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)

Stimulation of sensory nerves in the airway mucosa of the rat evokes the release of inflammatory peptides such as substance P, which can increase microvascular permeability, resulting in a phenomenon known as neurogenic plasma extravasation. The change in vascular permeability is mediated by NK-1 receptors and is caused by the formation of gaps between endothelial cells of postcapillary venules and small collecting venules, which are the same vessels as are affected by inflammatory mediators such as histamine and bradykinin. Respiratory tract infections caused by Sendai virus or Mycoplasma pulmonis can intensify neurogenic plasma extravasation in the airway mucosa, as indicated by the amount of microvascular leakage evoked by substance P or capsaicin. M. pulmonis infections can produce a 30-fold increase in the magnitude of neurogenic plasma extravasation, which is evident 4 wk after infection and may be permanent. A proliferation of venules in the airway mucosa and heightened sensitivity of these vessels to inflammatory mediators are key elements of the increase in plasma extravasation. Exposure of M. pulmonis-infected rats to ammonia exacerbates the infections and further augments the responsiveness of mucosal venules to inflammatory mediators. Despite this increased responsiveness, the vessels are not abnormally leaky in the absence of inflammatory stimuli. These findings emphasize the importance of airway infections as factors that can cause a potent, long-lasting increase in the sensitivity of the microvasculature of the airway mucosa to inflammatory mediators.
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PMID:Infections intensify neurogenic plasma extravasation in the airway mucosa. 144 6

Capsaicin increases the permeability of blood vessels in the rat tracheal mucosa through a mechanism involving the release of tachykinins from sensory nerves. This capsaicin-induced increase in vascular permeability is potentiated by viral infections of the respiratory tract. The present study was done to determine whether this "neurogenic plasma extravasation" can be inhibited by glucocorticoids, to learn the time course of this inhibition, and to determine whether glucocorticoids can prevent the potentiating effect of viral respiratory infections on neurogenic plasma extravasation. Groups of pathogen-free F344 rats were treated with dexamethasone for 2 or 8 h (4 mg/kg i.p.) or 48 or 120 h (0.5-4 mg/kg per d i.p.). Another group of rats was treated with dexamethasone for 120 h following the intranasal inoculation of Sendai virus. The magnitude of plasma extravasation produced by capsaicin or substance P was assessed after this treatment by using Monastral blue pigment and Evans blue dye as intravascular tracers. We found that dexamethasone reduced, in a dose-dependent fashion, the magnitude of plasma extravasation produced in the rat trachea by capsaicin and substance P. Significant inhibition was produced by a dose of dexamethasone as small as 0.5 mg/kg i.p. The effect of dexamethasone had a latency of several hours and reached a maximum after 2 d of treatment. Furthermore, dexamethasone prevented the potentiation of neurogenic plasma extravasation usually present after 5 d of Sendai virus respiratory infection.
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PMID:Glucocorticoids inhibit neurogenic plasma extravasation and prevent virus-potentiated extravasation in the rat trachea. 170 Jul 94

We examined the effects of viral respiratory infection by Sendai virus on airway responsiveness to tachykinins in guinea pigs. We measured the change in total pulmonary resistance induced by substance P or capsaicin in the presence or absence of the neutral endopeptidase inhibitor, phosphoramidon, in infected and in noninfected animals. In the absence of phosphoramidon, the bronchoconstrictor responses to substance P and to capsaicin were greater in infected than in noninfected animals. Phosphoramidon did not further potentiate the responses to substance P and to capsaicin in the infected animals, whereas it did so in noninfected animals. Studies performed in vitro showed that nonadrenergic noncholinergic bronchial smooth muscle responses to electrical field stimulation were also increased in tissues from infected animals and that phosphoramidon increased the response of tissues from noninfected animals greatly but increased the responses of tissues from infected animals only slightly. Responses to acetylcholine were unaffected by viral infection. Neutral endopeptidase activity was decreased by 40% in the tracheal epithelial layer of the infected animals. We suggest that respiratory infection by Sendai virus causes enhanced airway responsiveness to tachykinins by decreasing neutral endopeptidase-like activity in the airway epithelium.
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PMID:Virus induces airway hyperresponsiveness to tachykinins: role of neutral endopeptidase. 247 56

Upper respiratory tract virus infections may enhance airway responsiveness to histamine in normal subjects. We have studied the effects of parainfluenza Type I (Sendai) virus infection of the upper respiratory tract on the airway responsiveness to acetylcholine (ACh) and substance P administered by either the inhaled or intravenous route in the anesthetized guinea pig. Airway responses to electrical stimulation of the vagus nerves in the presence of atropine (1 mg.kg-1 i.v.) were also studied. After four to five days following virus infection, mean pulmonary insufflation pressure increased significantly in response to inhaled ACh compared to that in control animals. Responses to intravenous ACh were not enhanced. By contrast, responses to both intravenous and inhaled substance P were increased. In addition, mean pulmonary insufflation pressure after electrical stimulation of the vagus nerves for 30 seconds at 5 V, 5 msec (frequencies of 3, 10, and 30 Hz) were all enhanced after virus infection. We conclude that the increased airway responsiveness observed to the exogenous administration of the neurotransmitters ACh and substance P after viral respiratory infection may be due to different mechanisms possibly associated with an interference with the epithelium.
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PMID:Airway hyperresponsiveness to acetylcholine and to tachykinins after respiratory virus infection in the guinea pig. 768 Aug 45

