Altered expression and signalling of EP2 receptor in nasal polyps of AERD patients: role in inflammation and remodelling.

BACKGROUND: Down-regulation of the E-prostanoid (EP)2 receptor has been reported in aspirin exacerbated respiratory disease (AERD). We aimed to evaluate the expression and activation of EP receptors in AERD and their role in prostaglandin (PG) E2 signalling. METHODS: Samples were obtained from nasal mucosa of control subjects (NM-C, n=7) and from nasal polyps of AERD patients (NP-AERD, n=7). Expression of EP1-4 was assessed at baseline. Fibroblasts were stimulated with receptor agonists to measure cAMP levels, cell proliferation and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. RESULTS: NM-C and NP-AERD samples and fibroblasts expressed EP2, EP3 and EP4 at baseline. Lower expression of EP2 and higher expression of EP4 was observed in NP-AERD compared with NM-C. Stimulation with PGE2 and butaprost caused a higher increase in cAMP in NM-C than in NP-AERD. On the contrary, CAY10598 produced a higher production of cAMP in NP-AERD compared with NM-C. The anti-proliferative effect of PGE2 and butaprost was lower in NP-AERD than in NM-C fibroblasts. Similarly, the capacity of PGE2 and butaprost to inhibit GM-CSF release was lower in NP-AERD than in NM-C. CONCLUSIONS: The altered expression of EP2 in AERD may contribute to reduce the capacity of PGE2 to mediate anti-proliferative and anti-inflammatory effects.

United airways: the impact of chronic rhinosinusitis and nasal polyps in bronchiectasic patient's quality of life.

BACKGROUND: The nose and the bronchi belong, in anatomical and physiopathological terms, to the concept of united airways. Associations between upper and lower airways diseases have been demonstrated in allergic rhinitis and asthma, nasal polyposis (NP) and asthma, chronic rhinosinusitis (CRS) and chronic obstructive pulmonary disease, and more recently CRS/NP and bronchiectasis (BQ). OBJECTIVE: To evaluate the impact of CRS on quality of life (QoL) of patients with BQ, and to correlate these findings with the pulmonary status, nasal symptoms, and general health status. METHODS: In a prospective study, patients with BQ (n = 80) were evaluated for CRS and NP using EP(3)OS criteria, and severity of BQ using chest high resolution computed tomography (HRCT)-scan. Quality of life was assessed in all patients by using specific [Sinonasal Outcome Test-20 (SNOT-20), St George Respiratory Questionnaire (SGRQ)], and generic (Short Form-36; SF-36) questionnaires. RESULTS: Using SNOT-20, patients with CRS had worse QoL (2.1 +/- 0.1; P < 0.001) than patients without CRS (0.4 +/- 0.06). Using SGRQ total score, patients with CRS had worse QoL (43.7 +/- 2.2; P < 0.001) than patients without CRS (24.7 +/- 2.5). Using SF-36, patients with CRS had worse QoL, both in the physical summary (64 +/- 3.4; P < 0.05) and the mental summary (65.5 +/- 4.7; P < 0.05), than patients without CRS (physical summary [PS]: 76.2 +/- 3.3; mental summary [MS]: 78.3 +/- 5.3, respectively). Sinonasal Outcome Test-20 was correlated with SGRQ total score (r = 0.72; P < 0.01), and SF-36 physical summary (r = -0.63; P < 0.01). St George Respiratory Questionnaire was correlated with SF-36 on physical summary (r = -0.58; P < 0.05) and with forced expiratory volume in 1 s (r = -0.41; P < 0.05). CONCLUSION: These results suggested that CRS, measured by both specific and generic questionnaires, has a considerable impact on the QoL of patients with BQ.

Glucocorticoid therapy increases COX-2 gene expression in nasal polyps in vivo.

