RESUMEN
BACKGROUND: In 2022, the "New Capitalism Grand Design and Implementation Plan" was adopted in Japan, emphasizing the promotion and environmental development of startups. Given this context, an investigation into the startup and investment landscape in the allergy sector, both domestically and internationally, becomes imperative. METHODS: We analyzed 156 allergy-related startups from Japan, the US, and Europe from 2010 to 2021. Data on corporate information and investment trends were extracted from databases and VC websites. RESULTS: The total investment reached approximately 7.2 billion USD, with a ratio of 20:6:1 for the US, Europe, and Japan, respectively. The US showed a decline post its peak from 2016-2018, while Europe and Japan experienced growth. Notably, the US primarily invested in biopharmaceuticals for atopic dermatitis and food allergies, Europe in asthma-related apps, and Japan in healthcare apps and cross-border startups. DISCUSSION AND CONCLUSION: While Japan's investment environment in the allergy sector remains in its nascent stages and has room for development, the US and Europe are evidently ahead. Considering the rise of startups and funding limitations in Japan, external funding from regions like the US becomes a potential avenue. These findings are anticipated to contribute to the strategic activation of startups in allergy research and development.
Asunto(s)
Alergia e Inmunología , Humanos , Alergia e Inmunología/economía , Hipersensibilidad/terapia , Hipersensibilidad/inmunología , Japón , Inversiones en Salud , Europa (Continente) , Estados UnidosRESUMEN
BACKGROUND: In the enhancement of allergy care involving multidisciplinary and multiple medical departments, there is a perceived need for education that targets not only specialists but also non-specialists. However, research on the need for and methods of such education remains inadequate. OBJECTIVE: To design a remote allergy care education program for all medical practitioners and to validate its necessity and utility. METHODS: The Empowering Next Generation Allergist/immunologist toward Global Excellence Task Force (ENGAGE-TF), supported by the Japanese Society of Allergology, initiated a virtual educational program called 'Outreach Lectures' in collaboration with Keio University and Fukui University. This initiative was widely promoted through social media and various institutions, and a survey was conducted through its mailing list. RESULTS: 1139 responses were obtained. More than half were physicians from non-allergy specialties, representing a diverse range of healthcare professions. Over 70% expressed being 'very satisfied,' and over 60% found the difficulty level 'appropriate.' Free-form feedback revealed differences in learning focus based on profession and learning approach based on years of experience. CONCLUSION: The high participation rate (90%) of non-specialist physicians underscores the demand for addressing allergic conditions in primary care. The effectiveness of virtual / recurrent education, particularly for healthcare professionals with over 11 years of experience, was implied. Further follow-up investigation focusing on quantitative and objective assessment of educational effectiveness is indispensable.
Asunto(s)
Alergia e Inmunología , Hipersensibilidad , Encuestas y Cuestionarios , Humanos , Alergia e Inmunología/educación , Educación a DistanciaRESUMEN
BACKGROUND: Studies on the association between preserved ratio impaired spirometry (PRISm) and dementia are limited. Indeed, PRISm has often been overlooked or ignored as an index of lung function impairment. Therefore, we investigated the association of PRISm with the risk for the development of dementia in an older Japanese population. METHODS: A total of 1202 community-dwelling, older Japanese participants aged ≥65 years without dementia were followed up for a median of 5.0 years. Participants were categorized by spirometry as follows: normal spirometry (FEV1/FVC ≥0.70 and FEV1 ≥80% predicted), PRISm (≥0.70 and <80%), airflow limitation (AFL) Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 (<0.70 and ≥80%), and AFL GOLD 2 to 4 (<0.70 and <80%). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed using a Cox proportional hazards model. RESULTS: During the follow-up period, 122 participants developed dementia. The age- and sex-adjusted incidences of dementia in the participants with normal spirometry, PRISm, AFL GOLD 1, and AFL GOLD 2 to 4 were 20.5, 37.0, 18.4, and 28.6 per 1000 person-years, respectively. Participants with PRISm had a higher risk of dementia (HR 2.04 [95%CI, 1.19-3.49]) than those with normal spirometry after adjusting for confounders. Moreover, both reduced FEV1% predicted values and FVC% predicted values were associated with the risk for dementia. CONCLUSION: PRISm was associated with an increased risk of dementia in a general older Japanese population.
