11 research outputs found
Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects
status: publishe
Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury
Acetaminophen (APAP) intoxication is the foremost cause of drug-induced liver failure in developed countries. The only pharmacologic treatment option, N-acetylcysteine (NAC), is not effective for patients who are admitted too late and/or who have excessive liver damage, emphasizing the need for alternative treatment options. APAP intoxication results in hepatocyte death and release of danger signals, which further contribute to liver injury, in part by hepatic monocyte/macrophage infiltration and activation. Metallothionein (MT) 1 and 2 have important danger signaling functions and might represent novel therapeutic targets in APAP overdose. Therefore, we evaluated hepatic MT expression and the effect of anti-MT antibodies on the transcriptional profile of the hepatic macrophage population and liver injury following APAP overdose in mice. Hepatic MT expression was significantly induced in APAP-intoxicated mice and abundantly present in human livers. APAP intoxication in mice resulted in increased serum transaminase levels, extended necrotic regions on liver histology and induced expression of proinflammatory markers, which was significantly less pronounced in mice treated with anti-MT antibodies. Anti-MT antibody therapy attenuated proinflammatory macrophage polarization, as demonstrated by RNA sequencing analyses of isolated liver macrophages and in LPS-stimulated bone marrow-derived macrophages. Importantly, NAC and anti-MT antibodies were equally effective whereas administration of anti-MT antibody in combination with NAC exceeded the efficiency of both monotherapies in APAP-induced liver injury (AILI). We conclude that the neutralization of secreted MTs using a monoclonal antibody is a novel therapeutic strategy as mono- or add-on therapy for AILI. In addition, we provide evidence suggesting that MTs in the extracellular environment are involved in macrophage polarization
Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects
Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects
Innate lymphoid cells in isocyanate-induced asthma: role of microRNA-155
Occupational asthma, induced by workplace exposures to low molecular weight (LMW) agents such as toluene 2,4-diisocyanate (TDI), causes a significant burden to patients and society. Little is known about innate lymphoid cells (ILC) in TDI-induced asthma. A critical regulator of ILC function is microRNA-155, a microRNA associated with asthma
Expression of ACE2, the SARS-CoV-2 Receptor, in Lung Tissue of Patients With Type 2 Diabetes
Quantification and role of innate lymphoid cell subsets in Chronic Obstructive Pulmonary Disease
Objectives: Innate lymphoid cells (ILCs) secrete cytokines, such as IFN-γ, IL-13 and IL-17, which are linked to chronic obstructive pulmonary disease (COPD). Here, we investigated the role of pulmonary ILCs in COPD pathogenesis. Methods: Lung ILC subsets in COPD and control subjects were quantified using flow cytometry and associated with clinical parameters. Tissue localisation of ILC and T-cell subsets was determined by immunohistochemistry. Mice were exposed to air or cigarette smoke (CS) for 1, 4 or 24 weeks to investigate whether pulmonary ILC numbers and activation are altered and whether they contribute to CS-induced innate inflammatory responses. Results: Quantification of lung ILC subsets demonstrated that ILC1 frequency in the total ILC population was elevated in COPD and was associated with smoking and severity of respiratory symptoms (COPD Assessment Test [CAT] score). All three ILC subsets localised near lymphoid aggregates in COPD. In the COPD mouse model, CS exposure in C57BL/6J mice increased ILC numbers at all time points, with relative increases in ILC1 in bronchoalveolar lavage (BAL) fluid. Importantly, CS exposure induced increases in neutrophils, monocytes and dendritic cells that remained elevated in Rag2/Il2rg-deficient mice that lack adaptive immune cells and ILCs. However, CS-induced CXCL1, IL-6, TNF-α and IFN-γ levels were reduced by ILC deficiency. Conclusion: The ILC1 subset is increased in COPD patients and correlates with smoking and severity of respiratory symptoms. ILCs also increase upon CS exposure in C57BL/6J mice. In the absence of adaptive immunity, ILCs contribute to CS-induced pro-inflammatory mediator release, but are redundant in CS-induced innate inflammation
Necroptosis signaling promotes inflammation, airway remodeling, and emphysema in chronic obstructive pulmonary disease
Selective Replacement of Cholesterol with Cationic Amphiphilic Drugs Enables the Design of Lipid Nanoparticles with Improved RNA Delivery
The delivery of RNA across biological barriers can be
achieved
by encapsulation in lipid nanoparticles (LNPs). Cationic amphiphilic
drugs (CADs) are pharmacologically diverse compounds with ionizable
lipid-like features. In this work, we applied CADs as a fifth component
of state-of-the-art LNPs via microfluidic mixing. Improved cytosolic
delivery of both siRNA and mRNA was achieved by partly replacing the
cholesterol fraction of LNPs with CADs. The LNPs could cross the mucus
layer in a mucus-producing airâliquid interface model of human
primary bronchial epithelial cells following nebulization. Moreover,
CAD-LNPs demonstrated improved epithelial and endothelial targeting
following intranasal administration in mice, without a marked pro-inflammatory
signature. Importantly, quantification of the CAD-LNP molar composition,
as demonstrated for nortriptyline, revealed a gradual leakage of the
CAD from the formulation during LNP dialysis. Altogether, these data
suggest that the addition of a CAD prior to the rapid mixing process
might have an impact on the composition, structure, and performance
of LNPs