The aim of the present study was to evaluate the in vivo regulation of cyclooxygenase-2 in nasal polyps. In total, 65 patients with nasal polyps were randomly (3:1) treated with (n = 51; 33 with asthma) or without (n = 14) oral prednisone and intranasal budesonide for 2 weeks plus intranasal budesonide for 10 additional weeks. Biopsies were obtained at baseline and after 2 and 12 weeks of treatment. All samples were analysed for cyclooxygenase-1 and cyclooxygenase-2 mRNA. Attempts were made to detect cyclooxygenase-2 protein. At baseline, cyclooxygenase-1 and cyclooxygenase-2 expression did not differ between polyps from nonasthmatic and asthmatic patients. Cyclooxygenase-1 mRNA was unchanged by glucocorticoid treatment, while cyclooxygenase-2 mRNA increased in glucocorticoid-treated patients at week 2 compared with baseline and then decreased at week 12. Within subgroups, increased cyclooxygenase-2 mRNA was found at week 2 in polyps from nonasthmatic and asthmatic patients compared with baseline. At week 12, cyclooxygenase-2 expression remained high in nonasthmatics while it decreased in asthmatics. Cyclooxygenase-2 protein was not detected under any circumstances. Glucocorticoid therapy enhances cyclooxygenase-2 expression in vivo in nasal polyps, a finding that does not follow the generally accepted assumption that cyclooxygenase-2 expression is suppressed by glucocorticoids.

United airways again: high prevalence of rhinosinusitis and nasal polyps in bronchiectasis.

BACKGROUND: Although various relationships between the lower and upper airways have been found, the association of bronchiectasis with chronic rhinosinusitis and nasal polyps has not been thoroughly evaluated. This study was undertaken to examine the association of idiopathic and postinfective bronchiectasis with chronic rhinosinusitis and nasal polyposis. METHODS: In a prospective study, 56 patients with idiopathic and 32 with postinfective bronchiectasis were evaluated for chronic rhinosinusitis and nasal polyposis by using EP(3)OS criteria and assessing: symptoms score, nasal endoscopy, sinonasal and chest CT scan, nasal and lung function and nasal and exhaled NO. RESULTS: Most bronchiectasis patients (77%) satisfied the EP(3)OS criteria for chronic rhinosinusitis, with anterior (98.5%) and posterior (91%) rhinorrhea and nasal congestion (90%) being the major symptoms. Patients presented maxillary, ethmoidal and ostiomeatal complex occupancy with a total CT score of 8.4 +/- 0.4 (0-24). Using endoscopy, nasal polyps with a moderate score of 1.6 +/- 0.1 (0-3) were found in 25% of patients. Nasal NO was significantly lower in patients with nasal polyposis (347 +/- 62 ppb) than in those without them (683 +/- 76 ppb; P < 0.001), and inversely correlated (R = -0.36; P < 0.01) with the ostiomeatal complex occupancy. In the chest CT scan, patients with chronic rhinosinusitis showed a higher bronchiectasis severity score (7.2 +/- 0.5; P < 0.001) than patients without (3.7 +/- 0.7). The prevalence of chronic rhinosinusitis, nasal polyps and other outcomes were similar in idiopathic and postinfective bronchiectasis. CONCLUSIONS: The frequent association of chronic rhinosinusitis and nasal polyposis with idiopathic and postinfective BQ supports the united airways concept, and it suggests that the two type of bronchiectasis share common etiopathogenic mechanisms.

Regulation of glucocorticoid receptor in nasal polyps by systemic and intranasal glucocorticoids.