RESUMEN
Rationale: Several Western studies have reported that participants with preserved ratio impaired spirometry (PRISm) have higher risks of airflow limitation (AFL) and death. However, evidence in East Asian populations is limited. Objectives: To investigate the relationship between PRISm and the risks of death and incident AFL in a Japanese population. Methods: A total of 3,032 community-dwelling Japanese participants aged ⩾40 years were seen in follow-up for a median of 5.3 years by annual spirometry examinations. Participants were classified into lung function categories at baseline as follows: normal spirometry (FEV1/FVC ⩾0.70 and FEV1 ⩾80% predicted), PRISm (⩾0.70 and <80%), AFL Global Initiative for Chronic Obstructive Lung Disease 1 (<0.70 and ⩾80%), and AFL Global Initiative for Chronic Obstructive Lung Disease 2-4 (<0.70 and <80%). Hazard ratios (HRs) and their 95% confidence intervals were computed using a Cox proportional hazards model. Measurements and Main Results: During the follow-up period, 131 participants died, 22 of whom died of cardiovascular disease, and 218 participants developed AFL. When examining the prognosis of each baseline lung function category, participants with PRISm had higher risks of all-cause death (HR, 2.20; 95% confidence interval, 1.35-3.59) and cardiovascular death (HR, 4.07; 1.07-15.42) than those with normal spirometry after adjusting for confounders. Moreover, the multivariable-adjusted risk of incident AFL was greater in participants with PRISm than in those with normal spirometry (HR, 2.48; 1.83-3.36). Conclusions: PRISm was associated with higher risks of all-cause and cardiovascular death and a greater risk of the development of AFL in a Japanese community.
Asunto(s)
Pulmón , Enfermedad Pulmonar Obstructiva Crónica , Anciano , Volumen Espiratorio Forzado , Humanos , Japón/epidemiología , Pruebas de Función Respiratoria , Factores de Riesgo , Espirometría , Capacidad VitalRESUMEN
BACKGROUND: Human rhinoviruses (HRVs) infection is a common cause of exacerbations in pediatric patients with asthma. However, the effects of corticosteroids on HRV-induced exacerbations in pediatric asthma are unknown. We conducted a prospective observational study to determine the viral pathogens in school-age pediatric inpatients with asthma exacerbations. We assessed the effects of maintenance inhaled corticosteroids (ICS) on the detection rates of HRV species and treatment periods of systemic corticosteroids during exacerbations on pulmonary lung function after exacerbations. METHODS: Nasopharyngeal samples and clinical information were collected from 59 patients with asthma exacerbations between April 2018 and March 2020. Pulmonary function tests were carried out 3 months after exacerbations in 18 HRV-positive patients. Changes in forced expiratory volume in 1 second (FEV1)% predicted from baseline in a stable state were compared according to the treatment periods of systemic corticosteroids. RESULTS: Fifty-four samples collected from hospitalized patients were analyzed, and viral pathogens were identified in 45 patients (83.3%) using multiplex PCR assay. HRV-A, -B, and -C were detected in 16 (29.6%), one (1.9%), and 16 (29.6%) patients, respectively. The detection rates of HRV-C were lower in the ICS-treated group compared with those in the ICS-untreated group (p = 0.01), whereas maintenance ICS treatment did not affect the detection rate for viral pathogens in total and HRV-A. Changes in FEV1% predicted in patients treated with systemic corticosteroids for 6-8 days (n = 10; median, 4.90%) were higher than those in patients treated for 3-5 days (n = 8; median, - 10.25%) (p = 0.0085). CONCLUSIONS: Maintenance ICS reduced the detection rates of HRV (mainly HRV-C) in school-age inpatients with asthma exacerbations, and the treatment periods of systemic corticosteroids during exacerbations affected lung function after HRV-induced exacerbations. The protective effects of corticosteroids on virus-induced asthma exacerbations may be dependent upon the types of viral pathogen.
