Effects of COVID-19 pandemic-associated reduction in respiratory infections on infantile asthma development.

Background: It is speculated that the coronavirus disease 2019 (COVID-19) pandemic-associated reduction in the prevalence of respiratory tract infections has influenced the incidence of asthma in young children. Objectives: We investigated an association between the reduction in viral infections and the reduction in asthma in young children. Methods: The subjects were infants born in the early stages of the COVID-19 pandemic in Japan, which began in February 2020. A questionnaire survey related to asthma and allergy was conducted at 18 months and 3 years of age. These results were compared to those of age-matched infants during the nonpandemic period. Results: There were no epidemics of viral infectious diseases until the target child was 18 months old. At 18 months, the incidence of asthma/asthmatic bronchitis diagnosed by physicians in pandemic children was significantly lower than that in nonpandemic children. In 3-year-olds, no marked difference was observed between nonpandemic infants and pandemic children, except for an increase in respiratory syncytial virus infection in pandemic children. In a comparative study of the same children at ages 18 months and 3 years, an increased prevalence of asthma/asthmatic bronchitis was observed in pandemic children. Furthermore, the incidence of asthma after respiratory syncytial virus infection in pandemic infants was significantly lower than that in nonpandemic children. Conclusion: The COVID-19 pandemic-associated reduction in respiratory tract infections may have reduced the incidence of asthma in early childhood, and respiratory syncytial virus infection after 18 months of age had little effect on the onset of asthma. These results indicate the importance of preventing respiratory tract infections in early infancy.

Lung sound analysis for predicting recurrent wheezing in preschool children.

Background: In young healthy children, assessing airflow limitation may be difficult because of narrowing of the airways, which is a pathology of asthma, and responsiveness to bronchodilators. Objective: We investigated whether lung sound analysis could predict the development of recurrent wheezing (RW), which is one of the signs of asthma. Methods: In healthy children aged 3 to 24 months, we recorded and analyzed lung sounds before and after inhalation of bronchodilators and conducted a questionnaire survey. The children were followed up and assessed for the development of RW at age 3 years. Results: Of the 62 patients analyzed, 19 (30.6%) developed RW. The parameters ratio of power and frequency at 50% of the highest frequency of the dB power spectrum (RPF50) and ratio of power and frequency at 75% of the highest frequency of the dB power spectrum (RPF75), calculated by lung sound analysis, were lower in the RW group, with odds ratios of 0.77 (95% CI = 0.61-0.98) and 0.81 (95% CI = 0.66-0.99), respectively. The rate of change of lung sound analysis parameters after bronchodilator inhalation did not differ among the participants as a group; however, in the subgroup of children with a history of atopic dermatitis, the fourth area under the curve (B4) divided by the total area under the curve of 100 Hz to the highest frequency of the dB power spectrum (AT) and difference between the values of the ratio of power and frequency at 50% of the highest frequency of the dB power spectrum (ΔRPF50) were elevated in the RW group (P = .015 and P = .041, respectively). In the subgroup of children with total a IgE level greater than 20 kUA/L, the sensitivities and specificities for predicting the development of RW were 85.7% (95% CI = 48.7-99.3) and 68.8% (95% CI = 44.4-85.8), respectively, when the cutoff value of ΔRPF50 was set at 10.5%. Conclusion: The method of lung sound analysis allows noninvasive assessment of the airway, including airway hypersensitivity, in young children and may predict the risk of development of RW.

Tolerability and safety of a new elimination diet for pediatric eosinophilic gastritis and duodenitis.

BACKGROUND: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the "Rainbow Elimination Diet (ED)." The aims of this study were to evaluate the tolerability and safety of this diet. METHODS: A retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2-17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated. RESULTS: Nineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14-30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median -0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9-3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium. CONCLUSIONS: The Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

Lung sound analysis in infants with risk factors for asthma development.

