Objective alertness, rather than sleep duration, is associated with burnout and depression: A national survey of Japanese physicians.

Approximately 40% of Japanese physicians report working more than 960 hr of overtime annually, with 10% exceeding 1860 hr. To protect their health, annual overtime limits went into effect in 2024. The objective of this study was to investigate associations of self-reported sleep duration with psychological health and objective alertness. This was a cross-sectional National Survey for The Work Style Reform of Long Working Physicians. Physicians self-reported daily sleep duration, burnout (Abbreviated Maslach Burnout Inventory), depression (Center for Epidemiologic Studies Depression Scale) and traffic accidents. Alertness was then evaluated using the brief Psychomotor Vigilance Test. Of 20,382 physicians invited, 1226 completed the survey and brief Psychomotor Vigilance Test. Daily sleep duration was inversely associated with weekly work hours (ß = -5.4; 95% confidence interval -6.8 to -4.0, p < 0.0001). Sleep duration < 6 hr and ≥ 8 hr per day was associated with slower responses on the brief Psychomotor Vigilance Test (adjusted p < 0.05). An additional 10 hr worked per week was associated with a 0.40 point (95% confidence interval 0.08-0.72) increase in burnout severity and a 1.7% (95% confidence interval 0.1-3.3%) increase in odds of reporting a traffic accident. Increased brief Psychomotor Vigilance Test lapses, indicating lower alertness, were associated with worse symptoms of depression (ß = 0.23 points; 95% confidence interval 0.14-0.31, p < 0.0001) and burnout (ß = 0.25 points; 95% confidence interval 0.13-0.36, p < 0.0001). This study emphasizes the importance of sufficient sleep to maintain alertness, and supports limiting work hours for Japanese physicians to protect psychological health. Performance on the brief Psychomotor Vigilance Test may be a useful indicator of psychological health.

Working hours of full-time hospital physicians in Japan: a cross-sectional nationwide survey.

BACKGROUND: The culture of excessively long overtime work in Japan has not been recently addressed. New legislation on working hours, including a limitation on maximum overtime work for physicians, will be enforced in 2024. This study was performed to elucidate the working conditions of full-time hospital physicians and discuss various policy implications. METHODS: A facility survey and a physician survey regarding physicians' working conditions were conducted in July 2022. The facility survey was sent to all hospitals in Japan, and the physician survey was sent to all physicians working at half of the hospitals. The physicians were asked to report their working hours from 11 to 17 July 2022. In addition to descriptive statistics, a multivariate logistic regression analysis on the factors that lead to long working hours was conducted. RESULTS: In total, 11,466 full-time hospital physicians were included in the analysis. Full-time hospital physicians worked 50.1 h per week. They spent 45.6 h (90.9%) at the main hospital and 4.6 h (9.1%) performing side work. They spent 43.8 h (87.5%) on clinical work and 6.3 h (12.5%) on activities outside clinical work, such as research, teaching, and other activities. Neurosurgeons worked the longest hours, followed by surgeons and emergency medicine physicians. In total, 20.4% of physicians were estimated to exceed the annual overtime limit of 960 h, and 3.9% were estimated to exceed the limit of 1860 h. A total of 13.3% and 2.0% exceeded this level only at their primary hospital, after excluding hours performing side work. Logistic regression analysis showed that male, younger age, working at a university hospital, working in clinical areas of practice with long working hours, and undergoing specialty training were associated with long working hours after controlling for other factors. CONCLUSIONS: With the approaching application of overtime regulations to physicians, a certain reduction in working hours has been observed. However, many physicians still work longer hours than the designated upper limit of overtime. Work reform must be further promoted by streamlining work and task-shifting while securing the functions of university hospitals such as research, education, and supporting healthcare in communities.

Snoring, obstructive sleep apnea, and upper respiratory tract infection in elementary school children in Japan.

