Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toluene diisocyanate (TDI) produces rhinitis, nasal irritation, and increased synthesis and release of substance P (SP) from airway sensory nerves. Nerve growth factor (NGF) secretion in the nasal cavity is believed to mediate the irritant-induced upregulation of SP, but the cellular source of NGF in the nasal mucosa remains unclear. Studies to localize a source of NGF within the nasal mucosa are complicated by inflammatory-cell influx into the nasal mucosa following TDI, which obscures immunocytochemical identification of endogenous NGF sources. The purpose of this study was to determine the cellular source of NGF within the nasal mucosa following irritant exposure using a combined in vivo and ex vivo approach to reduce or eliminate contribution from inflammatory cells. Both nasal cavities of adult, male Sprague-Dawley rats were instilled with 5 microl of 10% TDI or control vehicle. After 15 min, nasal lavages were performed and the nasal mucosa was removed and placed into culture for 3 or 24 h. NGF was measured in the lavage supernatant and the culture media. Fifteen minutes after TDI exposure, NGF was significantly increased in the nasal lavage fluid. NGF levels in the culture medium of nasal mucosa from rats exposed to TDI ex vivo were significantly increased compared to controls following a 3-h culture. NGF levels in media after 24 h in culture was higher than at the 3-h point, but there was no difference between control and TDI groups. Since the nasal mucosa was removed prior to inflammatory cell influx, these findings suggest that cells in the nasal mucosa release NGF following exposure to TDI.
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PMID:The release of nerve growth factor from the nasal mucosa following toluene diisocyanate. 1602 Jan 93

The upper airway occupies a sentinel position with respect to the physical and chemical qualities of the inspired atmosphere. Responses of the upper airway can be acute or chronic, as well as primary (sensory) or secondary (physiologic). Olfaction and sensory irritation are cofactors in the perception of air quality. Secondary reflex responses to airborne irritants may include blockage (airflow obstruction), secretion (with or without associated inflammation), and alterations in mucociliary clearance. Of the above end points, obstruction has been documented in response to a variety of agents, including acetic acid vapor, ammonia, Cl2, ETS, mixed VOCs, vapors from carbonless copy paper, and (variably) SO2. Alterations in mucociliary clearance have been variably observed with SO2 and ETS exposure. A neutrophilic inflammatory response has been documented after acute exposure to either ozone or VOCs, and metaplastic mucosal changes after prolonged exposures to photochemical mixed air pollutants. Augmented reactivity to irritants is a phenotypic characteristic of both nonallergic and allergic rhinitis; however, understanding of underlying mechanisms remains elusive (75-78). Differential physiologic responsiveness to environmental irritant stimuli has been documented by allergic rhinitis status for acetic acid and Cl2 (objectively) and for mixed VOCs (subjectively only). Differential responsiveness by nonallergic rhinitis status has, to our knowledge, been documented for paper dust only, although a somewhat wider array of pollutants (including ETS and carbonless copy paper) has been studied in groups differing by self-reported pollutant reactivity. Interestingly, although the congestive response to allergens and irritants is similar, the underlying mechanisms appear to differ, with neither mast cell degranulation nor cholinergic parasympathetic reflexes appearing critical to the response (Fig. 3). Although neuropeptide release does not accompany Cl2-induced nasal obstruction, in one model system (hypertonic saline challenge), substance P release accompanied augmented secretions (80,81). In yet another hypertonic model (dry mannitol powder challenge), arachidonic acid metabolites characteristic of epithelial cell activation accompanied nasal obstruction (82). The relevance of these model systems to environmentally realistic (airborne) irritants remains unclear at this time. Overall, nonallergic rhinitis has received considerably less attention than has allergic rhinitis in the context of descriptive, pathophysiologic, and intervention studies. This statement applies equally in the context of environmental nonallergic rhinitis. As is hopefully evident from the above discussion, many potential research questions in this area remain to be addressed.
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PMID:Environmental nonallergic rhinitis. 1715 18