BACKGROUND AND OBJECTIVES: Using a lung sound analysis, the prognosis of asthma was investigated in infants with risk factors for asthma development by a long-term observation. METHODS: A total of 268 infants were included (median age: 8 months old). The lung sound parameters (the ratio of the third and fourth area to the total area under the curve [A3/AT and B4/AT], and the ratio of power and frequency at 50% and 75% of the highest frequency [RPF50 and RPF75]) were evaluated at the first visit. At 3 years old, using a questionnaire, we examined the relationship between the lung sound parameters and risk factors of asthma development. RESULTS: Among the 268 infants, 175 infants were in good health and 93 had a history of acute respiratory infection (ARI) within 7 days at the first visit. Among the 3- to 12-month-old infants with an ARI, the A3/AT, B4/AT values in those with a history of asthma/asthmatic bronchitis, atopic dermatitis, and atopy were smaller than in the infants without such histories. Among the 13- to 24-month-old infants with an ARI, the A3/AT and B4/AT values in those with a wheezing history were larger than in the infants without such a history. CONCLUSIONS: The characteristics of the lung sounds in infants with risk factors for asthma development were demonstrated over long-term follow-up. Lung sound analyses may be useful for assessing the airway condition of infants.

Comparison of Nonesophageal Eosinophilic Gastrointestinal Disorders with Eosinophilic Esophagitis: A Nationwide Survey.

BACKGROUND: Eosinophilic esophagitis (EoE) has increased rapidly and has been well characterized. However, no nationwide survey has been conducted regarding non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs), and they remain poorly understood. OBJECTIVE: To compare the clinical features and natural histories of non-EoE EGIDs and EoE by using the same questionnaire, for all ages. METHODS: We conducted a nationwide hospital-based survey of patients who visited hospitals from January 2013 through December 2017. We randomly selected 10,000 hospitals that perform endoscopy. We analyzed the demographics, symptoms, gastrointestinal histology, treatments, and natural histories of EoE and non-EoE EGIDs. RESULTS: A total of 2906 hospitals responded to the questionnaire. We identified 1542 patients and obtained detailed data for 786 patients, consisting of 39% EoE and 61% non-EoE EGIDs. The clinical characteristics were analyzed for patients who met the "definite" criteria that excluded comorbidities. Non-EoE EGIDs showed no gender difference, whereas EoE was male-predominant. Tissue eosinophilia was often seen in the small intestine (62%) and stomach (49%). The frequency of hypoproteinemia was high (27%) in childhood. Children also had more serious symptoms and complications than adults: restriction of daily life activity (P = .009), failure to grow/weight loss (P = .008), and surgery (P = .01). For both diseases, the most common natural history was the continuous type: 66% (95% confidence interval [CI]: 58-74) in EoE and 64% (95% CI: 55-72) in non-EoE EGIDs. CONCLUSIONS: The percentage of persistent patients with non-EoE EGIDs was almost the same as those with EoE. Complications were more frequent in children than in adults.

A Lung Sound Analysis in Infants with Risk Factors for Asthma During Acute Respiratory Infection.

Background: The parameters of lung sounds have been suggested as biomarkers of airway changes. Using a commercially available lung sound analyzer, we investigated the characteristics of the lung sounds in infants with acute respiratory infection (ARI). Methods: Infants with ARI who were 6 to 18 months of age were included in this study. The lung sound parameters, the ratio of the third area and fourth areas to the total area under the curve of the sound spectrum (A3/AT and B4/AT), and the ratio of power and frequency at 75% and 50% of the highest frequency of the power spectrum (RPF75 and RPF50) were evaluated. With an original Japanese questionnaire based on American Thoracic Society-Division of Lung Disease, the risk factors of asthma development in infants were examined. Results: One hundred ten infants with ARI and 248 infants in good health for comparison were included. All infants were completely analyzed, and then divided into 2 age groups for a stratification analysis (6-12 and 13-18 months). In the overall analysis, among infants with a history of wheezing, recurrent wheezing, allergy, and atopic dermatitis, the values of RPF50 of infants with ARI were significantly lower compared with those without ARI. In the 6- to 12-month-old group, the RPF50 values of atopy-positive infants with ARI were lower compared with those without ARI (P = 0.003). Conclusions: The lung sounds of the infants with asthma-developing risk factors were more affected by ARI than those of infants without risk factors. Analyzing the changes in the lung sounds induced by ARI may be useful for evaluating the characteristics of the airways in infants.