PURPOSE: Both obstructive sleep apnea (OSA) and the common cold are disorders of the upper respiratory tract, and may be associated. However, studies on the association between OSA and upper respiratory tract infections (URTI) in children are scarce. The aim of this study was to investigate possible associations between snoring, the severity of OSA, and URTI in elementary school children. METHODS: This was a cross-sectional study in a community cohort of elementary school children (first and second graders) in Japan. Information on sleep habits, history of URTI, and OSA risk was obtained from a parental questionnaire. Children underwent overnight tracheal sound recordings from which apnea-hypopnea index was estimated. Multivariable logistic analysis was employed to define the association between snoring, OSA, and URTI ≥ 3 episodes over six months. RESULTS: Of the 922 potential enrollees, 653 children and their parents (71%) agreed to participate in the study. Multivariable-adjusted ORs for URTI were 1.73 (95%CI: 1.16 to 2.59) in children who snored 1 to 4 nights per week and 2.82 (95%CI: 1.26 to 6.28) in snoring ≥ 5 nights per week compared with never snoring (reference). Likewise, subjectively reported louder snoring, as well as objectively defined louder sound levels, were significantly associated with URTI. In addition, OR for URTI in children with an estimated apnea-hypopnea index ≥ 2.0 events/hour was 2.65 (95%CI: 1.32 to 5.31) compared to children with apnea-hypopnea index less than 1.0 events/hour (reference). CONCLUSIONS: Snoring and severity of OSA as measured by nocturnal tracheal sound recordings were associated with increased susceptibility to URTI in elementary school children.

Impaired psychomotor vigilance associated with sleep-disordered breathing in women working in the care of older adults in Japan.

PURPOSE: With a rapidly aging society, there is increasing interest in the health of female workers in the field of care services for older adults due to increasing demands to maintain 24-h care and to support older adults without errors or accidents. Therefore, the purpose of this cross-sectional study was to examine the association between sleep-disordered breathing (SDB) and sustained attention in women caring for older adults in Japan. METHODS: The study was conducted in women aged 18-67 years old working in care service facilities for older adults in Japan. The sustained attention of participants was measured by the 10-min psychomotor vigilance task (PVT). SDB was assessed based on the respiratory disturbance index (RDI), which was measured using an ambulatory airflow monitor with a polyvinylidene fluoride (PVDF) film sensor to monitor the respiratory airflow of nasal and oral breathing. The participants wore the monitor to record the breathing status while asleep at home. The severity of SDB was categorized as follows: normal, RDI < 5 events/h; mild SDB, RDI 5-10 events/h; and moderate-to-severe SDB, RDI ≥ 10 events/h. RESULTS: Of 688 women enrolled, medians of age, body mass index (BMI), sleep duration, and prevalence of hypertension tended to be higher with increasing RDI. No significant association was found between RDI and PVT parameters. However, when we limited the analysis to women with BMI ≥ 22 kg/m2, those with moderate-to-severe SDB had significantly higher odds of having the slowest 10% reaction times compared to those without SDB (OR = 2.03; 95% CI = 1.17-3.53). The association did not decrease after adjusting to account for sleep duration, alcohol drinking habits, and history of hypertension (OR = 1.97; 95% CI = 1.10-3.52). A significant increasing trend was also found between RDI and the slowest 10% of reaction times (p for trend = 0.03). CONCLUSIONS: Our findings suggest that SDB is associated with reduced sustained attention in participants with BMI ≥ 22 kg/m2, although the number of assessments of SDB and PVT was only once per participant due to the nature of the cross-sectional study.

Phenyl-bonded monolithic silica capillary column liquid chromatographic separation and detection of fluorogenic derivatized intact proteins.

Prior to the identification of proteins for proteomics analysis in human cells, separation of fluorogenic derivatized proteins with a fluorogenic reagent, 7-chloro-N-[2-(dimethylamino)ethyl]-2,1,3-benzoxadiazole-4-sulfonamide, has typically been performed by using a conventional reversed-phase HPLC column. However, the number of proteins in human cells (HepaRG) that are separated by this conventional approach is limited to approximately 500. In this study, a nanoflow liquid chromatography system with an evaluated phenyl-bonded monolithic silica capillary column (0.1 mm i.d., 700 mm length) was used to increase the number of separated fluorogenic derivatized proteins. This system was used to separate derivatized human cell proteins (K562) and yeast (Saccharomyces cerevisiae) proteins as model cell proteomes. More than 1,300 protein peaks were separated/detected from both cell proteomes. We present a straightforward comparison of multiple separation profiles using a novel chromatogram display approach, termed the "spiderweb" chromatogram. In addition, to validate that the detected peaks are derived from proteins, a mass spectrometer was connected to the capillary column and deconvolution of the obtained mass spectra was performed. Furthermore, different molecular weight distribution profiles of the expressed proteins were observed between the two cell proteomes.

