Mϕs are the main innate immune cells in the lung at homeostasis, with important roles in host defence and immune modulation. Alveolar Mϕs (AMs) and interstitial Mϕs (IMs) are the two lung Mϕ subsets, ...so called according to the sites they reside in. These subsets are also defined by their origins and immunological microenvironment, which endow these cells with distinct features and plasticity. This review summarizes the latest definitions and functions of lung Mϕs during homeostasis and provides exemplar of their divergent roles in lung fibrosis.
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Review describes the latest definitions and functions of lung macrophages during homeostasis and provides examples of their different roles in the development and progression of lung fibrosis.
The respiratory epithelium is the major interface between the environment and the host. Sophisticated barrier, sensing, anti-microbial and immune regulatory mechanisms have evolved to help maintain ...homeostasis and to defend the lung against foreign substances and pathogens. During influenza virus infection, these specialised structural cells and populations of resident immune cells come together to mount the first response to the virus, one which would play a significant role in the immediate and long term outcome of the infection. In this review, we focus on the immune defence machinery of the respiratory epithelium and briefly explore how it repairs and regenerates after infection.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection carries a substantial risk of severe and prolonged illness; treatment options are currently limited. We assessed the efficacy ...and safety of inhaled nebulised interferon beta-1a (SNG001) for the treatment of patients admitted to hospital with COVID-19.
We did a randomised, double-blind, placebo-controlled, phase 2 pilot trial at nine UK sites. Adults aged 18 years or older and admitted to hospital with COVID-19 symptoms, with a positive RT-PCR or point-of-care test, or both, were randomly assigned (1:1) to receive SNG001 (6 MIU) or placebo by inhalation via a mouthpiece daily for 14 days. The primary outcome was the change in clinical condition on the WHO Ordinal Scale for Clinical Improvement (OSCI) during the dosing period in the intention-to-treat population (all randomised patients who received at least one dose of the study drug). The OSCI is a 9-point scale, where 0 corresponds to no infection and 8 corresponds to death. Multiple analyses were done to identify the most suitable statistical method for future clinical trials. Safety was assessed by monitoring adverse events for 28 days. This trial is registered with Clinicaltrialsregister.eu (2020-001023-14) and ClinicalTrials.gov (NCT04385095); the pilot trial of inpatients with COVID-19 is now completed.
Between March 30 and May 30, 2020, 101 patients were randomly assigned to SNG001 (n=50) or placebo (n=51). 48 received SNG001 and 50 received placebo and were included in the intention-to-treat population. 66 (67%) patients required oxygen supplementation at baseline: 29 in the placebo group and 37 in the SNG001 group. Patients receiving SNG001 had greater odds of improvement on the OSCI scale (odds ratio 2·32 95% CI 1·07-5·04; p=0·033) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (hazard ratio 2·19 95% CI 1·03-4·69; p=0·043). SNG001 was well tolerated. The most frequently reported treatment-emergent adverse event was headache (seven 15% patients in the SNG001 group and five 10% in the placebo group). There were three deaths in the placebo group and none in the SNG001 group.
Patients who received SNG001 had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo, providing a strong rationale for further trials.
Synairgen Research.
The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between ...countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.
Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause of this disease, many questions remain. In ...this Review, we perform a mechanistic interrogation of the immune activities that contribute to granuloma formation in sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared and divergent immune activities. We examine how Mycobacterium tuberculosis is sensed by the immune system; how the granuloma is initiated, formed, and perpetuated in tuberculosis compared with sarcoidosis; and the role of major innate and adaptive immune cells in shaping these processes. Finally, we draw these findings together around several recent high-resolution studies of the granuloma in situ that utilized the latest advances in single-cell technology combined with spatial methods to analyze plausible disease mechanisms. We conclude with an overall view of granuloma formation in sarcoidosis.
Abstract In order to increase the absorption of hydrophilic macromolecules in the small intestine, permeation enhancers such as chitosan (CS) and its derivatives have been evaluated. The aim of the ...current work was to investigate, on molecular levels, the effect of CS on tight junction (TJ) integrity in Caco-2 cells. The observed changes in transepithelial-electrical-resistance measurements and the staining patterns of the monolayer Caco-2 cells demonstrate that CS can transiently and reversibly open the TJs between cells, thus enhancing the paracellular permeability. TJ ultra-structures examined by transmission electron microscopy support the concept that CS did induce transient opening of TJs. We then assessed TJ disruption at the gene and protein expression levels. Our data indicate that exposure to CS followed by recovery resulted in a significant increase in claudin-4 ( Cldn4 ) gene transcription. Additionally, CS treatment induced redistribution of the TJ protein CLDN4 intracellularly following by its degradation in lysosomes, which represented an important contributing factor in TJ weakening, leading to the opening of TJs. The recovery of TJ after CS disruption required CLDN4 protein synthesis. These results suggest that CS regulates TJs by inducing changes in transmembrane CLDN4 protein. Understanding the mechanism of interaction between CS and epithelial cells is of paramount importance and needs to be established to aid further development in the use of CS to mediate the trans-epithelial drug delivery.