Botulinum toxin (BTX) types A and B have been used with success in cosmetic dermatology and hyperhidrosis treatment. The present review focuses on other uses of BTX in dermatology. Discussed in particular are the available data on BTX in inflammatory diseases, proctology, and some other indications. From studies in various types of eczema, it seems that BTX-A not only acts as a potent inhibitor of acetylcholine but also as an inhibitor of substance P and of glutamate as well. By those mechanisms, BTX-A may be antipruritic, which may help explain the benefits of BTX-A in lichen simplex and dyshidrotic hand eczema. In Hailey-Hailey disease, facial eccrine hidrocystomas, salivary fistulas, and intrinsic rhinitis, BTX-A blocks the secretion of sweat/saliva/mucus. BTX-A has important applications in proctology where it has become the most powerful nonsurgical therapy for anal fissures. In proctalgia fugax and after hemorrhoidectomy, BTX-A is analgesic. Current treatment applications of BTX-A and its limitations are reviewed in this paper.
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PMID:Botulinum toxin in dermatology - beyond wrinkles and sweat. 1717 93

Neurokinins are known to induce neurogenic inflammation related to respiratory diseases. The effects of CS-003 ([1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)-oxide hydrochloride]), a novel triple neurokinin receptor antagonist, on several respiratory disease models were evaluated in guinea pigs. As we have already shown that CS-003 is intravenously effective, we first determined if CS-003 was orally effective. CS-003 dose-dependently inhibited substance P-induced tracheal vascular hyperpermeability, neurokinin A- and neurokinin B-induced bronchoconstriction with ID(50) values of 3.6, 1.3 and 0.89 mg/kg (p.o.), respectively. CS-003 (10 mg/kg, p.o.) inhibited the number of coughs induced by capsaicin aerosol (P<0.01) and the antitussive effect was comparable to that of codeine. CS-003 (10 mg/kg, p.o.) also inhibited airway hyperresponsiveness to methacholine chloride in ovalbumin-induced asthma models (P<0.01), a milder one and a severer one. On the other hand, montelukast (10 mg/kg, p.o.), a leukotriene receptor antagonist, significantly inhibited the hyperresponsiveness only in the milder model (P<0.05). In an ovalbumin-induced rhinitis model, oral administration of CS-003 inhibited nasal blockade in a dose-dependent manner and the inhibitory effect was comparable to that of dexamethasone (10 mg/kg, p.o.). CS-003 (i.v.) also dose-dependently inhibited cigarette smoke-induced bronchoconstriction, tracheal vascular hyperpermeability and mucus secretion. These data show that CS-003, a potent orally active triple neurokinin receptor antagonist, may be useful for the treatment of respiratory diseases associated with neurokinins, such as allergic asthma, allergic rhinitis, chronic obstructive pulmonary disease and cough.
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PMID:Novel triple neurokinin receptor antagonist CS-003 inhibits respiratory disease models in guinea pigs. 1870 8

Nasal hyperreactivity is one of the most important underlying mechanisms in both allergic (AR) and idiopathic rhinitis (IR). In order to study the pathomorphological changes in this entity, tissue samples from patients with AR, IR, and from patients without chronic inflammation were taken during nasal surgery. Primary antibodies against Substance P (SP), calcitonin gene-related peptide (CGRP), and endothelial nitric oxide synthases (NOS III) were applied and the immunocomplexes were visualized by immunocytochemistry. The nasal mucosa of patients with AR and IR showed similarities on the ultrastructural level. Neurogenic inflammation was indicated by a strong innervation pattern with sensory nerve fibers containing SP and CGRP. We could show that extensive edema and cellular infiltration might be characteristic for AR. On other hand there was no evidence of eosinophilic or NO involvement in IR. Finally, on the ultrastructural level, AR and IR showed many similarities. Based on these findings anti-inflammatory therapy modalities could be recommended for both types of rhinitis.
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PMID:Allergic and idiopathic rhinitis: an ultrastructural study. 1912 68

