Elevated Substance P Content in Induced Sputum from Patients with Asthma and Patients with Chronic Bronchitis

Tomaki, Masafumi; Ichinose, Masakazu; Miura, M.; Hirayama, Yoshitaka; Yamauchi, H.; Nakajima, Noriko; Shirato, Kunio

doi:10.1164/ajrccm/151.3_pt_1.613

Cited by 162 publications

(55 citation statements)

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“…SP has been shown to be an important contributor to airway inflammation and disease. Recent data from animal studies show that RSV upregulates the SP receptor (20,33), and elevated levels of SP have been detected in patients with asthma and obstructive airway disease (38). Previously, we observed elevated pulmonary SP levels associated with RSV infection in BALB/c mice and showed that treatment with anti-SP antibodies was effective in reducing the number of inflammatory cells and proinflammatory cytokine expression (40).…”

Section: Discussionmentioning

confidence: 87%

Neutralizing Anti-F Glycoprotein and Anti-Substance P Antibody Treatment Effectively Reduces Infection and Inflammation Associated with Respiratory Syncytial Virus Infection

Haynes

Tonkin

Anderson

et al. 2002

J Virol

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Respiratory syncytial virus (RSV) is the most important virus mediating lower respiratory tract illness in infants and young children. RSV infection is associated with pulmonary inflammation and increased levels of substance P (SP), making the airways and leukocytes that express SP receptors susceptible to the proinflammatory effects of this peptide. This study examines combining neutralizing anti-F glycoprotein and anti-SP antibody treatment of RSV-infected BALB/c mice to inhibit RSV replication and inflammation associated with infection. BALB/c mice were prophylactically treated with antibody prior to RSV infection or were therapeutically treated at day 2 or 6 post-RSV infection. Prophylactic or therapeutic treatment with anti-SP antibodies promptly reduced pulmonary inflammatory cell infiltration and decreased the number of cells expressing proinflammatory cytokines, while anti-F antibody treatment reduced virus titers. The results suggest that combined anti-viral and anti-SP antibody treatment may be effective in treating RSV disease.Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children worldwide. A member of the Paramyxoviridae family, RSV is an enveloped virus containing a negative-sense single-stranded RNA genome. The protective immune response to RSV infection is primarily directed against the two major surface viral glycoproteins, i.e., the G (attachment) and F (fusion) glycoproteins. The F glycoprotein appears to be most important for induction of protective immunity and is associated with a high serum neutralizing antibody response (6, 37) and activation of CD14 and Toll-like receptor-4 (21). Some monoclonal antibodies against the F glycoprotein provide passive protection against RSV disease (8,13,18,42); therefore, the F glycoprotein has been the focus for therapeutic intervention in RSV disease.At present, there is no RSV vaccine available, and the only options to address disease are prophylactic administration of enriched anti-RSV human immune globulin (Respigam) or anti-F glycoprotein monoclonal antibodies (palivizumab [Synagis]), both of which are recommended only for young children at high risk for RSV disease. In addition, ribavirin (Virazole), the only specific antiviral agent approved for RSV infection, has limited efficacy (10, 19, 41; M. I. Marks and J. McBride, abstract from Ribavirin Therapy for Respiratory Syncytial Virus Infections: a Scientific Workshop, Sept., 1989, Pediatr. Infect. Dis. J. 9:S84, 1990), and its use is limited for treatment of RSV infection in immune-compromised patients (10, 43).Treatment with anti-RSV human immune globulin or anti-F glycoprotein neutralizing antibodies is effective in decreasing the titer of virus but does not appear to ameliorate the disease process, suggesting that a substantial portion of disease is associated with the host response to infection (27). The importance of the host response to infection is also suggested by the prominence of obstructed-airway disease and wheezing durin...

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Section: Discussionmentioning

confidence: 87%

Neutralizing Anti-F Glycoprotein and Anti-Substance P Antibody Treatment Effectively Reduces Infection and Inflammation Associated with Respiratory Syncytial Virus Infection

Haynes

Tonkin

Anderson

et al. 2002

J Virol

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“…In fact, the amount of substance P in sputum has been found elevated after hypertonic saline inhalation [23]. Interestingly, montelukast can almost block the bronchoconstrictor effect of sulphur dioxide in asthma [24]; this acute response is believed to be largely mediated through neural pathways and possibly includes mast cells [25].…”

Section: Discussionmentioning

confidence: 99%

Montelukast attenuates the airway response to hypertonic saline in moderate-to-severe COPD

