Search

Background: Mucus hypersecretion and neutrophil infiltration are important characteristics of airway inflammation. Epidermal growth factor receptor (EGFR) transactivation induces mucus and inflammatory cytokine secretion from airway epithelial cells. To elucidate the roles of EGFR in airway inflammation, the in vitro effects on mucin production and interleukin (IL) 8 secretion from cultured airway epithelial cells and the in vivo effects on mucus hypersecretion and neutrophil infiltration in rat nasal mucosa of the EGFR tyrosine kinase inhibitor AG1478 were examined., Methods: The in vitro effects of AG1478 treatment of cultured NCI-H292 cells on lipopolysaccharide (LPS) induced or tumor necrosis factor (TNF) α induced MUC5AC mucin and IL-8 secretion were evaluated. Hypertrophic and metaplastic changes of goblet cells, mucus production and neutrophil infiltration in rat nasal epithelium were induced by intranasal instillation of LPS in vivo, and the inhibitory effects of AG1478 by intraperitoneal injection or intranasal instillation were examined., Results: AG1478 (1-1000 nM) significantly inhibited both LPS-induced and TNF-α-induced secretion of MUC5AC and IL-8 from cultured NCI-H292 cells in a dose-dependent manner. The expression of MUC5AC and IL-8 messenger RNAs was also significantly inhibited. Intranasal instillation of AG1478 one hour after intranasal LPS instillation significantly inhibited LPS-induced goblet cell metaplasia, mucus production, and neutrophil infiltration in rat nasal epithelium, as did intraperitoneal injection of AG1478 one hour before LPS instillation., Conclusions: These results indicated that EGFR transactivation plays an important role in mucin and IL-8 secretion from airway epithelial cells. Intranasal instillation of an EGFR tyrosine kinase inhibitor may be a new therapeutic approach for the treatment of upper airway inflammation.

Objective: Low-dose, long-term use of 14-membered macrolides is effective for treatment of patients with chronic airway inflammation such as diffuse panbronchiolitis or chronic rhinosinusitis. However, long-term use of macrolides can promote the growth of drug-resistant bacteria, and the development of anti-inflammatory macrolides that lack antibiotic effects is desirable. Previously, we developed EM900, a novel 12-membered erythromycin A derivative, which has potent anti-inflammatory and immunomodulatory activities and lacks any antibacterial activity. We examined the anti-inflammatory effects of EM900 on mucus secretion from airway epithelial cells., Methods: To examine the in vivo effects of EM900 on airway inflammation, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium via intranasal instillation of lipopolysaccharides. In vitro effects of EM900 on airway epithelial cells were examined using cultured human airway epithelial (NCI-H292) cells. Mucus secretion was evaluated via enzyme-linked immunosorbent assays with an anti-MUC5AC monoclonal antibody., Results: Oral administration of EM900 or clarithromycin (CAM) significantly inhibited LPS-induced mucus production from rat nasal epithelium. EM900, CAM, or erythromycin significantly inhibited MUC5AC secretion induced by tumor necrosis factor-α from NCI-H292 cells. MUC5AC mRNA expression was also significantly lower in EM900-treated cells., Conclusion: These results indicated that a novel non-antibiotic macrolide, EM900 exerted direct inhibitory effects on mucus secretion from airway epithelial cells, and that it may have the potential to become a new anti-inflammatory drug for the treatment of chronic rhinosinusitis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

To examine the in vivo effects of the 15-member macrolide, azithromycin (AZM), on mucus hypersecretion, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal instillation of ovalbumin (OVA) in OVA-sensitized rats, or by intranasal lipopolysaccharides (LPS) instillation. Oral administration of AZM (5-10 mg/kg) or clarithromycin (CAM, 5-10 mg/kg) significantly inhibited OVA- and LPS-induced mucus production, whereas josamycin (JM) or ampicillin (ABPC) showed no effect. In vitro effects of AZM on airway epithelial cells were examined using NCI-H292 cells and human nasal epithelial cells cultured in air-liquid interface. Mucus secretion was evaluated by enzyme-linked immunosorbent assay using an anti-MUC5AC monoclonal antibody. AZM or CAM significantly inhibited tumor necrosis factor-α (TNF-α) (20 ng/mL)-induced MUC5AC secretion from NCI-H292 cells at 10⁻⁶-10⁻⁷ M, whereas JM or ABPC showed no effect. AZM significantly inhibited TNF-α (20 ng/mL)-induced MUC5AC secretion from human nasal epithelial cells at 10⁻⁴ M. MUC5AC mRNA expression was also significantly inhibited. These results indicate that the 15-member macrolide, AZM, exerts direct inhibitory effects on mucus secretion from airway epithelial cells and that it may be useful for the treatment of mucus hypersecretion caused by allergic inflammation and LPS stimulation.