Asunto(s)
Antiasmáticos , Asma , Niño , Humanos , Antiasmáticos/uso terapéutico , Rhinovirus , Pacientes Internos , Administración por Inhalación , Asma/tratamiento farmacológico , Asma/inducido químicamente , CorticoesteroidesRESUMEN
BACKGROUND: Adrenaline is the first-line medication for managing anaphylaxis. A better understanding of prescription trends for adrenaline auto-injectors (AAIs) is important to improving patient care as well as information on health education interventions and medical guidelines. However, it has been difficult to gather comprehensive data in a sustainable manner. Thus, we aimed to investigate trends in AAI prescriptions in Japan. METHODS: We searched the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), a unique and comprehensive database of health insurance claims, and investigated prescriptions for AAIs for all ages (April 2017 to March 2018). We assessed the annual number of prescriptions per person as well as prescription rates per 100,000 population per year by age, sex, and geographic region. RESULTS: A total of 88,039 subjects (56,109 males, 31,930 female) and 116,758 devices (1.33 AAIs per patient per year) were prescribed AAIs at least once a year for all ages. The prescription rate for AAIs was 69.5 per 100,000 population-years. Patients aged 0-9 years were prescribed AAIs at the rate of 278.9 per 100,000 population-years. Patients aged 0-19 years were 6.4 times more likely to be prescribed AAIs than those over 20 years of age. Males were more frequently prescribed AAIs than females in all age groups, except for those aged 20-24 years. We also evaluated differences in prescription rates by geographic region. CONCLUSIONS: This comprehensive evaluation revealed trends in AAI prescriptions, thus helping develop preventive strategies with respect to anaphylaxis in Japan.
Asunto(s)
Anafilaxia , Epinefrina , Adulto , Anafilaxia/tratamiento farmacológico , Anafilaxia/epidemiología , Epinefrina/uso terapéutico , Femenino , Humanos , Seguro de Salud , Japón/epidemiología , Masculino , Prescripciones , Estudios RetrospectivosRESUMEN
BACKGROUND: Airway epithelial barrier function is maintained by the formation of tight junctions (TJs) and adherens junctions (AJs). Inhalation of cigarette smoke causes airway epithelial barrier dysfunction and may contribute to the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). We assessed the effects of cigarette smoke on barrier function and expression of multiple TJ and AJ proteins in the bronchial epithelium. We also examined whether treatment with glucocorticosteroids (GCSs), long-acting ß2-agonists (LABAs), and human cathelicidin LL-37 can protect against cigarette smoke extract (CSE)-induced barrier dysfunction. METHODS: Calu-3 cells cultured at the air-liquid interface were pretreated with or without GCSs, LABAs, GCSs plus LABAs, or LL-37, and subsequently exposed to CSE. Barrier function was assessed by transepithelial electronic resistance (TEER) measurements. Gene and protein expression levels of TJ and AJ proteins were analyzed by quantitative PCR and western blotting, respectively. Immunofluorescence staining of TJ and AJ proteins was performed. RESULTS: CSE decreased TEER and increased permeability in a concentration-dependent manner. CSE suppressed gene expression of claudin-1, claudin-3, claudin-4, claudin-7, claudin-15, occludin, E-cadherin, junctional adhesion molecule-A (JAM-A) and zonula occludens-1 (ZO-1) within 12 h post-CSE exposure, while suppressed protein expression levels of occludin at 12 h. CSE-treated cells exhibited discontinuous or attenuated immunostaining for claudin-1, claudin-3, claudin-4, occludin, ZO-1, and E-cadherin compared with untreated cells. GCS treatment partially restored CSE-induced TEER reduction, while LABA treatment had no effect. GCS and LABA combination treatment had no additive effect on CSE-induced TEER reduction and gene suppression of TJ and AJ proteins. Human cathelicidin LL-37 counteracted CSE-induced TEER reduction and prevented disruption of occludin and ZO-1. LL-37 also attenuated CSE-induced decreases in gene and protein expression levels of occludin. CONCLUSIONS: CSE caused airway epithelial barrier dysfunction and simultaneously downregulated multiple TJ and AJ proteins. GCS and LABA combination treatment had no additive effect on CSE-induced TEER reduction. LL-37 counteracted CSE-induced TEER reduction and prevented disruption of occludin and ZO-1. Use of LL-37 to counteract airway epithelial barrier dysfunction may have significant benefits for respiratory diseases such as asthma and COPD.