Objective evaluation of wheezing in normal infants.

BACKGROUND: To evaluate the frequency of wheezing in infants, the presence of wheezing was examined in normal infants using a breath sound analyzer, METHODS: A total of 443 infants (age range, 3-24 months) were included in the present study. The existence of audible wheezing and faint wheezing/inaudible wheezing-like noises (FW) was confirmed on chest auscultation and a sound spectrogram. The breath sound parameters of the sound spectrum, frequency limiting 99% of power spectrum (F99 ), roll-off from 600 to 1,200 Hz (slope) and spectrum curve indices, total area under the curve of dB data (A3 /AT and B4 /AT ), and ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF50 and RPF75 ) were calculated. Using an original Japanese questionnaire, we examined the characteristics of the airway condition of all infants. RESULTS: Finally, a total of 398 infants were analyzed in the present study, and 283 were in good health while 115 had acute respiratory infection (ARI) in the last 7 days. No infants had audible wheezing on auscultation. Three infants without ARI (1.1%) and 10 infants with ARI (8.7%) had FW. In the evaluation of breath sound parameters, there were no marked differences between the infants with and without FW. CONCLUSIONS: Using a breath sound analyzer, wheezing and FW were recognized in only a few infants in good health. Infants recognized to have audible wheezing in daily practice may be at risk of developing recurrent wheezing/asthma.

A breath sound analysis in children with cough variant asthma.

BACKGROUND: Cough variant asthma (CVA) is characterized by a chronic cough and bronchial hyperresponsiveness without confirmation of wheezing. Using a breath sound analyzer, we evaluate the characteristics of breath sound in children with CVA. METHODS: Nine children with CVA (median age, 7.0 years) participated. The existence of breath sounds was confirmed by sound spectrogram. Breath sound parameters, the frequency limiting 50% and 99% of the power spectrum (F50 and F99), the roll-off from 600 to 1200 Hz (Slope) and spectrum curve indices, the ratio of the third and fourth area to the total area of the power spectrum (P3/PT and P4/PT) and the ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF75 and RPF50) were calculated before and after ß2 agonist inhalation. A spirogram and/or forced oscillation technique were performed in all subjects. RESULTS: On a sound spectrogram, wheezing was confirmed in seven of nine patients. All wheezing on the image was polyphonic, and they almost disappeared after ß2 agonist inhalation. An analysis of the breath sound spectrum showed that PT, P3/PT, P4/PT, RPF50 and RPF75 were significantly increased after ß2 agonist inhalation. CONCLUSIONS: Children with CVA showed a high rate of inaudible wheezing that disappeared after ß2 agonist inhalation. Changes in the spectrum curve indices also indicated the bronchial reversibility. These results may suggest the characteristics of CVA in children.

Characteristics of breath sound in infants with risk factors for asthma development.

BACKGROUND: Breath sound parameters have been suggested as biomarkers of the airway narrowing in children. Using a commercially available breath sound analyzer, the characteristics of the airway condition were investigated in infants with the risk factors for asthma development. METHODS: A total of 443 infants (mean age, 9.9 months; range, 3-24 months) were included in the present study. The breath sound parameters of the frequency limiting 99% of the power spectrum (F99), the roll-off from 600 to 1200 Hz (Slope) and spectrum curve indices, the total area under the curve of the dBm data (A3/AT) and the ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF75 and RPF50), were evaluated. Using an ATS-DLD based original Japanese questionnaire, we examined the characteristics of airway condition of infants. RESULTS: Finally, 283 infants in good health were included in the present study. The RPF75, RPF50, Slope and F99 in infants with positive results of allergy and atopic dermatitis were significantly increased more than those in the infants with negative result. CONCLUSIONS: Our data highlight the characteristics of breath sounds in infants with risk factors for asthma. The breath sound analysis may be useful for assessing the airways of infants for asthma development.

Glucocorticoids inhibit MUC5AC production induced by transforming growth factor-α in human respiratory cells.