Association of employment and company size with lung cancer screening participation among Japanese based on the socioeconomic conditions using the Comprehensive Survey of Living Conditions.

BACKGROUND: The proportion of non-regularly employed persons has increased in Japan, but few studies have examined the relationship between employment status and lung cancer screening (LCS) participation. METHODS: Authors analyzed data from the 2010 Comprehensive Survey of Living Conditions in Japan. The anonymous responses of 28,951 people aged 40-69 years old were analyzed. Authors defined nine employment status categories: unemployed, regularly employed in a large-, middle-, and small-scale company, non-regularly employed in a large-, middle-, and small-scale company, self-employed, and other. LCS participation in the past year was surveyed through a self-reported questionnaire. Sex-specific prevalence ratios (PRs) and 95% confidence intervals (CIs) for LCS participation for all employment status categories, using the regularly employed in a middle-scale company category as the reference, were calculated using multivariable Poisson regression analysis, after adjusting for potentially confounding factors. RESULTS: Multivariable-adjusted PRs (95% CI) for LCS participation for the regularly employed in a large-scale company were 1.33 (1.25-1.41) in men and 1.53 (1.38-1.71) in women. Multivariable-adjusted PRs (95% CI) for LCS participation for the non-regularly employed in a middle- and small-scale company compared with the regularly employed in a middle-scale company were 0.81 (0.72-0.92) and 0.62 (0.50-0.76) in men, and 0.89 (0.80-0.99) and 0.80 (0.71-0.91) in women, respectively. CONCLUSION: Regularly employed in a large-scale company had significantly higher LCS participation, and non-regularly employed in a middle- or small-scale company showed significantly lower LCS participation than those who were regularly employed in a middle-scale company.

Association between marital status and insomnia-related symptoms: findings from a population-based survey in Japan.

BACKGROUND: Marital status is one of the socio-economic factors associated with health. Several studies have indicated a significant association between marital status and insomnia. The increases in the percentages of unmarried people in Japan are expected to produce a significant impact on insomnia. The purpose of this study was to examine the association between marital status and insomnia. METHODS: The participants were 35 288 people aged 30-59 years selected from the 2010 comprehensive survey of living conditions. We categorized marital status into five groups: single, married couples living with other family members, married couples living without other family members, widowed and divorced. Insomnia-related symptoms (IRS) were based on the participants who chose the answer, 'I couldn't sleep'. Sex-specific multivariable odds ratios (ORs) and 95% confidence intervals (CI) of IRS according to marital status were calculated using the logistic regression model, which was adjusted for potential confounding factors. RESULTS: The proportions of people with IRS were 2.5% in men and 2.8% in women. The multivariable ORs (95% CI) were 1.15 (0.89-1.49) for single, 1.69 (1.11-2.58) for divorced and 1.01 (0.73-1.39) for married couples living without other family members in men, and 1.56 (1.20-2.03) for single, 2.43 (1.83-3.22) for divorced and 1.31 (1.01-1.71) for married couples living without other family members in women. CONCLUSIONS: We found divorced men and single, divorced and married women living without other family members had higher IRS than those who were married couples living with other family members in Japanese. This association was more evident in unemployed men.

The association between obesity and hyperactivity/anxiety among elementary school students in Japan.