Although antihistamines have been in common use for treatment of allergic diseases including rhinitis for >60 years and topical therapy of the respiratory tract has been common for centuries, it is only in the past few years that topical intranasal antihistamine therapy has been widely used for treatment of allergic rhinitis. Much research has been done over the past several years showing broad anti-inflammatory effects of these medications, involving many different pathways. Effects have been shown on mediators including histamine, leukotrienes, platelet-activating factor, and substance P, as well as on cytokines, adhesion molecules, and chemokines involved in chemotaxis. It is significant that these effects have been seen at clinically relevant concentrations of the topical drugs, as opposed to the situation with oral antihistamines where anti-inflammatory effects are generally found only at concentrations much higher than that achieved with routine dosing. Clinically, it appears that this delivery of high local concentrations allows for other pharmacologic activity to be expressed. These anti-inflammatory actions may be part of the reason why these drugs also are effective in relieving many symptoms of nonallergic rhinitis, where histamine has much less of a role and where oral antihistamines have traditionally been of minimal help.
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PMID:Intranasal antihistamines for allergic rhinitis: mechanism of action. 1977 56

Rhinitis is a symptomatic inflammatory disorder of the nose with different causes such as allergic, nonallergic, infectious, hormonal, drug induced, and occupational and from conditions such as sarcoidosis and necrotizing antineutrophil cytoplasmic antibodies positive (Wegener's) granulomatosis. Allergic rhinitis affects up to 40% of the population and results in nasal (ocular, soft palate, and inner ear) itching, congestion, sneezing, and clear rhinorrhea. Allergic rhinitis causes extranasal untoward effects including decreased quality of life, decreased sleep quality, obstructive sleep apnea, absenteeism from work and school, and impaired performance at work and school termed "presenteeism." The nasal mucosa is extremely vascular and changes in blood supply can lead to obstruction. Parasympathetic stimulation promotes an increase in nasal cavity resistance and nasal gland secretion. Sympathetic stimulation leads to vasoconstriction and consequent decrease in nasal cavity resistance. The nasal mucosa also contains noradrenergic noncholinergic system, but the contribution to clinical symptoms of neuropeptides such as substance P remains unclear. Management of allergic rhinitis combines allergen avoidance measures with pharmacotherapy, allergen immunotherapy, and education. Medications used for the treatment of allergic rhinitis can be administered intranasally or orally and include oral and intranasal H(1)-receptor antagonists (antihistamines), intranasal and systemic corticosteroids, intranasal anticholinergic agents, and leukotriene receptor antagonists. For intermittent mild allergic rhinitis, an oral or intranasal antihistamine is recommended. In individuals with persistent moderate/severe allergic rhinitis, an intranasal corticosteroid is preferred. When used in combination, an intranasal H(1)-receptor antagonist and a nasal steroid provide greater symptomatic relief than monotherapy. Allergen immunotherapy is the only disease-modifying intervention available.
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PMID:Chapter 5: Allergic rhinitis. 2279 78

Sensory nerve endings within the airway epithelial cells and the solitary chemoreceptor cells, synapsing with sensory nerves, respond to airborne irritants. Transient receptor potential (TRP) channels (A1 and V1 subtypes, specifically) on these nerve endings initiate local antidromic reflexes resulting in the release of neuropeptides such as substance P and calcitonin G-related peptides. These neuropeptides dilate epithelial submucosal blood vessels and may therefore increase transudation across these vessels resulting in submucosal edema, congestion, and rhinitis. Altered expression or activity of these TRP channels can therefore influence responsiveness to irritants. Besides these pathogenic mechanisms, additional mechanisms such as dysautonomia resulting in diminished sympathetic activity and comparative parasympathetic overactivity have also been suggested as a probable mechanism. Therapeutic effectiveness for this condition has been demonstrated through desensitization of TRPV1 channels with typical agonists such as capsaicin. Other agents effective in treating nonallergic rhinitis (NAR) such as azelastine have been demonstrated to exhibit TRPV1 channel activity through the modulation of Ca(2+) signaling on sensory neurons and in nasal epithelial cells. Roles of antimuscarinic agents such as tiotropium in NAR have been suggested by associations of muscarinic cholinergic receptors with TRPV1. The associations between these channels have also been suggested as mechanisms of airway hyperreactivity in asthma. The concept of the united airway disease hypothesis suggests a significant association between rhinitis and asthma. This concept is supported by the development of late-onset asthma in about 10-40 % of NAR patients who also exhibit a greater severity in their asthma. The factors and mechanisms associating NAR with nonallergic asthma are currently unknown. Nonetheless, free immunoglobulin light chains and microRNA alteration as mediators of these inflammatory conditions may play key roles in this association.
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PMID:Neural Abnormalities in Nonallergic Rhinitis. 2613 Apr 69


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