BACKGROUND: Mucus hypersecretion from airway epithelium is a characteristic feature of severe asthma. Glucocorticoids (GCs) may suppress mucus production and diminish the harmful airway obstruction. We investigated the ability of GCs to suppress mRNA expression and protein synthesis of a gene encoding mucin, MUC5AC, induced by transforming growth factor (TGF)-α in human mucoepidermoid carcinoma (NCI-H292) cells and the molecular mechanisms underlying the suppression. METHODS: We determined if GCs such as dexamethasone (DEX), budesonide (BUD), and fluticasone (FP) could suppress MUC5AC production induced by a combination of TGF-α and double-strand RNA, polyinosinic-polycytidylic acid (polyI:C). MUC5AC mRNA expression and MUC5AC protein production were evaluated. The signaling pathways activated by TGF-α and their inhibition by GCs were tested using a phosphoprotein assay and MUC5AC promoter assay. RESULTS: DEX significantly suppressed the expression of MUC5AC mRNA and MUC5AC protein induced by TGF-α. The activation of the MUC5AC promoter by TGF-α was significantly inhibited by DEX. DEX did not affect activation of downstream pathways of the EGF receptor or mRNA stability of MUC5AC transcripts. DEX, BUD, and FP suppressed MUC5AC protein expression induced by a combination of TGF-α and polyI:C in a dose-dependent manner. CONCLUSIONS: GCs inhibited MUC5AC production induced by TGF-α alone or a combination of TGF-α and polyI:C; the repression may be mediated at the transcriptional but not post-transcriptional level.

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis.

Systemic-onset juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly understood. To detect disease-related copy number variations (CNVs), we performed single-nucleotide polymorphism array analysis in 50 patients with s-JIA. We detected many CNVs, but most of them were inherited from either of normal-phenotype parents. However, in one patient, we could identify two de novo microduplications at 19q13.42 with the size of 77 and 622 kb, separated by a 109-kb segment of normal copy number. The duplications encompass NLRP family (NLRP2, NLRP9 and NLRP11) as well as IL11 and HSPBP1, all of which have an important role in inflammatory pathways. These genes may significantly contribute to the pathogenesis of s-JIA.

Changes in the highest frequency of breath sounds without wheezing during methacholine inhalation challenge in children.

BACKGROUND AND OBJECTIVE: It is difficult for clinicians to identify changes in breath sounds caused by bronchoconstriction when wheezing is not audible. A breath sound analyser can identify changes in the frequency of breath sounds caused by bronchoconstriction. The present study aimed to identify the changes in the frequency of breath sounds during bronchoconstriction and bronchodilatation using a breath sound analyser. METHODS: Thirty-six children (8.2 +/- 3.7 years; males : females, 22 : 14) underwent spirometry, methacholine inhalation challenge and breath sound analysis. Methacholine inhalation challenge was performed and baseline respiratory resistance, minimum dose of methacholine (bronchial sensitivity) and speed of bronchoconstriction in response to methacholine (Sm: bronchial reactivity) were calculated. The highest frequency of inspiratory breath sounds (HFI), the highest frequency of expiratory breath sounds (HFE) and the percentage change in HFI and HFE were determined. The HFI and HFE were compared before methacholine inhalation (pre-HFI and pre-HFE), when respiratory resistance reached double the baseline value (max HFI and max HFE), and after bronchodilator inhalation (post-HFI and post-HFE). RESULTS: Breath sounds increased during methacholine-induced bronchoconstriction. Max HFI was significantly greater than pre-HFI (P < 0.001), and decreased to the basal level after bronchodilator inhalation. Post-HFI was significantly lower than max HFI (P < 0.001). HFI and HFE were also significantly changed (P < 0.001). The percentage change in HFI showed a significant correlation with the speed of bronchoconstriction in response to methacholine (P = 0.007). CONCLUSIONS: Methacholine-induced bronchoconstriction significantly increased HFI, and the increase in HFI was correlated with bronchial reactivity.

Effect of bronchoconstriction on exhaled nitric oxide levels in healthy and asthmatic children.