BACKGROUND: Poor response of nasal polyps to glucocorticoids (GCs) may be because of abnormal expression of GC receptors (GR) alpha and beta or to downregulation of GRalpha. We aimed to evaluate the in vivo regulation of GR isoforms in GC-treated nasal polyps and to assess the relationship between clinical response to GCs and GR levels. METHODS: Patients with nasal polyps were randomly (3:1) treated (n = 51) or not (n = 14) with oral prednisone and intranasal budesonide for 2 weeks, plus intranasal budesonide for 10 additional weeks. Nasal symptoms were evaluated. Biopsies were obtained before (w0) and after 2 (w2) and 12 (w12) weeks of treatment, and analysed for their inflammatory content and GR mRNA (10(2) cDNA copies/mug total RNA) and protein (% immunoreactive inflammatory cells) expression. Healthy nasal mucosa (n = 11) was also investigated. Data are presented as median and 25-75th percentile. RESULTS: At w0, nasal polyps expressed less GRalpha mRNA (1343;683-2263; P < 0.05) and GR protein (41;29-54; P < 0.05) than nasal mucosa (2474;1346-2933; 60;51-72, respectively). GRbeta immunoreactivity was higher in nasal polyps (11;4-19; P < 0.05) than in nasal mucosa (5;2-5). At w2, increased GRalpha mRNA (2010;1037-2732; P < 0.01) and GR protein (56;27-71; P = 0.056) were found compared with w0 (1177;759-2058; 37;29-55, respectively). At w12, GRalpha mRNA and GR protein were similar to w0. GRbeta expression was unaltered by treatment. Neither GRalpha nor GRbeta correlated with nasal symptoms. GR immunoreactivity negatively correlated with eosinophils (r = -0.478; P < 0.001). CONCLUSIONS: GRalpha is downregulated in nasal polyps and upregulated by GC treatment. Neither GRalpha nor GRbeta appear to determine the sensitivity to GCs in nasal polyposis.

Upregulation of COX-1 and COX-2 in nasal polyps in cystic fibrosis.

BACKGROUND: Since abnormalities in prostanoid metabolism occur in the lower airway of patients with cystic fibrosis (CF), it is likely that they could also be detected in the nose. METHODS: The degree of mRNA and protein expression of cyclo-oxygenase (COX) enzymes 1 (COX-1) and 2 (COX-2) was examined using quantitative reverse competitive polymerase chain reaction (RT-PCR) and Western blot analysis in the nasal polyps from 10 patients with CF, nasal polyps from 10 non-CF patients and 11 nasal mucosa specimens. The results are presented as 10(6) cDNA molecules/mug total RNA and the densitometric ratio between protein and beta-actin. RESULTS: COX-1 mRNA levels were significantly higher in CF nasal polyps (median 2.34, 25-75th percentiles 1.6-3.2) than in the nasal mucosa (0.78, 0.11-1.21), while there was no difference with non-CF nasal polyps (1.11, 0.80-3.15). COX-1 protein levels were significantly higher in CF nasal polyps (3.63, 2.71-4.27) than in nasal mucosa (1.55, 0.66-2.33) and non-CF nasal polyps (2.19, 1.72-3.68). COX-2 mRNA was significantly higher in CF nasal polyps (3.34, 2.42-7.05) than in nasal mucosa (1.69, 0.19-3.50). No differences were found in COX-2 mRNA expression between CF and non-CF polyps (1.38, 0.12-6.07). COX-2 protein levels were also significantly higher in CF nasal polyps (0.23, 0.04-0.34) than in non-CF nasal polyps (0.011, 0.009-0.016) or nasal mucosa (0.014, 0.014-0.016). CONCLUSIONS: Upregulation in the expression of COX-1 and COX-2 could explain the high production of prostanoids reported in CF. These findings raise questions regarding the potential use of selective or non-selective COX-2 non-steroidal anti-inflammatory treatment in CF.

Effect of desloratadine on epithelial cell granulocyte-macrophage colony-stimulating factor secretion and eosinophil survival.

