Chronic airway inflammation, one of the pathophysiologic features of bronchial asthma, is suspected to be responsible for irreversible pathological changes of airways, called airway remodeling. To examine the mechanisms of airway remodeling in asthma, we investigated the expression of epidermal growth factor (EGF) and its receptor immunohistochemically in asthmatic human airways. Airway specimens from seven patients with asthma were obtained from autopsied and surgically resected lungs. Control specimens were obtained from lungs of eight subjects without asthma and other pulmonary complications at autopsy. We stained those specimens by the avidin-biotin-peroxidase complex (ABC) method with anti-human polyclonal EGF antibody and monoclonal EGF receptor antibodies. Three different portions of airways-large bronchi (about 1 cm in diameter), small bronchi (about 3 mm in diameter), and peripheral airways (less than 2 mm in diameter)-were examined. The thickness of the bronchial smooth muscle and basement membrane was significantly greater in the asthmatic airways than in controls. Clear immunoreactivities of EGF were widely observed on bronchial epithelium, glands, and smooth muscle in asthmatic airways. In the controls, the bronchial epithelium and the bronchial glands partially expressed faint EGF immunoreactivity. For the EGF receptor, clear immunoreactivities were also observed on bronchial epithelium, glands, smooth muscle, and basement membrane in asthmatic airways. In control airways, only part of the bronchial epithelium and smooth muscle weakly expressed EGF receptor immunoreactivity. These results suggest a possible contribution of EGF to the pathophysiology of bronchial asthma, including airway remodeling.
Japan Medical Association Center for Clinical Trials JMA-IIA00146.
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
Although the prevalence of serum precipitating antibodies for farmer's lung disease (FLD) is lower in smokers than in nonsmokersand FLDpredominates in nonsmokers, the affects of smoking on the clinical course of the disease is not known.Wecomparedthe clinical findings and the prognosis between 12 smokers (SM-FLD)and 31 non-smokers with FLD(NS-FLD). There was no difference in age, sex, working years on farm, clinical symptoms, laboratory findings, radiographic findings, between the two groups. However, for the type of onset on the first visit for FLD, "acute single episode" type was less common,and "recurrent" and "insidious onset" types were more common in SM-FLD than in NS-FLD (8.3 vs 58.1, 91.7 vs 41.9%, respectively, p<0.05). Although working status and mask wearing status were not significantly different between the two groups after the diagnosis of FLD, patients with symptoms and/or radiographic abnormalities of FLD of more than 6 months were found more frequently in SM-FLD than in NS-FLD (66.7 vs 19.4%, p<0.005). And also SM-FLDhad more recurrences of FLD than NS-FLD after the initial diagnosis ofFLD (1.58±1.56 vs 0.47±1.07, p<0.05). SM-FLDtended to have lower %VCthan NS-FLD (73.6±7.4 vs 88.5±3.9%, respectively, p=0.06). Regarding the prognosis, the 10-year survival rates were 70.7% in SM-FLD, and 91.5% in NS-FLD(p<0.05). These results suggest that smoking may make FLDinsidious and chronic, and deteriorates the clinical outcome. (Internal Medicine 34: 966-971, 1995)
Background-Goblet cell hyperplasia (GCH) is a prominent feature in animal models of atopic asthma produced by immunisation and following multiple challenges with antigens. The aim of this study was to examine the eVect of a 2 agonist on the development of GCH induced by the immune response. Methods-Brown Norway rats were immunised and challenged with an aerosol of ovalbumin for four weeks. Salbutamol (0.5 mg/kg/day) or vehicle was continuously delivered for the four weeks using a subcutaneously implanted osmotic minipump. The density of goblet cells, other morphological changes, and airway responsiveness to methacholine were evaluated 24 hours after the final challenge.
Background We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. Methods We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. Results Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. Conclusions We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.
To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 × 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.
Cytokines produced by T-lymphocytes may have significant roles in the airway inflammation seen in bronchial asthma. Gamma interferon (IFN-gamma), a T-cell derived cytokine, is known to modify functions of both immune and non-immune cells. In this study, we investigated whether IFN-gamma can modify guinea pig airway functions in vitro. The isometric tension of guinea pig airway strips was measured in a tissue bath filled with Krebs-Henseleit solution. Contracting responses to carbachol and KCl, and the relaxing response to isoproterenol (ISO) were examined. Effects of IFN-gamma were examined by comparing responses of the strips incubated with or without IFN-gamma (1000 U.ml-1; 25,000 U.ml-1). Contracting responses to carbachol and KCl were not affected by the incubation with IFN-gamma other than slight increased in maximum contraction by carbachol after 5 hours incubation with 25,000 U.ml-1 of IFN-gamma. Both 1 and 5 h incubation of strips with 25,000 U.ml-1 IFN-gamma significantly increased the sensitivity to ISO (p < 0.01 and p < 0.05, respectively) without affecting maximum relaxation. The effect of IFN-gamma on ISO relaxation was abolished by the denudation of airway epithelium from strips, indomethacin (2 microM), and cycloheximide (70 microM) but not by N omega-nitro-L-arginine methyl ester (30 microM). In addition, heat-inactivated IFN-gamma and bacterial endotoxin (LPS, 0.625 pg.ml-1) had no effect on ISO relaxation. These results suggest that IFN-gamma is able to modify airway smooth muscle response to beta-adrenergic agonist by inducing release of prostanoids from airway epithelium.
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