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/farmacología , Bronquios/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Humo/efectos adversos , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Productos de Tabaco/efectos adversos , Bronquios/metabolismo , Línea Celular , Impedancia Eléctrica , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , Humanos , Permeabilidad , Transducción de Señal , Proteínas de Uniones Estrechas/genética , Uniones Estrechas/genética , Uniones Estrechas/metabolismo , CatelicidinasAsunto(s)
Asma , Productos Biológicos , Humanos , Asma/tratamiento farmacológico , Asma/mortalidad , Japón/epidemiología , Productos Biológicos/uso terapéutico , Masculino , Femenino , Anciano , Antiasmáticos/uso terapéutico , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Anciano de 80 o más AñosRESUMEN
Background: Human metapneumovirus (hMPV) infection is implicated in exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Research into the pathogenesis of infection is restricted to animal models, and information about hMPV replication and inflammatory and immune responses in human disease is limited. Methods: Human primary bronchial epithelial cells (PBECs) from healthy and asthmatic subjects and those with COPD were infected with hMPV, with or without glucocorticosteroid (GCS) exposure. Viral replication, inflammatory and immune responses, and apoptosis were analyzed. We also determined whether adjuvant interferon (IFN) can blunt hMPV infection in vitro and in a murine model. Results: hMPV infected human PBECs and viral replication was enhanced in cells from patients with COPD. The virus induced gene expression of IFN-stimulated gene 56 (ISG56) and IFN-ß, as well as IFN-γ-inducible protein 10 (IP-10) and regulated on activation, normal T cell expressed and secreted (RANTES), and more so in cells from patients with COPD. GCS exposure enhanced hMPV replication despite increased IFN expression. Augmented virus replication associated with GCS was mediated by reduced apoptosis via induction of antiapoptotic genes. Adjuvant IFN treatment suppressed hMPV replication in PBECs and reduced hMPV viral titers and inflammation in vivo. Conclusions: hMPV infects human PBECs, eliciting innate and inflammatory responses. Replication is enhanced by GCS and adjuvant IFN is an effective treatment, restricting virus replication and proinflammatory consequences of hMPV infections.
Asunto(s)
Glucocorticoides/farmacología , Interferón gamma/farmacología , Metapneumovirus , Infecciones por Paramyxoviridae/virología , Enfermedad Pulmonar Obstructiva Crónica/virología , Animales , Apoptosis/efectos de los fármacos , Asma/virología , Bronquios/citología , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Humanos , Ratones , Ratones Endogámicos BALB C , Modelos Biológicos , Mucosa Respiratoria/citología , Replicación Viral/efectos de los fármacosRESUMEN
Double-stranded RNA derived from viruses induces host immune responses. PD-L1, also known as B7-H1, is an immune-checkpoint molecule associated with the escape of viruses from host immune systems, which plays a role in the persistence of viral infection, resulting in exacerbations of underlying diseases such as asthma and chronic obstructive pulmonary disease. Interleukin (IL)-22 is produced from various immune cells and has protective properties on mucosal tissue. The binding of IL-22 to IL-22 receptor induces STAT3 activation. We investigated the effect of IL-22 on the expression in airway epithelial cells in vitro and in mouse lungs in vivo after the stimulation with an analog of viral double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C). Stimulation with poly I:C upregulated PD-L1 expression on BEAS-2B cells. This upregulation of PD-L1 was attenuated by IL-22 administration. STAT3 phosphorylation was induced by IL-22 and poly I:C. Treatment of cells with STAT3 siRNA abolished the effect of IL-22 on the poly I:C-induced upregulation of PD-L1. This upregulation of PD-L1 was also attenuated by IL-11, a cytokine inducing STAT3 phosphorylation, in BEAS-2B cells. In mouse lung cells in vivo, IL-22 suppressed poly I:C-induced upregulation of PD-L1. These results suggest that IL-22 attenuates virus-induced upregulation of PD-L1 in airway epithelial cells via a STAT3-dependent mechanism.