BACKGROUND: Second-generation antihistamines are H(1) receptor antagonists and may have additional anti-inflammatory effects. OBJECTIVE: The aims of the study were to evaluate the effect of desloratadine (DL) on cytokine secretion by epithelial cells from both nasal mucosa (NM) and polyps (NP), and on eosinophil survival primed by epithelial cell secretions. METHODS: Epithelial cells were cultured and stimulated with fetal bovine serum (FBS), IL-1beta or TNF-alpha with and without DL for 24 h. Culture supernatant cytokines concentration were measured by ELISA. Peripheral blood eosinophils were incubated with human epithelial cell conditioned media (HECM) and DL. Eosinophil survival was assessed by Trypan blue dye exclusion. Results are expressed as mean+/-SEM of cytokine concentration (pg/mL) or eosinophil survival index (%). RESULTS: FBS increased granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), IL-6, IL-8, and TGF-beta(1) secretion in epithelial cell cultures from both NM and NP. Only GM-CSF secretion was significantly (P<0.05) inhibited by a dose-response of DL compared with positive controls, in both NM (10(-5) m: 125+/-36 pg/mL, 10(-6) m: 95+/-22 pg/mL vs. control: 256+/-91 pg/mL, n=6) and NP (10(-5) m: 80+/-29 pg/mL, 10(-6) m: 109+/-45 pg/mL vs. control: 333+/-212 pg/mL, n=6). DL also showed an inhibitory effect on HECM-induced eosinophil survival from both NM and NP. At 72 h, DL significantly (P<0.01) inhibited eosinophil survival induced by HECM from NM (10(-5) m: 19.9+/-5.5%, n=9; 10(-6) m: 28.7+/-7.7%, n=9) and NP (10(-5) m: 6.2+/-2.8%, n=11) compared with HECM alone (NM: 42.1+/-7.3%; NP: 45.3+/-8.1%). CONCLUSION: The inhibitory effects of DL on epithelial cell GM-CSF secretion and on eosinophil survival induced by epithelial cell secretions, suggest that this H(1) antagonist may regulate eosinophil inflammation in upper airways.

Glucocorticoid receptors in human airways.

Inhaled and intranasal glucocorticoids are the most common and effective drugs for controlling symptoms and airway inflammation in respiratory diseases such as asthma, allergic rhinitis, and nasal polyposis. The last few years have seen a growing understanding of the mechanisms of glucocorticoid action and, in particular, the receptor that mediates glucocorticoid actions, the glucocorticoid receptor (GR). In this revision we present an update on the GR gene, the expression and regulation of its gene products, namely GRalpha and GRbeta, as well as their alterations in pathological states. GRalpha is responsible for the induction and repression of target genes, it is expressed in virtually all human cells and tissues, and its expression is known to be downregulated by glucocorticoids. GRbeta has been found to act as a dominant negative inhibitor of GRalpha-mediated transactivation in in vitro studies with transfected cells, but it does not appear to have a significant inhibitory effect on GRalpha-mediated transrepression. In addition, for most tissues the expression of GRbeta, at least at the mRNA level, is extremely low compared with that of GRalpha. Some pro-inflammatory cytokines appear to upregulate the expression of GRbeta, and increased GRbeta expression has been reported in diseases associated with glucocorticoid resistance or insensitivity, such as bronchial asthma, nasal polyposis, and ulcerative colitis. However, the possible role of GRbeta in modulating glucocorticoid sensitivity and/or resistance in vivo has been highly debated and it is not yet clear.

Expression of glucocorticoid receptors alpha and beta in steroid sensitive and steroid insensitive interstitial lung diseases.