BACKGROUND: Exhaled nitric oxide (eNO) has recently been proposed to be a noninvasive marker of airway inflammation in asthma. OBJECTIVE: To evaluate the effect of bronchoconstriction by means of methacholine inhalation challenge on levels of eNO in children. METHODS: Spirometry, impulse oscillometry, and eNO measurements were performed before and after methacholine inhalation challenge (bronchoconstriction phase) and after beta2-agonist inhalation (bronchodilation phase) in 92 children (62 children with asthma, 13 wheezy children, and 17 healthy children). RESULTS: A significant decrease occurred in the eNO level after methacholine inhalation challenge (P < .01). This decrease did not correlate with the percentage decrease in forced expiratory volume in 1 second or with the change in large airway resistance (R20), but it did correlate with the percentage decline in maximal expiratory flow at 50% vital capacity and with the change in small airway resistance (R5-R20). The eNO decrease lasted for 15 minutes after beta2-agonist inhalation in the group with a high percentage decrease in R5-R20 (>200%). On the other hand, in the group with a low percentage decrease in R5-R20 (< or =200%), eNO recovered to the previous level immediately after beta2-agonist inhalation. CONCLUSIONS: The eNO level significantly decreases after methacholine inhalation challenge. This decrease primarily depends on bronchoconstriction of the small airways.

Effects of skin care with shower therapy on children with atopic dermatitis in elementary schools.

For elementary school children with atopic dermatitis, a skin care program using shower therapy was performed during the school lunch break for 6 weeks from June to July in 2004 and 2005. All 53 participants showed an improvement in their atopic dermatitis during the 6-week periods studied. Skin care with daily showering at an elementary school was thus found to be effective for the treatment of atopic dermatitis.

Association of cord blood cytokine levels with wheezy infants in the first year of life.

As antenatal environment may influence the development of atopy-predisposing immune response, cord blood cytokine productions may be an important predictor for wheezing. We investigated cord blood cytokines in a prospective birth cohort, intensively monitored for wheezy infant outcome at 1 yr. Cord blood serum samples from 269 children were assayed for interleukin (IL)-1beta, -2, -4 to -8, -10, -12 (p70), -13, and -17, interferon-gamma, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), monocyte chemotactic protein-1, and macrophage inflammatory protein-1beta. Associations between family histories, antenatal and perinatal factors, cord blood cytokine concentrations, and wheezy infant outcomes (wheezing more than two times) were analyzed. In cord blood sera from 269 children, there were associations between high levels of IL-6, -8 and G-CSF concentrations, and cesarean section. Data at 1 yr were obtained from 213 infants, including 33 wheezy infants. Risk of wheezing was related to gestational age, birth weight, cesarean section, and maternal eczema, but not to bacterial/viral infection during pregnancy, maternal asthma, maternal smoking, or paternal history. High level of cord blood IL-8 concentration had a significant association with wheezy infant outcomes at 1 yr (p = 0.025). By using multivariate logistic regression analysis, birth weight [odds ratio(OR) = 0.998, 95% confidence interval (CI) = 0.997-1.000] and maternal eczema (OR = 5.356, 95% CI = 1.340-21.41), but no other factors, were significant predictors of wheezy infants. Birth weight, gestational age, and maternal history were important risk factors for wheezing in the first year of life. Several cord blood cytokine productions were influenced by cesarean section, and IL-8 may be a predictor for recurrent wheezing at 1 yr.

Double-stranded RNA and TGF-alpha promote MUC5AC induction in respiratory cells.

