening reactivity session including 20 min of stress, relaxation, or control followed by a capsaicin injection in the forearm. Cardiovascular variables and levels of IL-6 were measured before and after the manipulation, and at regular intervals up to 60 min post-capsaicin. Group assignment did not differentially affect change in IL-6 over time, either before or after capsaicin. Small but significant increases in IL-6 were seen at 60 min post-capsaicin. These findings suggest that an acute stress manipulation does not modulate IL-6 within this time frame. Although IL-6 did increase following a neurogenic inflammatory stimulus, it did so subsequent to the maximum flare, suggesting that flare mechanisms are independent of IL-6.