Recently, deep learning via convolutional neural networks (CNNs) has largely superseded conventional methods for proton (
H)-MRI lung segmentation. However, previous deep learning studies have ...utilized single-center data and limited acquisition parameters.
Develop a generalizable CNN for lung segmentation in
H-MRI, robust to pathology, acquisition protocol, vendor, and center.
Retrospective.
A total of 809
H-MRI scans from 258 participants with various pulmonary pathologies (median age (range): 57 (6-85); 42% females) and 31 healthy participants (median age (range): 34 (23-76); 34% females) that were split into training (593 scans (74%); 157 participants (55%)), testing (50 scans (6%); 50 participants (17%)) and external validation (164 scans (20%); 82 participants (28%)) sets.
1.5-T and 3-T/3D spoiled-gradient recalled and ultrashort echo-time
H-MRI.
2D and 3D CNNs, trained on single-center, multi-sequence data, and the conventional spatial fuzzy c-means (SFCM) method were compared to manually delineated expert segmentations. Each method was validated on external data originating from several centers. Dice similarity coefficient (DSC), average boundary Hausdorff distance (Average HD), and relative error (XOR) metrics to assess segmentation performance.
Kruskal-Wallis tests assessed significances of differences between acquisitions in the testing set. Friedman tests with post hoc multiple comparisons assessed differences between the 2D CNN, 3D CNN, and SFCM. Bland-Altman analyses assessed agreement with manually derived lung volumes. A P value of <0.05 was considered statistically significant.
The 3D CNN significantly outperformed its 2D analog and SFCM, yielding a median (range) DSC of 0.961 (0.880-0.987), Average HD of 1.63 mm (0.65-5.45) and XOR of 0.079 (0.025-0.240) on the testing set and a DSC of 0.973 (0.866-0.987), Average HD of 1.11 mm (0.47-8.13) and XOR of 0.054 (0.026-0.255) on external validation data.
The 3D CNN generated accurate
H-MRI lung segmentations on a heterogenous dataset, demonstrating robustness to disease pathology, sequence, vendor, and center.
4.
Stage 1.
iNKT cells modulate severe influenza by reducing accumulation of inflammatory monocytes in lungs; possibly by targeting infected inflammatory monocytes for lysis.
Little is known of how a strong ...immune response in the lungs is regulated to minimize tissue injury during severe influenza A virus (IAV) infection. Here, using a model of lethal, high‐pathogenicity IAV infection, we first show that Ly6ChiLy6G– inflammatory monocytes, and not neutrophils, are the main infiltrate in lungs of WT mice. Mice devoid of iNKT cells (Jα18−/− mice) have increased levels of inflammatory monocytes, which correlated with increased lung injury and mortality (but not viral load). Activation of iNKT cells correlated with reduction of MCP‐1 levels and improved outcome. iNKT cells were able to selectively lyse infected, MCP‐1‐producing monocytes in vitro, in a CD1d‐dependent process. Our study provides a detailed profile and kinetics of innate immune cells in the lungs during severe IAV infection, highlighting inflammatory monocytes as the major infiltrate and identifying a role for iNKT cells in control of these cells and lung immune‐pathology.
Multiferroics are of interest for memory and logic device applications, as the coupling between ferroelectric and magnetic properties enables the dynamic interaction between these order parameters. ...Here, we report an approach to control and switch local ferromagnetism with an electric field using multiferroics. We use two types of electromagnetic coupling phenomenon that are manifested in heterostructures consisting of a ferromagnet in intimate contact with the multiferroic BiFeO(3). The first is an internal, magnetoelectric coupling between antiferromagnetism and ferroelectricity in the BiFeO(3) film that leads to electric-field control of the antiferromagnetic order. The second is based on exchange interactions at the interface between a ferromagnet (Co(0.9)Fe(0.1)) and the antiferromagnet. We have discovered a one-to-one mapping of the ferroelectric and ferromagnetic domains, mediated by the colinear coupling between the magnetization in the ferromagnet and the projection of the antiferromagnetic order in the multiferroic. Our preliminary experiments reveal the possibility to locally control ferromagnetism with an electric field.
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