BACKGROUND: We aimed to evaluate the association between hyperactivity/anxiety and obesity among elementary school students in Matsuyama City, Japan. METHODS: We conducted a cross-sectional study of all 46 elementary school students (24, 296 students) in Matsuyama City. The questionnaire included question items from the Strengths and Difficulties Questionnaire (SDQ), as well as questions about height and weight. The students were classified into two groups according to Rohrer index. After separating the data by gender, we examined the association between (1) obesity and hyperactivity, (2) obesity and anxiety, and (3) obesity and combination of hyperactivity and anxiety, by estimating relative risk using Poisson regression model. We also conducted stratified analyses to examine the effect modification by age groups and unbalance of diet on those associations. Moreover, we calculated relative excess risk due to the interaction (RERI) to examine whether there was an additive interaction between hyperactivity and anxiety. RESULTS: Sixteen thousand forty-eight students were included in the present analysis. The prevalence ratio (PR) of being obese in girls who had both hyperactivity and anxiety was higher compared to girls without those symptoms (PR = 1.80; 95% CI 1.04-3.13). There was no significant difference in the prevalence ratio for obesity in boys, whether they were hyperactive, anxious, or neither. RERI was 0.00 for boys and 0.18 for girls. CONCLUSION: We found a significant association between obesity and co-existence of hyperactivity and anxiety among elementary school girls. Our findings strengthen the need to further explore the association between childhood obesity, hyperactivity, and anxiety.

Correction to: The Association Between Obesity and Hyperactivity/Anxiety Among Elementary School Students in Japan.

The original article has been corrected.

Association Between Employment Status and Short Sleep Duration Among Middle-Aged Japanese: the Survey on Time Use and Leisure Activities.

BACKGROUND: Short sleep duration (SSD) is reported to be highly associated with socio-economic status. There are few studies on the relationship between employment status and SSD in Japan. METHOD: The authors used the 2006 Survey on Time Use and Leisure Activities conducted by the Ministry of Internal Affairs and Communications Japan, which provides representative samples of Japanese people. The anonymous data of 120,783 people aged 30-59 years were analyzed. Authors defined five categories of employment status: "unemployed," "regularly employed," "non-regularly employed," "self-employed," and "other." Authors also defined a sleep duration shorter than 5 h per night as SSD. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of SSD using regular employment as the reference group were calculated using the logistic regression model, adjusting for potential confounding factors, i.e., age, marital status, education level, communication device use, and the amount of time spent on various daily activities. RESULTS: The prevalence of SSD was 2.8% (1639/58,308) in men and 3.2% (1976/62,475) in women. The multivariable-adjusted OR (95% CI) of SSD for the self-employed was 0.78 (0.65-0.92) in men and 1.78 (1.43-2.21) in women after adjustment for potential confounding factors, i.e., age, marital status, education level, and communication device use. Further adjustment for the time spent on daily activities revealed that the OR (95% CI) of SSD for the self-employed was 0.78 (0.65-0.92) in men and 1.89 (1.52-2.36) in women. CONCLUSION: Self-employed women had a higher prevalence of SSD. By contrast, self-employed men had a lower prevalence of SSD.

Changes in bone metabolism after gastric cancer surgery in male patients: a prospective observational study.

BACKGROUND: Several retrospective studies have shown that bone disorders occur after gastric cancer surgery. This study was designed to prospectively evaluate the changes in bone metabolism after gastrectomy for gastric cancer. METHODS: We prospectively enrolled 39 men with early gastric cancer who underwent gastrectomy. We excluded women to avoid the effects of menopause. We employed dual energy X-ray absorptiometry (DEXA) to measure bone mineral density (BMD) of the lumbar spine. DEXA was performed before and 1 and 2 years after surgery. The serum levels of alkaline phosphatase (ALP), 1,25-dihydroxy vitamin D [1,25(OH)2VD], 25-hydroxy vitamin D [25(OH)VD], and estradiol were measured before surgery and every 3 months until 2 years after surgery. RESULTS: DEXA revealed that BMD significantly decreased by 0.036 ± 0.033 g/cm2 12 months after gastrectomy (P < 0.001) and by 0.046 ± 0.040 g/cm2 24 months after gastrectomy (P < 0.001). The serum ALP level significantly increased by 38.31 ± 103.8 IU/L 24 months after surgery (P = 0.013). The serum 25(OH)VD level significantly decreased by 4.88 ± 6.42 ng/ml 24 months after surgery (P < 0.001), whereas the serum 1,25(OH)2VD levels were consistently in the normal range. The serum estradiol level significantly increased by 2.94 ± 7.49 pg/ml 12 months after gastrectomy (P = 0.035). A lower preoperative body mass index (BMI) significantly correlated with the reduction in BMD 12 months after surgery; the correlation coefficient was 0.37 (P = 0.025). CONCLUSIONS: This study showed that a significant decrease in BMD was observed for up to 24 months after gastrectomy, not only 12 months.