BACKGROUND: Sensitivity to glucocorticoids may be related to the concentration of glucocorticoid receptors alpha (GRalpha) and beta (GRbeta). A study was undertaken to assess GRalpha and GRbeta expression in steroid insensitive interstitial lung disease (idiopathic pulmonary fibrosis (IPF)) and steroid sensitive interstitial lung diseases (sarcoidosis and cryptogenic organising pneumonia (COP)). METHODS: Lung tissue was obtained from control subjects and from patients with IPF, sarcoidosis, and COP. Pulmonary function tests were carried out at the time of lung biopsy and every 3 months. GRalpha and GRbeta expression was evaluated by both competitive RT-PCR and immunohistochemistry. Data are presented as median and 25-75th percentile. RESULTS: GRalpha mRNA expression (10(5) cDNA copies/ micro g total RNA) was higher in patients with steroid sensitive interstitial lung diseases (10.0; 7.8-14.9; n = 11) than in patients with IPF (4.4; 3.2-6.6; n = 19; p<0.001). GRbeta expression was at least 1000 times lower than that of GRalpha and did not differ between the three groups. A negative correlation was found between GRalpha mRNA levels and the fibrotic pathology score of the tissue (r = -0.484, p<0.01) and a positive correlation was found between GRalpha mRNA levels and improvement in forced vital capacity (r = 0.633; p<0.01) after treatment of patients with glucocorticoids. Immunoreactivity for GR protein was also higher in patients with sarcoidosis and COP than in those with IPF. CONCLUSION: The variable response of some interstitial lung diseases to steroid treatment may be the result of differences in the expression of GRalpha.

Nuclear factor-kappaB activity is down-regulated in nasal polyps from aspirin-sensitive asthmatics.

BACKGROUND: We examined whether a decreased activity of nuclear factor(NF)-kappaB), a transcriptional regulator of cyclooxygenase-2 (COX-2), could account for down-regulation of COX-2 in nasal polyps of aspirin-sensitive asthmatics. METHODS: Nasal polyps were obtained from 17 aspirin-intolerant asthma/rhinitis patients (AIAR; 7 men, mean age 48 +/- 12 years) and 23 aspirin-tolerant asthma/rhinitis patients (ATAR; 12 men, mean age 65 +/- 11 years). COX-2 mRNA expression was measured using semiquantitative reverse transcriptase competitive polymerase chain reaction (RT-PCR), and the results were expressed as mean +/- standard error of 106 molecules of mRNA/ micro g of total RNA. NF-kappaB binding was measured with 32P-labeled oligonucleotides and electrophoretic mobility shift assay (EMSA), and the results were expressed as a percentage with respect to the mean EMSA obtained in 19 healthy nasal mucosa. RESULTS: The mean levels of COX-2 mRNA expression (0.25 +/- 0.06) and NF-kappaB activity (89 +/- 13) in nasal polyps from AIAR were significantly lower than in polyps from ATAR (COX-2 = 1.58 +/- 0.50, and NF-kappaB = 143 +/- 12, P < 0.01 and P < 0.05, respectively). Levels of COX-2 mRNA and NF-kappaB activity in polyps from patients on corticosteroid therapy did not differ statistically from those who were not on this therapy before polypectomy. CONCLUSION: This study shows that the low expression of COX-2 mRNA in nasal polyps from aspirin-sensitive patients is associated with a down-regulation of NF-kappaB activity.

Effect of budesonide and nedocromil sodium on IL-6 and IL-8 release from human nasal mucosa and polyp epithelial cells.

We investigated the effect of budesonide and nedocromil sodium on the secretion of IL-6 and IL-8 by cultured epithelial cells from healthy nasal mucosa and nasal polyps. Human epithelial cell conditioned media was generated with fetal calf serum (FCS) in the presence or absence of budesonide and/or nedocromil sodium. Budesonide inhibited FCS-induced IL-6 and IL-8 release in a dose-dependent manner. The IC25 (25% inhibitory concentration) of budesonide on IL-6 release was higher in nasal polyp than in nasal mucosa epithelial cells (34 nM vs. 200 pM). The IC25 of budesonide on IL-8 release was higher in nasal mucosa than in nasal polyps (145 pM vs. 4 pM). Nedocromil sodium caused a dose-related inhibitory effect on IL-8 release from nasal mucosa (IC25, 207 nM), while it only had a significant effect in nasal polyps at 10(-5) M. Nedocromil sodium had no effect on IL-6 release. The inhibitory effect of budesonide was higher than that of nedocromil sodium on both nasal polyps and nasal mucosa. Budesonide and nedocromil sodium may exert their anti-inflammatory action in the respiratory mucosa by modulating the secretion of IL-6 and IL-8. The different effect of budesonide and nedocromil sodium on IL-6 and IL-8 release may be explained by differences in the mechanisms which regulate the upregulation of these cytokines in inflammatory responses.