Objectives: Prostaglandin (PG) E2 is a potential anti-inflammatory mediator that attenuates airway inflammation. To elucidate the functions of the PGE2 receptors (EP1, EP2, EP3, and EP4) in allergic inflammation, we examined the in vivo effects of EP agonists on mucus hypersecretion and eosinophil infiltration in rat nasal epithelium., Methods: We induced hypertrophic and metaplastic changes in goblet cells in nasal epithelium of ovalbumin-sensitized rats by intranasal challenge with ovalbumin. The effects of subcutaneous injections of EP agonists on mucus production and eosinophil infiltration were examined., Results: The EP4 agonist (1 to 100 microg/kg) dose-dependently inhibited ovalbumin-induced mucus production. The EP2 and EP3 agonists (100 microg/kg) also significantly inhibited mucus production. The EP3 agonist inhibited antigen-induced eosinophil infiltration, whereas the EP1 agonist showed no effect. This suppression of mucus production by the EP4 agonist was only effective when the EP4 agonist was given in the effector phase; administration in the induction phase resulted in no effect., Conclusions: These results indicate that PGE2 acts as an anti-inflammatory mediator via the EP receptors of airways in allergic inflammation. Selective EP agonists may provide a new therapeutic strategy for airway mucus hypersecretion.

Objectives: We examined the in vivo effects of agonists for prostaglandin E2 receptors (EP1, EP2, EP3, and EP4) on mucus hypersecretion. We also examined the in vitro effects of EP agonists on airway epithelial cells., Methods: For the in vivo study, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal lipopolysaccharide (LPS) instillation. For the in vitro study, we used NCI-H292 cells and cultured human nasal epithelial cells., Results: Subcutaneous injection of the EP4 agonist (1 to 100 microg/kg) dose-dependently inhibited LPS-induced mucus production and neutrophil infiltration. The EP3 agonist (100 microg/kg) also had some inhibitory effects on mucus production, whereas the EP1 and EP2 agonists showed no effect. The LPS-induced mucus secretion was significantly inhibited by the EP3 and EP4 agonists at 10(-6) mol/L in cultured epithelial cells. The LPS-induced interleukin-8 secretion was also inhibited by the EP3 and EP4 agonists., Conclusions: These results indicate that the EP4 agonist inhibited LPS-induced airway mucus hypersecretion directly or indirectly through the suppression of interleukin-8 secretion and neutrophil infiltration.

To examine the in vivo effects of macrolide antibiotics on mucus hypersecretion, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal instillation of ovalbumin (OVA) in OVA-sensitized rats and by intranasal LPS instillation. Oral administration of clarithromycin (CAM) (5-10 mg/kg) significantly inhibited OVA- and LPS-induced mucus production and neutrophil infiltration, whereas josamycin and ampicillin showed no effect. In vitro effects of macrolide antibiotics on airway epithelial cells were examined using NCI-H292 cells and human nasal epithelial cells cultured in air-liquid interface. Mucus secretion was evaluated by ELISA using anti-mucin monoclonal antibodies (anti-MUC5AC and HCS18). CAM and erythromycin significantly inhibited spontaneous and tumor necrosis factor-alpha (20 ng/ml)-induced mucus secretion from NCI-H292 cells at 10-6 to 10-7 M and from human nasal epithelial cells at 10-4 to 10-5 M. MUC5AC messenger RNA expression was also significantly inhibited. These results indicate that the 14-member macrolide antibiotics, CAM and erythromycin, exert direct inhibitory effects on mucus secretion from airway epithelial cells and that they may be useful for the treatment of mucus hypersecretion caused by allergic inflammation and LPS stimulation.