Pseudomonas aeruginosa-derived flagellin stimulates IL-6 and IL-8 production in human bronchial epithelial cells: A potential mechanism for progression and exacerbation of COPD.

Background and purpose of the study:Pseudomonas aeruginosa commonly colonizes the airway of patients with chronic obstructive pulmonary disease (COPD) and exacerbates their symptoms. P. aeruginosa carries flagellin that stimulates toll-like receptor (TLR)-5; however, the role of flagellin in the pathogenesis of COPD remains unclear. The aim of the study was to evaluate the mechanisms of the flagellin-induced innate immune response in bronchial epithelial cells, and to assess the effects of anti-inflammatory agents for treatment. Materials and methods: We stimulated BEAS-2B cells with P. aeruginosa-derived flagellin, and assessed mRNA expression and protein secretion of interleukin (IL)-6 and IL-8. We also used mitogen-activated protein kinases (MAPK) inhibitors to assess the signaling pathways involved in flagellin stimulation, and investigated the effect of clinically available anti-inflammatory agents against flagellin-induced inflammation. Results: Flagellin promoted protein and mRNA expression of IL-6 and IL-8 in BEAS-2B cells and induced phosphorylation of p38, ERK, and JNK; p38 phosphorylation-induced IL-6 production, while IL-8 production resulted from p38 and ERK phosphorylation. Fluticasone propionate (FP) and dexamethasone (DEX) suppressed IL-6 and IL-8 production in BEAS-2B cells, but clarithromycin (CAM) failed to do so. Conclusions:P. aeruginosa-derived flagellin-induced IL-6 and IL-8 production in bronchial epithelial cells, which partially explains the mechanisms of progression and exacerbation of COPD. Corticosteroids are the most effective treatment for the suppression of flagellin-induced IL-6 and IL-8 production in the bronchial epithelial cells.

The association of coffee consumption and oxygen desaturation index during sleep among Japanese male workers.

BACKGROUND AND OBJECTIVE: Coffee is a major caffeine-containing food source that can be used for treatment of apnea in prematurity. However, few studies have examined the association between coffee consumption and sleep-disordered breathing (SDB). We investigated whether coffee consumption is associated with the oxygen desaturation index (ODI) as a marker of SDB among middle-aged Japanese male workers. METHODS: The subjects were 1126 male local government workers aged 22-59 who participated in SDB screening in 2011-2012. Daily coffee consumption was assessed by a self-administered questionnaire. We measured 3% oxygen desaturation (3%ODI) during a night's sleep using a pulse oximeter. A general linear model was used to calculate the multivariate-adjusted means of 3%ODI per quartile of coffee consumption. We further analyzed the data after stratifying by overweight and current smoking status. RESULTS: A inverse association between coffee consumption and 3%ODI was found. The multivariate-adjusted mean of 3%ODI for the lowest and highest coffee consumption groups were 11.9 times/h and 10.6 times/h (p for trend = 0.06), respectively; 14.6 and 11.5 times/h (p for trend = 0.01) in overweight participants; and 12.7 and 11.0 times/h (p for trend = 0.06) in non-smokers. No associations were found in non-overweight and smoking workers. CONCLUSIONS: Our results suggest that higher coffee consumption was associated with lower 3% ODI as a marker of SDB in overweight and non-smoking workers.

Recurrent sick leave and resignation rates among female cancer survivors after return to work: the Japan sickness absence and return to work (J-SAR) study.