Immunohistochemistry was combined with retrograde labeling to characterize the effect of respiratory infection with Sendai virus on the number of Substance P/Neurokinin A-containing vagal afferent neurons whose cell bodies resided in the nodose ganglia and whose receptive fields were located in guinea pig trachea. Of the neurons labeled from the trachea of vehicle-inoculated guinea pigs, few stained positively for Substance P/Neurokinin A (approximately 3% of total labeled neurons). These neurons had small diameter cell bodies (mode = 16-20 microm), a feature of nociceptive-like C-fibers. Viral infection (Day 4 after inoculation) was associated with a significantly greater number of labeled neurons containing Substance P/Neurokinin A (approximately 20% of total labeled neurons). The majority of these had a relatively large cell body diameter (mode = 36- 40 microm), a feature of nonnociceptive afferent neurons. This induction appeared to be reversible as there were significantly fewer Substance P/Neurokinin A positive neurons in nodose ganglia from virus-inoculated guinea pigs at Day 28 after inoculation, a time point when virus-induced airway inflammation had all but resolved. These findings support the hypothesis that viral infection leads to a qualitative change in the vagal afferent innervation of guinea pig airways such that both small diameter nociceptive-like neurons and large diameter nonnociceptive neurons express tachykinins.
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PMID:Expression of tachykinins in nonnociceptive vagal afferent neurons during respiratory viral infection in guinea pigs. 1195 47

We studied the role of the peptide substance P, signaling through the neurokinin-1 (NK-1) receptor, on methamphetamine-induced loss of dopamine transporter sites, a well-documented marker of toxicity in the striatum of the mouse brain, because this peptide is under dynamic regulation by the neurotransmitter dopamine. Methamphetamine is a psychostimulant that induces dopamine overflow from dopamine terminals of the striatum. Mice were given four injections of methamphetamine (7.5 mg/kg of body weight) at two-hour intervals and were sacrificed three days after the treatment. Dopamine transporter levels in the striatum were assessed by receptor autoradiography with [(125)I]RTI-121. Exposure to methamphetamine resulted in significant loss of dopamine transporters in the caudate-putamen. This loss was prevented by preexposure (30 min before the first injection of methamphetamine) of the neurokinin-1 receptor antagonist L-733,060. The inactive enantiomer of L-733,060 (L-733,061) failed to protect dopamine transporter sites from methamphetamine, suggesting specificity for the neurokinin-1 receptor. Moreover, the protective effect of L-733,060 was observed in mice that were 10 weeks of age or older (dopamine transporter sites in mice six and eight weeks old were not protected from methamphetamine by the neurokinin-1 receptor antagonist). The results demonstrate that the deleterious effect of methamphetamine on dopamine transporter sites of the striatum is mediated via the neurokinin-1 receptor. The involvement of the NK-1 receptor appears after the eighth week of postnatal life, suggesting that the link between dopamine transporters and the neurokinin-1 receptor becomes functional at approximately the time when the mouse reaches reproductive age.
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PMID:Ontogeny of neurokinin-1 receptor mediation of methamphetamine neurotoxicity in the striatum of the mouse brain. 1210

The diffuse neuroendocrine system consists of specialised endocrine cells and peptidergic nerves and is present in all organs of the body. Substance P (SP) is secreted by nerves and inflammatory cells such as macrophages, eosinophils, lymphocytes, and dendritic cells and acts by binding to the neurokinin-1 receptor (NK-1R). SP has proinflammatory effects in immune and epithelial cells and participates in inflammatory diseases of the respiratory, gastrointestinal, and musculoskeletal systems. Many substances induce neuropeptide release from sensory nerves in the lung, including allergen, histamine, prostaglandins, and leukotrienes. Patients with asthma are hyperresponsive to SP and NK-1R expression is increased in their bronchi. Neurogenic inflammation also participates in virus-associated respiratory infection, non-productive cough, allergic rhinitis, and sarcoidosis. SP regulates smooth muscle contractility, epithelial ion transport, vascular permeability, and immune function in the gastrointestinal tract. Elevated levels of SP and upregulated NK-1R expression have been reported in the rectum and colon of patients with inflammatory bowel disease (IBD), and correlate with disease activity. Increased levels of SP are found in the synovial fluid and serum of patients with rheumatoid arthritis (RA) and NK-1R mRNA is upregulated in RA synoviocytes. Glucocorticoids may attenuate neurogenic inflammation by decreasing NK-1R expression in epithelial and inflammatory cells and increasing production of neutral endopeptidase (NEP), an enzyme that degrades SP. Preventing the proinflammatory effects of SP using tachykinin receptor antagonists may have therapeutic potential in inflammatory diseases such as asthma, sarcoidosis, chronic bronchitis, IBD, and RA. In this paper, we review the role that SP plays in inflammatory disease.
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PMID:The role of substance P in inflammatory disease. 1533 52

Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have breathing abnormalities, such as apnea and breathing irregularity, and respiratory infection is the most common cause of death in these individuals. Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. We also found that Mecp2-null mice, which also have breathing problems, often exhibit inflammatory lung injury. These injuries occurred in specific sites in the lung lobes. In addition, polarizable foreign materials were identified in the injured lungs of Mecp2-null mice. These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. Among them, neuropeptide substance P (SP) immunostaining was reduced in Mecp2-null brainstem. These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.
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PMID:Pathogenesis of Lethal Aspiration Pneumonia in Mecp2-null Mouse Model for Rett Syndrome. 2893 90