Leukotriene receptor antagonists pranlukast and montelukast for treating asthma

Introduction: The prevalence of bronchial asthma, which is a chronic inflammatory disorder of the airway, is increasing worldwide. Although inhaled corticosteroids (ICS) play a central role in the treatment of asthma, they cannot achieve good control for all asthmatics, and medications such as leukotriene receptor antagonists (LTRAs) with bronchodilatory and anti-inflammatory effects often serve as alternatives or add-on drugs. Areas covered: Clinical trials as well as basic studies of montelukast and pranlukast in animal models are ongoing. This review report clarifies the current status of these two LTRAs in the treatment of asthma and their future direction. Expert opinion: LTRAs could replace ICS as first-line medications for asthmatics who are refractory to ICS or cannot use inhalant devices. Further, LTRAs are recommended for asthmatics under specific circumstances that are closely associated with cysteinyl leukotrienes (cysLTs). Considering the low incidence of both severe adverse effects and the induction of tachyphylaxis, oral LTRAs should be more carefully considered for treating asthma in the clinical environment. Several issues such as predicted responses, effects of peripheral airway and airway remodeling and alternative administration routes remain to be clarified before LTRAs could serve a more effective role in the treatment of asthma

Respiratory Bronchiolitis-associated Interstitial Lung Disease with Unusual Histopathological Findings

Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is a mild inflammatory reaction commonly seen in asymptomatic young male cigarette smokers. This report describes unusual pathological findings in a 63-yearold Japanese female with RB-ILD. She had a 40 pack-year smoking history. Chest computed tomography showed multiple patchy shadows, especially in the right lower lobe. Diagnosis could not be established by bronchoalveolar lavage and transbronchial lung biopsy. Thoracoscopic lung biopsy was performed from right S5 and S9, which demonstrated the typical pathological findings of RB-ILD, including the presence of pigmented macrophages within respiratory bronchioles, thickening of alveolar septa by fibrosis, accumulation of intrapulmonary blue bodies and lack of granulomatous changes. Our patient had atypical RB-ILD based on old age at presentation (commonly -40 years of age), marked fibrosis and presence of numerous blue bodies

Chemical Pleurodesis Could Exacerbate Lymphedema of Yellow Nail Syndrome

Chemical pleurodesis is sometimes performed for the management of intractable pleural effusion. We describe a woman with yellow nail syndrome (YNS), which is characterized by yellow discoloration of the nails, lymphedema, and pleural effusion. At the age of 43, she was hospitalized with edema of the lower limbs. Despite a number of medical treatments, massive lymphedema of lower limbs developed over a period of three years, resulting in skin cracks and subsequent infection, septicemia and multiple organ failure. At autopsy, abnormally dilated lymph and blood vessels were evident in soft tissue throughout the whole body. She had undergone chemical pleurodesis at 36 years of age for reduction of pleural effusion associated with YNS. Our case illustrates possible complication of chemical pleurodesis to YNS, which resulted in accumulation of lymph flow into the lower half of the body

Clearance of Aspergillus fumigatus is impaired in the airway in allergic inflammation

Background Aspergillus fumigatus (Af) sometimes colonizes and persists within the respiratory tree in some patients with asthma. To date, the precise reasons why the clearance of Af is impaired in patients with asthma remain unknown. Objective To characterize the effects of allergic airway inflammation on clearance of Af. Methods Control and Dermatophagoides farinae (Df) allergen-sensitized BALB/c mice were intranasally infected with Af. After 2 and 9 days of infection, the pathology, fungal burden, and cytokine profile in lung tissue were compared. In a different set of experiments, the phagocytotic activity of alveolar macrophages and the expression of their pathogen recognition receptors also were determined. Results The Af conidia and neutrophilic airway inflammation disappeared by day 9 after infection in control mice. In Df-sensitized mice, Af conidia and neutrophilic and eosinophilic airway inflammation persisted at day 9 after infection. Compared with control mice, Df allergen-sensitized mice showed significant increases in interleukin (IL)-5 and decreases in IL-12 and interferon-γ in lung tissues at day 2 after infection. Most importantly, compared with Af-infected non-Df-sensitized mice, IL-17 in lung tissues was significantly decreased in Df allergen-sensitized Af-infected mice at day 2 after infection but was significantly increased at day 9. Alveolar macrophages isolated from Df allergen-sensitized mice exhibited significant decreases in phagocytotic activity and expression of Toll-like receptor-4 and dectin-1 compared with those from control mice. Conclusion In the airway of patients with allergy, T-helper cell type 2-dominant immunity potentially affects the expression of pathogen recognition receptors and attenuates cellular defense against Af. Prolonged IL-17 production also could play an important role