Viral infection is a major trigger for exacerbation of asthma and induces overproduction of mucins. We investigated whether dsRNA could amplify the induction of mucin by TGF-alpha in human bronchial epithelial cells, as well as the molecular mechanisms regulating MUC5AC expression. Human pulmonary mucoepidermoid carcinoma (NCI-H292) cells and normal human bronchial epithelial cells were exposed to polyinosinic-cytidyric acid (poly(I:C)) and TGF-alpha. Then, MUC5AC protein production, mRNA expression, and promoter activity were evaluated. Cells were pretreated with a selective inhibitor of ERK, and phosphorylation of ERK was examined by Western blotting. Furthermore, the expression of MAPK phosphatase 3 (MKP3) mRNA was evaluated and the effect of MKP3 overexpression was assessed. Poly(I:C) synergistically increased MUC5AC induction by TGF-alpha in both NCI-H292 and normal human bronchial epithelial cells. This increase was dependent on MUC5AC gene transcription. A MEK1/2 inhibitor (U0126) significantly inhibited MUC5AC production. Phosphorylation of ERK was enhanced by poly(I:C). TGF-alpha stimulation up-regulated MKP3 mRNA expression, while costimulation with poly(I:C) inhibited this up-regulation dose-dependently. Enhanced expression of MUC5AC mRNA by poly(I:C) in wild-type cells was completely suppressed in cells transfected with the MKP3 expression vector. dsRNA can synergistically amplify the induction of MUC5AC mucin by TGF-alpha. This synergistic effect on MUC5AC production may be due to enhanced activation of ERK through inhibition of MKP3 by poly(I:C).

A flow- and pressure-controlled offline method of exhaled nitric oxide measurement in children.

BACKGROUND: Exhaled nitric oxide (eNO) is a noninvasive marker of airway inflammation. However, previous studies show that the offline value is lower than the online value. OBJECTIVE: To compare a standard offline eNO measurement apparatus with a modified apparatus that can monitor flow volume and respiratory pressure. METHODS: We studied 73 cooperative individuals aged 5 to 28 years (32 children: mean age, 8.3 years; 41 adults: mean age, 21.5 years). We modified the standard device by including a flow meter with a manometer and attaching a plastic tube connected to a 3-way valve to control the resistance. The online and offline (measured using the modified device and the standard device) eNO determinations were compared in a single session and were analyzed using a nitric oxide analyzer. RESULTS: There was a good relationship between the online and modified offline eNO measurements in children. The modified offline method showed a stronger correlation with the online method (r = .97 vs. r = .92), and the modified offline eNO value was more similar to the online eNO value than to the standard offline value. The mean difference between the online and standard offline eNO values was 52%, whereas the mean difference between the online and modified offline eNO values was only 10%. CONCLUSIONS: Using the offline method, we can easily control the resistance and flow volume to reach the same value measured by the online method in childhood respiratory diseases.

Differential regulation of eotaxin expression by dexamethasone in normal human lung fibroblasts.

Lung fibroblasts are a major source of several cytokines including CC chemokine eotaxin. We aimed to study the regulation of eotaxin-1/CCL11 production by dexamethasone and analyze its molecular mechanisms in human lung fibroblasts. Normal human lung fibroblast cells were exposed to IL-4 (40 ng/ml) and/or dexamethasone (10(-6)-10(-9) M), and eotaxin mRNA expression and production was evaluated. Mechanisms of transcriptional regulation were assessed by Western blotting and dual luciferase assay for eotaxin promoter. The effects of dexamethasone on suppressor of cytokine signaling (SOCS)-1 and eotaxin mRNA expression in the cells transfected with expression vector (pAcGFP1-C1) or short interfering RNA (siRNA) for SOCS-1 were also investigated. Within 24 hours, dexamethasone inhibited IL-4-induced eotaxin mRNA expression and protein production, while eotaxin production was markedly increased at 48 and 72 hours after coincubation with IL-4 and dexamethasone. IL-4-induced eotaxin promoter activity was inhibited by dexamethasone at 8 hours, but enhanced at 48 hours after coincubation. Dexamethasone suppressed SOCS-1 mRNA expression but enhanced IL-4-induced STAT6 phosphorylation at 36 to 48 hours after coincubation. Enhanced expression of eotaxin mRNA by dexamethasone 48 hours after coincubation was completely diminished in the cells transfected with either expression vector or siRNA for SOCS-1. These results indicated that dexamethasone, depending on the exposure duration, can either inhibit or enhance IL-4-induced expression and production of eotaxin in the lung fibroblasts. The mechanisms of later enhanced production may depend on the prolonged transcriptional activity of the eotaxin gene, in part due to inhibition of SOCS-1 expression.