Asunto(s)
Antígeno B7-H1/metabolismo , Interleucinas/metabolismo , ARN Viral/inmunología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Técnicas de Silenciamiento del Gen , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación , Poli I-C/inmunología , Receptores de Interleucina/metabolismo , Mucosa Respiratoria/virología , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Regulación hacia Arriba , Interleucina-22RESUMEN
Since its discovery in 2001, human metapneumovirus (hMPV) has been identified as an important cause of respiratory tract infection in young children, second only to the closely related respiratory syncytial virus (RSV). Clinical evidence suggests that hMPV is associated with acute exacerbations of asthma in both children and adults, and may play a role in initiating asthma development in children. Animal models have demonstrated that airway hyperresponsiveness (AHR) and inflammation are triggered following hMPV infection, and hMPV is able to persist in vivo by inhibiting innate immune responses and causing aberrant adaptive responses. In this review, we discuss the prevalence of hMPV infection in pediatric and adult populations and its potential role in asthma exacerbation. We also review recent advances made in animal models to determine immune responses following hMPV infection, and compare to what is known about RSV.
Asunto(s)
Asma/virología , Metapneumovirus , Infecciones por Paramyxoviridae/complicaciones , Infecciones por Virus Sincitial Respiratorio/complicaciones , Virus Sincitial Respiratorio Humano , Enfermedad Aguda , Animales , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata , Infecciones por Paramyxoviridae/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunologíaRESUMEN
Transforming growth factor-ß (TGFB) regulates cell proliferation, differentiation, apoptosis, and matrix homeostasis and is intimately involved in fibrosis. TGFB expression is increased in fibrotic lung diseases, such as idiopathic pulmonary fibrosis, and in chronic inflammatory conditions, such as chronic obstructive pulmonary disease and asthma. In addition to exhibiting profibrotic activities, the protein exhibits profound immune-suppressive actions involving both innate and adaptive responses, but often this aspect of TGFB biology is overlooked. Recent investigations have demonstrated that TGFB causes wide-ranging immune suppression, including blunting of pivotal early innate IFN responses. These activities permit severe virus infections, often followed by secondary bacterial infections, which may last longer, with augmented inflammation, scarring, fibrosis, and loss of lung function. Strategies to oppose TGFB actions or to enhance IFN responses may help ameliorate the detrimental consequences of infection in patients with diseases characterized by TGFB overexpression, inflammation, and fibrosis.