BACKGROUND: To date, there have not been any workforce-based Japanese cohort studies investigating work sustainability after return to work (RTW). The objective of this study was to investigate the post-RTW cumulative recurrent sick leave rate and cumulative resignation rate among female cancer survivors. METHODS: Among Japanese employees who were registered in the Japan sickness absence and return to work (J-SAR) study, the subjects were those female employees who returned to work after sick leave due to newly clinically diagnosed cancer (C01-C99; ICD-10), based on a physician's certificate, between 2000 and 2011. The last day of the follow-up period was December 31, 2012. The recurrent sickness leave rate and resignation rate were calculated using competing risk survival analysis. RESULTS: Of 223 cancer survivors, 61 took further physician-certified sick leave after their RTW. The median duration of the post-RTW work period among all cancer survivors was 10.6 years. The work continuance rates of the female cancer survivors were 83.2 and 60.4% at 1 and 5 years after they returned to work, respectively. There was a steep reduction in the work continuance rate during the first post-RTW year. There were considerable differences in the work continuance rate according to the primary cancer site. Cumulative recurrent sick leave rates of 11.8 and 28.9% were seen at 1 and 5 years after the subjects returned to work. The cumulative resignation rate was 5.0 and 10.7% at 1 and 5 years after the subjects returned to work. Most recurrent sick leave occurred in the first year after the subjects returned to work, followed by the second year. CONCLUSIONS: Sixty percent of female cancer survivors were still working at 5 years after returning to work, although the work continuance rates for different types of cancer varied significantly.

Prevalence of sleep-disordered breathing among women working in the aged care services in Japan.

OBJECTIVES: The aim of this study was to examine the prevalence of sleep-disordered breathing (SDB) in women working in the field of aged care in Japan. METHODS: A cross-sectional study was conducted for female employees aged 18-60 years in aged care facilities in Japan. The analyzed set consisted of 712 participants with complete data. SDB was determined by respiratory disturbance index (RDI), measured using an ambulatory airflow monitor with a polyvinylidene fluoride film sensor to detect nasal and oral airflow overnight at home. Based on the findings of previous studies, RDI 10 was considered equivalent to apnea-hypopnea index (AHI) 15. RESULTS: The prevalence of moderate-to-severe SDB (RDI ≥ 10) was 22.8%. The mean age was 38.1 years, and mean sleeping time of participants was 6.1 h. The median body mass index (BMI) was 22.0. Women with moderate-to-severe SDB (RDI ≥ 10) had a higher age, neck circumference, neck-height ratio, BMI, systolic blood pressure, and increased prevalence of hypertension, short sleepers (amount of sleep on the SDB testing day < 6 h), and habitual snorers, compared to women with no or mild SDB (RDI < 10). CONCLUSIONS: Our study found that women working in the aged care services in Japan were heavily burdened by SDB even though they were relatively young and slim. To prevent CVD from developing in the future, programs through which workplaces can help their employees improve their lifestyle, and early diagnosis and treatment of SDB are highly recommended.

Bronchial epithelial cells produce CXCL1 in response to LPS and TNFα: A potential role in the pathogenesis of COPD.

RATIONALE: Neutrophilic airway inflammation plays a central role in chronic obstructive pulmonary disease (COPD). CXC chemokine ligand (CXCL)1 is a neutrophil chemokine involved in the pathogenesis of COPD. However, its clinical significance in COPD patients is poorly understood. AIM OF THE STUDY: To assess the production of CXCL1 by bronchial epithelial cells in response to lipopolysaccharide (LPS) and tumor necrosis factor (TNF)α. MATERIALS AND METHODS: We measured sputum CXCL1 and CXCL8 levels in patients with COPD, asthma, and asthma-COPD overlap (ACO), and compared them to those of patients with interstitial pneumonia (IP). Using primary human bronchial epithelial cells and BEAS-2B cells, CXCL1 protein release and mRNA expression were measured after LPS or TNFα stimulation. We evaluated signal transduction mechanisms for CXCL1 production using nuclear factor-κ B (NF-kB) and mitogen-activated protein kinase (MAPK) inhibitors, and examined the effects of anti-inflammatory agents on CXCL1 production in BEAS-2B cells. RESULTS: Sputum CXCL1 levels in COPD and ACO patients were higher than in IP patients, whereas sputum CXCL8 levels were not. Sputum CXCL1 levels were not affected by inhaled corticosteroid usage, whereas sputum CXCL8 levels tended to be affected. LPS and TNFα stimulated CXCL1 production and mRNA expression in bronchial epithelial cells. NF-kB and MAPK p38 were involved in LPS-induced CXCL1 production. Therapeutic anti-inflammatory agents minimally attenuated CXCL1 production and considerably inhibited CXCL8 production in BEAS-2B cells. CONCLUSIONS: Sputum CXCL1 levels is a potentially better diagnostic marker for COPD than sputum CXCL8 levels, which is explained by that CXCL1 production in bronchial epithelial cells is less affected by therapeutic anti-inflammatory agents than CXCL8 production.