Zühlke

Kanniess²,

Richter³

et al. 2003

Eur Respir J

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This study assessed the effect of the leukotriene receptor antagonist montelukast on hypertonic saline-induced airway obstruction.A total of 29 patients with chronic obstructive pulmonary disease (forced expiratory volume in one second (FEV1), 42 ¡ 4% predicted) received either 10 mg montelukast and 3 h later placebo via metered-dose inhaler (MDI) (M), or placebo and 3h later 200 mg salbutamol (S), or two doses of placebo (P), in a randomised order. Patients inhaled salbutamol 1 h after MDI and the challenge was performed 15 min later (3% saline, 5 min). Data are given as per cent changes versus baseline.Compared to P, S caused significant bronchodilation in FEV1 (7.3%) and forced inspiratory volume in one second (FIV1) (4.5%), and M in FIV1 (1.5%). The salineinduced fall in FEV1 was lower after M (-5.8%), compared with S (-10.3%) and P (-13.1%). FEV1 (11.3%) and FIV1 (7.6%) was improved over baseline after recovery by M but not P and S. Recovery times regarding FEV1 (8.5 min) and FIV1 (15.2 min) were shortest after M, respective values for S being 16.8 and 20.4 min, and for P 15.9 and 21.2 min. Effects were strongest in patients with low baseline FEV1 and/or inhaled corticosteroids.Data from this study indicate beneficial effects of montelukast on hypertonic salineinduced airway responses in patients with chronic obstructive pulmonary disease, particularly those with severe disease. The major effect was an accelerated recovery leading to values above baseline. Eur Respir J 2003; 22: 926-930.

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“…A reduced SP-like immunoreactivity (SP-LI) content of asthmatic airways compared with nonasthmatic subjects has been reported, suggesting an augmented SP release in asthma [10]. Supporting this hypothesis, bronchoalveolar lavage fluid [11] and induced sputum [12] from asthmatics were found to contain increased amounts of SP-LI. SP and NKA contract human airways in vitro and in vivo, NKA being more potent than SP and asthmatics being more sensitive than normal subjects [5,[13][14][15][16][17].…”

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confidence: 82%

The effect of the NK2 tachykinin receptor antagonist SR 48968 (saredutant) on neurokinin A-induced bronchoconstriction in asthmatics

Schoor¹,

Joos²,

Chasson³

et al. 1998

Eur Respir J

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Substance P (SP) and neurokinin (NK) A are members of the tachykinin peptide family and have been implicated as neurotransmitters which mediate the excitatory part of the nonadrenergic, noncholinergic (e-NANC) nervous system [1][2][3]. In the human airways, they are contained within sensory unmyelinated C nerve fibres, which are distributed beneath or within the airway epithelium, around blood vessels and glands, within the bronchial smooth muscle layer and around local ganglion cells [4][5][6][7][8]. Recent findings in both experimental animals and humans, however, suggest that non-neural cells (endothelial cells, eosinophils and macrophages), either resident or circulating, can also be a source of tachykinins and that immune stimuli can boost tachykinin production from immunocytes [9]. A reduced SP-like immunoreactivity (SP-LI) content of asthmatic airways compared with nonasthmatic subjects has been reported, suggesting an augmented SP release in asthma [10]. Supporting this hypothesis, bronchoalveolar lavage fluid [11] and induced sputum [12] from asthmatics were found to contain increased amounts of SP-LI. SP and NKA contract human airways in vitro and in vivo, NKA being more potent than SP and asthmatics being more sensitive than normal subjects [5,[13][14][15][16][17]. Other potentially important airway effects of tachykinins include mucus secretion, cough, vasodilatation, increased vascular permeability and a broad array of pro-inflammatory effects involving various types of leukocytes [1][2][3].SP and NKA interact with their target cells in the airways through specific tachykinin receptors, with SP being the preferential agonist for the tachykinin NK1 receptor and NKA the preferential agonist for the tachykinin NK2 receptor [18]. Increased expression of NK1 [19] and NK2 [20] tachykinin receptor gene messenger ribonucleic acid (mRNA) in asthmatic airways has been reported. In isolated normal human airways in vitro, tachykinin-induced bronchoconstriction is mediated predominantly by tachykinin NK2 receptors [8,[21][22][23]; recently, however, involvement of tachykinin NK1 receptors has also been noted [24,25]. Tachykinin NK1 receptor stimulation appears to be important in eliciting neurogenic inflammation [1][2][3]18]. On the screening day and during the study periods, increasing concentrations of NKA (3.3×10 -9 to 1.0×10 -6 mol·mL -1 ) were inhaled, until the forced expiratory volume in one second (FEV1) and specific airway conductance (sGaw) decreased by at least 20 and 50%, respectively. During the study periods, 100 mg SR 48968 or matched placebo was ingested in a double-blind, randomized, crossover fashion and NKA provocation was performed at 1.5 and 24 h after dosing. At 1.5 h, the mean (SEM) log10 provocative concentration of NKA causing a 20% fall in FEV1 (PC20 FEV1) was -6.25 (0.20) after SR 48968 and -6.75 (0.17) after placebo (p=0.05); the mean log10 provocative concentration of NKA causing a 35% fall in sGaw (PC35 sGaw) was -7.02 (0.28) after SR 48968 and -7.64 (0.19) after placebo (p=0.05). A...

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Elevated Substance P Content in Induced Sputum from Patients with Asthma and Patients with Chronic Bronchitis

Cited by 162 publications

References 0 publications

Neutralizing Anti-F Glycoprotein and Anti-Substance P Antibody Treatment Effectively Reduces Infection and Inflammation Associated with Respiratory Syncytial Virus Infection

Neutralizing Anti-F Glycoprotein and Anti-Substance P Antibody Treatment Effectively Reduces Infection and Inflammation Associated with Respiratory Syncytial Virus Infection

Montelukast attenuates the airway response to hypertonic saline in moderate-to-severe COPD

The effect of the NK2 tachykinin receptor antagonist SR 48968 (saredutant) on neurokinin A-induced bronchoconstriction in asthmatics

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