Asunto(s)
Inmunidad Innata , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Humanos , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Pulmón/virología , Modelos Biológicos , Fibrosis Pulmonar/microbiología , Fibrosis Pulmonar/virología , Transducción de SeñalRESUMEN
Spirometry in health checkup may contribute to early diagnosis of chronic obstructive pulmonary disease (COPD) and asthma. Although post-bronchodilator airflow limitation is essential for definite diagnosis of COPD and post-bronchodilator normalization of airflow is suggestive of asthma, this test has not been prevailed in health checkup. The objective of this study was to estimate the prevalence of airflow limitation defined by pre- and post-bronchodilator spirometry in health checkup. Post-bronchodilator spirometry was conducted for participants with airflow limitation in a town-wide health checkup for residents aged 40 years and older in Hisayama, a town in the western part of Japan. The prevalence of pre- and post-bronchodilator airway limitation defined by FEV1/FVC < 70% were estimated. A total of 2,232 participants underwent pre-bronchodilator spirometry. In males, the age of current smokers was significantly younger than those of never smokers and former smokers. In females, the ages of current- and former smokers were significantly younger than never smokers. The values of %FEV1 and %FVC in current smokers were significantly lower than those in former smokers and never smokers. Two hundred sixty nine subjects, 85% of total subjects with a pre-bronchodilator FEV1/FVC < 70%, completed post-bronchodilator spirometry. The prevalence of pre-bronchodilator airflow limitation was 14.6% in males and 13.7% in females, and the prevalence of post-bronchodilator airway limitation was 8.7% and 8.7%, respectively. Post-bronchodilator spirometry in health checkup would reduce the number of subjects with probable COPD to two-third. Recommendation for those examinees to take further evaluations may pave the way for early intervention.
Asunto(s)
Broncodilatadores/farmacología , Salud , Ventilación Pulmonar/efectos de los fármacos , Características de la Residencia , Anciano , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Japón , Masculino , Persona de Mediana Edad , Prevalencia , EspirometríaRESUMEN
BACKGROUND: CD86-CD28 interaction has been suggested as the principal costimulatory pathway for the activation and differentiation of naïve T cells in allergic inflammation. However, it remains uncertain whether this pathway also has an essential role in the effector phase. We sought to determine the contribution of CD86 on dendritic cells in the reactivation of allergen-specific Th2 cells. METHODS: We investigated the effects of the downregulation of CD86 by short interfering RNAs (siRNAs) on Th2 cytokine production in the effector phase in vitro and on asthma phenotypes in ovalbumin (OVA)-sensitized and -challenged mice. RESULTS: Treatment of bone marrow-derived dendritic cells (BMDCs) with CD86 siRNA attenuated LPS-induced upregulation of CD86. CD86 siRNA treatment impaired BMDCs' ability to activate OVA-specific Th2 cells. Intratracheal administration of CD86 siRNA during OVA challenge downregulated CD86 expression in the airway mucosa. CD86 siRNA treatment ameliorated OVA-induced airway eosinophilia, airway hyperresponsiveness, and the elevations of OVA-specific IgE in the sera and IL-5, IL-13, and CCL17 in the bronchoalveolar lavage fluid, but not the goblet cell hyperplasia. CONCLUSION: These results suggest that local administration of CD86 siRNA during the effector phase ameliorates lines of asthma phenotypes. Targeting airway dendritic cells with siRNA suppresses airway inflammation and hyperresponsiveness in an experimental model of allergic asthma.
Asunto(s)
Asma/prevención & control , Antígeno B7-2/metabolismo , Hiperreactividad Bronquial/prevención & control , Pulmón/metabolismo , Tratamiento con ARN de Interferencia , Células Th2/metabolismo , Animales , Asma/genética , Asma/inmunología , Asma/metabolismo , Asma/fisiopatología , Antígeno B7-2/genética , Hiperreactividad Bronquial/genética , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Broncoconstricción , Células Cultivadas , Técnicas de Cocultivo , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Inmunoglobulina E/sangre , Pulmón/inmunología , Pulmón/fisiopatología , Activación de Linfocitos , Ratones Endogámicos BALB C , Ovalbúmina , Fenotipo , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/inmunología , Eosinofilia Pulmonar/metabolismo , Eosinofilia Pulmonar/prevención & control , Interferencia de ARN , Células Th2/inmunología , TransfecciónRESUMEN