Background: We have produced hypertrophic and metaplastic changes of goblet cells in nasal epithelium of ovalbumin (OVA)-sensitized rats by intranasal challenge with OVA. A variety of allergic mediators and inflammatory cells are capable of stimulating goblet cell degranulation (epithelial mucus secretion); however, little is known about the mechanism by which antigen induces mucus hypersecretion., Objective: Our aim was to explain the mechanism of goblet cell degranulation in allergic inflammation., Methods: Antigen-induced goblet cell degranulation was evaluated by the transient decrease of epithelial mucosubstance 1 to 6 hours after intranasal challenge with OVA in nasal epithelium of OVA-sensitized rats. The effects of the H(1)-antagonist (d -chlorpheniramine malate), H(2)-antagonist (cimetidine), atropine, indomethacin, cysteinyl leukotriene (cysLT) antagonist (ONO1078), and antirat PMN antiserum on OVA-induced goblet cell degranulation were examined., Results: Goblet cell secretion 1 hour after OVA challenge was significantly inhibited by H(1)-antagonist, atropine, and cysLT antagonist, whereas the secretion 6 hours after the challenge was significantly inhibited by cysLT antagonist and antirat PMN antiserum. Circulating PMN cells and mucosal infiltrating eosinophils were completely abolished by antirat PMN antiserum., Conclusions: These results indicate the different mechanisms of goblet cell secretion between early-phase (1 hour after OVA challenge) and late-phase (6 hours after the challenge) reactions. Histamine stimulates early-phase secretion through the H(1)-receptor of cholinergic nerve terminals, and infiltrating inflammatory cells (eosinophils and/or neutrophils) play a role in late-phase secretion. CysLTs (leukotrienes C(4), D(4), and E(4)) are important for both early-phase and late-phase secretion.

Mucus hypersecretion and eosinophil infiltration are important characteristics of eosinophilic inflammation in upper airways, such as allergic rhinitis and chronic rhinosinusitis with nasal polyp. EGFR transactivation induces mucus and inflammatory cytokine secretion from airway epithelial cells. However, the roles of EGFR in eosinophilic inflammation in upper airways are still unknown. The purpose of the study is to elucidate the effects of the EGFR inhibitor AG1478 on eosinophilic airway inflammation. AG1478 significantly inhibited thrombin-induced GM-CSF secretion from nasal epithelial cells and thrombin-induced secretion of eotaxin-1 and RANTES from nasal fibroblasts. Intranasal instillation of AG1478 inhibited OVA-induced goblet cell metaplasia, mucus production and eosinophil/neutrophil infiltration in rat nasal epithelium, as did intraperitoneal injection of AG1478. These results indicate that EGFR transactivation plays an important role in eosinophilic airway inflammation. Intranasal instillation of an EGFR inhibitor may be a new therapeutic approach for the treatment of intractable eosinophilic inflammation in upper airways. [ABSTRACT FROM AUTHOR]

Background: Heparin is one of the most important anticoagulant drugs. It has been known that heparin also possesses anti-inflammatory activities. Mucus hypersecretion is an important characteristic of airway inflammation. However, little is known about the regulatory effects of heparin on mucus hypersecretion in airway epithelial cells. To elucidate the anti-inflammatory function of heparin in airway epithelial cells, we examined the in vivo effects of heparin on mucus hypersecretion and neutrophil infiltration in rat nasal epithelium. We also examined the in vitro effects of heparin on mucin production and IL-8 secretion from cultured human airway epithelial cells. Methods: We induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal lipopolysaccharide (LPS) instillation. The effects of intranasal instillation with heparin on mucus production and neutrophil infiltration were examined. in vitro effects of heparin on airway epithelial cells were examined using cultured NCI-H292 cells. Mucus secretion was evaluated by enzyme-linked immunosorbent assay using an anti-MUC5AC monoclonal antibody. Results: Intranasal instillation with unfractionated heparin (UFH; 100 IU/0.1 mL) or low molecular weight heparin (LMWH; 100 IU/0.1 mL) at 30 minutes before LPS instillation significantly inhibited LPS-induced mucus production and neutrophil infiltration in rat nasal epithelium. UFH or LMWH inhibited tumor necrosis factor alpha (10 ng/mL)-induced secretion of MUC5AC and IL-8 from NCI-H292 cells in a dose-dependent manner (0.01-10 IU/mL). MUC5AC mRNA expression was also significantly inhibited. Conclusion: These results indicate that heparin inhibits airway mucus hypersecretion in airway epithelial cells directly and indirectly through the suppression of IL-8 secretion and neutrophil infiltration. [ABSTRACT FROM AUTHOR]