Expression of the human glucocorticoid receptor alpha and beta isoforms in human respiratory epithelial cells and their regulation by dexamethasone.

Two isoforms of the human glucocorticoid receptor (hGR) have been described, hGRalpha and hGRbeta. We analyzed the expression and regulation of both hGR isoforms in human respiratory epithelial cells (BEAS-2B, A549, and primary nasal epithelial cells). In BEAS-2B cells, the expression of hGRalpha messenger RNA (mRNA) was much higher than that of hGRbeta mRNA. Dexamethasone (DEX) (10(-6) M) downregulated hGRalpha mRNA at 6 and 24 h (55 +/- 8 and 58 +/- 5% of control, respectively; P < 0.01), whereas it decreased hGRbeta mRNA only at 6 h (55 +/- 7% of control; P < 0.01). Downregulation of hGRalpha and hGRbeta mRNAs occurred even in the presence of cycloheximide. Actinomycin-D studies revealed that DEX enhanced the stabilization of hGRalpha and hGRbeta messages. hGRalpha but not hGRbeta protein was detected in BEAS-2B, A549, and nasal epithelial cells. After 24 h of incubation, 10(-6) M DEX decreased the expression of hGRalpha protein in BEAS-2B, A549, and nasal epithelial cells (16 +/- 4, 14 +/- 4, and 28 +/- 7% of control, respectively; P < 0.01). These results suggest that in respiratory epithelial cells: (1) hGRalpha is much more expressed than hGRbeta at both the mRNA and protein levels; (2) hGRalpha is downregulated by corticosteroids both in cell lines (BEAS-2B, A549) and in nasal primary cells; and (3) transcriptional, post-transcriptional, and post-translational mechanisms appear to be involved in the regulation of hGR expression by corticosteroids.

Regulation of cyclooxygenase-1 and -2 expression in human nasal mucosa. Effects of cytokines and dexamethasone.

BACKGROUND: Cyclooxygenase (COX) converts arachidonic acid in prostanoids. COX exists in two isoforms, COX-1 is the constitutive whereas COX-2 is the inducible isoform. The regulation of COX-1 and COX-2 expression in nasal mucosa has not been previously reported. AIM: We studied expression and regulation by cytokines and corticosteroids of COX-1 and COX-2 in human nasal mucosa. Cultured human nasal explants from patients undergoing corrective nasal mucosal resection were examined for COX-1 and COX-2 expression by semiquantitative competitive PCR and Western blot. METHODS: Explants were incubated with pro-(IFNgamma, IL-1beta, and TNF-alpha) and anti(IL-10) inflammatory cytokines and dexamethasone. The mechanisms which regulate COX-2 mRNA expression were studied using inhibitors of translation (Actinomycin D) and transcription (Cicloheximide). RESULTS: The baseline expression of COX-2 mRNA was higher than COX-1 mRNA. Once in culture, there was a slight spontaneous up-regulation of COX-1 and a strong COX-2 mRNA and protein up-regulation. The incubation of nasal explants with pro-inflammatory cytokines increased the expression of COX-2 mRNA and protein, from 1 to 24 h of incubation in a dose-related manner. The regulation of these effects occurred at both transcriptional and post-transcriptional levels. Dexamethasone and IL-10 abrogated cytokine-induced COX-2 mRNA and protein expression. Pro-inflammatory cytokines, dexamethasone and IL-10 had no effect on COX-1 mRNA expression. CONCLUSIONS: As prostanoids have important regulatory effects on the immunologically mediated inflammatory responses, our findings throw some light on the mechanisms that regulate the enzymes which produce these metabolites in the human airway.