Efferocytosis, which is the homeostatic phagocytosis of apoptotic cells, prevents the release of toxic intracellular contents and subsequent tissue damage. Impairment of efferocytosis was reported in alveolar macrophages (AMs) of patients with chronic obstructive pulmonary disease (COPD), a common disease caused by smoking. In COPD, histone deacetylase (HDAC) activity is reduced in AMs. We investigated whether the reduction of HDAC activity is associated with the impairment of efferocytosis. Murine AMs were collected by bronchoalveolar lavage and their ability to efferocytose apoptotic human polymorphonuclear leukocytes was assessed. Pre-treatment of AMs with cigarette smoke extract (CSE) or trichostatin A (TSA), an HDAC inhibitor, suppressed efferocytosis and CSE reduced HDAC activity. TSA inhibited the activity of Rac, a key mediator of efferocytosis. These TSA-induced impairments were restored by treatment of AMs with aminophylline, a potent activator of HDAC. To further elucidate the underlying mechanism, we explored a role of CD9 in TSA-induced impairment of efferocytosis. CD9 is a transmembrane protein of the tetraspanin family that facilitates the uptake of several pathogens and other material. TSA profoundly down-regulated the expression of CD9 on AMs. The expression of CD9 was partly down-regulated by the Rac inhibitor. Pretreatment with an anti-CD9 mAb or CD9 small interfering RNA inhibited efferocytosis, which was attributable to the reduced binding of AMs to apoptotic cells. These results suggest that smoking impairs efferocytosis via inhibition of HDAC/Rac/CD9 pathways. Aminophylline/theophylline is effective in restoring the impairment of efferocytosis and might have benefit for the treatment of patients with COPD.
Asunto(s)
Apoptosis/inmunología , Histona Desacetilasas/metabolismo , Macrófagos Alveolares/patología , Neutrófilos/citología , Fagocitosis/inmunología , Fumar/efectos adversos , Tetraspanina 29/antagonistas & inhibidores , Proteínas de Unión al GTP rac/antagonistas & inhibidores , Animales , Voluntarios Sanos , Histona Desacetilasas/inmunología , Humanos , Macrófagos Alveolares/enzimología , Macrófagos Alveolares/inmunología , Ratones , Ratones Endogámicos C57BL , Neutrófilos/enzimología , Neutrófilos/inmunología , Fumar/inmunología , Tetraspanina 29/inmunología , Tetraspanina 29/metabolismo , Proteínas de Unión al GTP rac/inmunología , Proteínas de Unión al GTP rac/metabolismoRESUMEN
Mucin overproduction is a common feature of chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and exacerbates their underlying respiratory condition. Surfactant protein D (SP-D) protects against airway diseases through modulation of immune reactions, but whether it also exerts direct effects on airway epithelial cells has remained unclear. Therefore, we sought to investigate the inhibitory role of SP-D on mucin production in airway epithelial cells. We prepared air-liquid interface (ALI) cultures of human primary bronchial epithelial cells (HBECs), which recapitulated a well-differentiated human airway epithelium. Benzo(a)pyrene (BaP), a key toxicant in cigarette smoke, induced mucin 5AC (MUC5AC) production in ALI-cultured HBECs, airway secretory cell lines, and airway epithelia of mice. Then, the protective effects of SP-D against the BaP-induced mucin overproduction were examined. BaP increased MUC5AC production in ALI cultures of HBECs, and this effect was attenuated by SP-D. SP-D also suppressed the BaP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and MUC5AC expression in NCI-H292 goblet-like cells, but not in NCI-H441 club-like cells. Signal regulatory protein α (SIRPα) was found to be expressed in HBECs and NCI-H292 cells but absent in NCI-H441 cells. In NCI-H292 cells, SP-D activated SH2 domain-containing tyrosine phosphatase-1 (SHP-1), downstream of SIRPα, and knockdown of SIRPα abolished the suppressive effects of SP-D on BaP-induced ERK phosphorylation and MUC5AC production. Consistent with these in vitro findings, intratracheal instillation of SP-D prevented the BaP-induced phosphorylation of ERK and Muc5ac expression in airway epithelial cells in a mouse model. SP-D acts directly on airway epithelial cells to inhibit mucin secretion through ligation of SIRPα and SHP-1-mediated dephosphorylation of ERK. Targeting of SIRPα is therefore a potential new therapeutic approach to suppression of mucin hypersecretion in chronic airway diseases such as COPD and asthma.