Fatal Asthma with Rhabdomyolysis Induced by Hair Dye

Hair dyes have been reported to cause exacerbation of asthma in hairdressers through occupational exposure. We report a 54-year-old housewife who developed a fatal asthma attack following the use of a hair dye at home. She was admitted semiconscious with multiple organ failure. Laboratory findings were indicative of rhabdomyolysis. Skin prick and interdermal tests with hair dyes were performed. Hair dyes can be nonspecific stimuli that cause an asthma attack. But in our case, we cannot deny the possibility that the attack resulted from antigen-antibody reaction by the hair dye. We should warn that hair dyes can cause an asthma attack not only through occupational exposure but also through occasional domestic use

Associations of chemical composition and sources of PM2.5 with lung function of severe asthmatic adults in a low air pollution environment of urban Nagasaki, Japan

Previous studies have linked ambient PM2.5 to decreased pulmonary function, but the influence of specific chemical elements and emission sources on the severe asthmatic is not well understood. We examined the mass, chemical constituents, and sources of PM2.5 for short-term associations with the pulmonary function of adults with severe asthma in a low air pollution environment in urban Nagasaki, Japan. We recruited 35 asthmatic adults and obtained the daily record of morning peak expiratory flow (PEF) in spring 2014–2016. PM2.5 filters were extracted from an air quality monitoring station (178 days) and measured for 27 chemical elements. Source apportionment was performed using Positive Matrix Factorization (PMF). We fitted generalized linear model with generalized estimating equation (GEE) method to estimate changes in PEF (from personal monthly maximum) and odds of severe respiratory deterioration (first ≥ 15% PEF reduction within a 1-week interval) associated with mass, constituents, and sources of PM2.5, with adjustment for temperature and relative humidity. Constituent sulfate (SO42−) and PM2.5 from oil combustion and traffic were associated with reduced PEF. An interquartile range (IQR) increase in SO42− (3.7 μg/m3, average lags 0–1) was associated with a decrease of 0.38% (95% confidence interval = −0.75% to −0.001%). An IQR increase in oil combustion and traffic-sourced PM2.5 (2.64 μg/m3, lag 1) was associated with a decrease of 0.33% (−0.62% to −0.002%). We found a larger PEF decrease associated with PM2.5 from dust/soil on Asian Dust days. There was no evidence linking total mass and metals to reduced pulmonary function. The ventilatory capacity of adults with severe asthma is susceptible to specific constituents/sources of PM2.5 such as sulfate and oil combustion and traffic despite active self-management of asthma and low air pollution levels in the study location

Effect of Respiratory Syncytial Virus Infection on Plasmacytoid Dendritic Cell Regulation of Allergic Airway Inflammation.

Background: Respiratory syncytial virus (RSV) can infect myeloid dendritic cells (mDCs) and regulate their function in the development of allergy. It has been widely reported that plasmacytoid DCs (pDCs) play a critical role in antiviral innate immunity. In contrast, not much is known about the role of pDCs in the interaction between allergy and viral infection. The purpose of the present study was to investigate the effect of RSV infection on pDC function in the regulation of allergic airway inflammation in a murine model of Dermatophagoides farinae-sensitized allergic asthma. Methods: Splenic pDCs isolated from D. farinae-sensitized donor mice were infected with live RSV ex vivo. Subsequently, these pDCs were inoculated into the airways of D. farinae-sensitized recipient mice. Lung pathology, lung tissue cytokine profiles, the number of regulatory T cells (T(reg)) and mDCs as well as the effects of IL-10 neutralization in the lung tissue of recipient mice were determined. Results: Intranasal inoculation of D. farinae-sensitized pDCs significantly inhibited the development of allergic airway inflammation and both Th1 and Th2 immunity. Live RSV infection of these pDCs prior to inoculation interfered with their inhibitory effects through decreasing T(reg) and IL-10 and increasing mDCs. Conclusions: In asthmatic airways, pDCs mediate tolerance to inhaled allergens through the regulation of T(reg), IL-10 and mDCs. RSV infection of pDCs potentially inhibits their immunotolerogenic effects and thus exacerbates allergic airway inflammation

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. 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