Effect of topical anti-inflammatory drugs on epithelial cell-induced eosinophil survival and GM-CSF secretion.

Topical anti-inflammatory drugs decrease eosinophil infiltration. This action may be due to an effect on the release of epithelial cell products responsible for promoting eosinophil survival. We investigated the effect of fluticasone propionate, budesonide, beclomethasone dipropionate and nedocromil sodium on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and on eosinophil survival induced by secretions from cultured nasal epithelial cells. Human epithelial cell-conditioned media (HECM) were generated by cultured epithelial cells obtained from healthy subjects undergoing corrective nasal surgery. Normodense eosinophils isolated from peripheral blood were incubated with HECM generated with and without the drugs. All of the drugs tested inhibited eosinophil survival, and response was dose-dependent. Fluticasone propionate had the highest inhibitory potency (25% inhibitory concentration (IC25) 1x10(-9) M), followed by budesonide (IC25 3.3x10(-8) M), beclomethasone dipropionate (IC25 1.5x10(-6) M), and nedocromil sodium IC25 5x10(-6) M). Likewise, fluticasone was the strongest steroid in inhibiting release of GM-CSF (IC25 8.4x10(-11) M), followed by budesonide (IC25 2x10(-9) M), beclomethasone dipropionate (IC25 13x10(-8) M), and nedocromil sodium (IC25 >10(-5) M). A significant correlation was found between both inhibitory effects (r=0.955; p<0.05). Topical anti-inflammatory drugs may decrease eosinophil survival by abrogating the promoting effect of epithelial cells. These drugs may exert part of their therapeutic effect by modulating GM-CSF release. The following rank of potency was observed: fluticasone propionate > budesonide > beclomethasone dipropionate > nedocromil sodium. The study of the interaction between epithelial cells and eosinophils may be a useful method for investigating and comparing the potency of topical drugs.

Effects of topical anti-inflammatory drugs on eosinophil survival primed by epithelial cells. Additive effect of glucocorticoids and nedocromil sodium.

BACKGROUND: Eosinophil infiltration is a hallmark of the inflammatory response in rhinitis and in nasal polyposis. OBJECTIVE: We studied the effect of steroids and nedocromil sodium on eosinophil survival primed by epithelial cells from healthy (nasal mucosa) and inflamed (nasal polyp) respiratory tissue. METHODS: Blood eosinophils were incubated with increasing concentrations (10(-11)-10(-5) M) of topical steroids (fluticasone propionate, budesonide, triamcinolone acetonide and beclomethasone dipropionate) and/or nedocromil sodium prior to the addition of human epithelial cell conditioned media (HECM), eosinophil viability was measured and IC50 for each drug was calculated. RESULTS: All four steroids and nedocromil sodium caused a dose-related inhibition of HECM-induced eosinophil survival. The IC50 of steroids were lower in eosinophils primed by mucosa HECM than on those primed by polyp HECM (fluticasone, 4 nM vs 114 nM; budesonide, 21 nM vs 280 nM; triamcinolone, 7 nM vs 853 nM; and beclomethasone, 171 nM vs 181 nM). The combined inhibitory effect of 10(-7) M budesonide plus 10(-5) M nedocromil (43.8 +/- 10.8%, P<0.03) was significantly higher than budesonide (28.5 +/- 9.2%) or nedocromil (16.7 +/- 5.4%) alone and close to 10(-5) M budesonide (52.3 +/- 11%). No differences were found in cytokine (IL-8, IL-6, GM-CSF, TNF alpha, IL-1beta and RANTES) concentrations between HECM from mucosa and polyps. CONCLUSION: These results suggest that topical anti-inflammatory drugs may diminish airway eosinophilic infiltration by decreasing eosinophil viability, that nasal polyp epithelial cell secretions may induce steroid resistance in eosinophils, and that nedocromil sodium has additive effects with steroids.