IL-17A synergistically stimulates TNF-α-induced IL-8 production in human airway epithelial cells: A potential role in amplifying airway inflammation.

BACKGROUND: Recent reports have suggested an involvement of neutrophilic inflammation driven by interleukin (IL)-17 from Th17 cells, especially in severe, refractory asthma. It remains unknown about the possible interactions of this cytokine and other proinflammatory cytokines to direct neutrophilic airway inflammation. MATERIALS AND METHODS: We evaluated the effects of IL-17A, IL-17E, and IL-17F in combination with other stimuli such as tumor necrosis factor (TNF) -α on the production and expression of IL-8 in human bronchial epithelial cells. We also studied their effects on other cytokine production. The possible role of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways was evaluated by specific inhibitors. We examined the effects of anti-asthma drugs, such as steroids or salmeterol. RESULTS: IL-17A alone induced only a minimal effect on IL-8 expression. IL-17A, but not IL-17E or IL-17F, in combination with TNF-α showed a synergistic effect on IL-8 expression. Similar findings were found when combination with IL-1ß and IL-17A were used, but such was not the case with lipopolysaccharide (LPS). In addition, we further found such synergy on GM-CSF production. The synergy with TNF-α and IL-17A was significantly inhibited by MAPKs inhibitors. Corticosteroids such as fluticasone propionate and dexamethasone, but not salmeterol, partially suppressed the IL-17A and TNF-α-induced IL-8 production. CONCLUSIONS: IL-17A in the combination with TNF-α or IL-1ß showed a synergistic augmenting effect on IL-8 and GM-CSF production in human airway epithelial cells.

Clarithromycin ameliorates pulmonary inflammation induced by short term cigarette smoke exposure in mice.

BACKGROUND: Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. METHODS: C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. RESULTS: The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. CONCLUSION: We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice.

Interleukin-10 modulates pulmonary neutrophilic inflammation induced by cigarette smoke exposure.

AIM OF THE STUDY: Interleukin (IL)-10 is an anti-inflammatory cytokine, but its role in cigarette smoke (CS)-induced inflammation and chronic obstructive pulmonary disease (COPD) has not been fully elucidated. The purpose of this study was to investigate the effect of IL-10 deficiency on CS-induced pulmonary inflammation in mice in vivo and in vitro. MATERIALS AND METHODS: IL-10-deficient and wild-type control mice with a C57BL6/J genetic background were exposed to CS, and inflammatory cells in bronchoalveolar lavage fluid (BALF) and mRNA of cytokines in lung were evaluated with enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: During 12 days of daily CS exposure to wild-type mice, neutrophil counts in BAL fluid and tumor necrosis factor (TNF)-α mRNA expression were increased, peaked at day 8, and then declined on day 12 when the level of IL-10 reached its peak. In IL-10-deficient mice, neutrophil recruitment and TNF-α mRNA levels induced by CS exposure were significantly greater than those in wild-type mice. Keratinocyte-derived chemokine (KC; murine ortholog of human CXCL8) and granulocyte macrophage colony-stimulating factor (GM-CSF) mRNA levels or matrix metalloproteinase(MMP)-9 protein levels were not correlated with neutrophil count. CONCLUSIONS: IL-10 had a modulatory effect on CS-induced pulmonary neutrophilic inflammation and TNF-α expression in mice in vivo and therefore appears to be an important endogenous suppressor of airway neutrophilic inflammation.