Ciprofloxacin is actively transported across bronchial lung epithelial cells using a calu-3 air interface cell model

Ciprofloxacin is a well-established broad-spectrum fluoroquinolone antibiotic that penetrates well into the lung tissues; still, the mechanisms of its transepithelial transport are unknown. The contributions of specific transporters, including multidrug efflux transporters, organic cation transporters, and organic anion-transporting polypeptide transporters, to the uptake of ciprofloxacin were investigated in vitro using an air interface bronchial epithelial model. Our results demonstrate that ciprofloxacin is subject to predominantly active influx and a slight efflux component. Copyright © 2013, American Society for Microbiology. All Rights Reserved

Repurposing of statins via inhalation to treat lung inflammatory conditions

© 2018 Elsevier B.V. Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism. Recent research has identified statins to have other protective pleiotropic properties including anti-inflammatory, anti-oxidant, muco-inhibitory effects that may be beneficial for the treatment of chronic inflammatory lung diseases. However, clinical studies have yielded conflicting results. This review will summarise some of the current evidences for statins pleiotropic effects that could be applied for the treatment of chronic inflammatory lung diseases, their mechanisms of actions, and the potential to repurpose statins as an inhaled therapy, including a detailed discussion on their different physical-chemical properties and how these characteristics could ultimately affect treatment efficacies. The repurposing of statins from conventional anti-cholesterol oral therapy to inhaled anti-inflammatory formulation is promising, as it provides direct delivery to the airways, reduced risk of side effects, increased bioavailability and tailored physical-chemical properties for enhanced efficacy

How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research.

The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment

Inhaled Liposomal Ciprofloxacin Nanoparticles Control the Release of Antibiotic at the Bronchial Epithelia

The cycle of respiratory tract infection (RTI) and inflammation in patients with chronic obstructive lung diseases, such as cystic fibrosis (CF), periodically develops into exacerbations, where chronic colonization of the airway by bacteria causes severe decline in lung function, leading to increased hospitalization and high mortality rates (1, 2). Current antibiotic inhalation treatments approved for the management of chronic airway infections in cystic fibrosis are limited to tobramycin (TOBI®) and more recently, aztreonam (Cayston®). A major drawback to these localized treatments of RTIs is the rapid absorption and clearance of antibiotics from the lungs requiring multiple daily inhalations of high concentration antibiotic solutions. Hence, liposomal ciprofloxacin nanoparticles were developed to prolong lung residence time of the antibiotics, with the view to enhance antimicrobial activity and reduce the burden of therapy for the patients and their relatives who often have to assist them. Although in vivo studies with aerosolized delivery of liposomal ciprofloxacin have previously been performed on human and animal subjects, in vitro cell models may be better suited to study the transport, interactions of drugs and carrier systems, and drug localization within and on the airway cell epithelium at a molecular level. Therefore, the aim of this study was to investigate the newly developed system allowing nebulized liposomal ciprofloxacin to be delivered directly to the bronchial epithelial surface in an established air interface Calu-3 cell model

In vitro and ex vivo methods predict the enhanced lung residence time of liposomal ciprofloxacin formulations for nebulisation

Liposomal ciprofloxacin formulations have been developed with the aim of enhancing lung residence time, thereby reducing the burden of inhaled antimicrobial therapy which requires multiple daily administration due to rapid absorptive clearance of antibiotics from the lungs. However, there is a lack of a predictive methodology available to assess controlled release inhalation delivery systems and their effect on drug disposition. In this study, three ciprofloxacin formulations were evaluated: a liposomal formulation, a solution formulation and a 1:1 combination of the two (mixture formulation). Different methodologies were utilised to study the release profiles of ciprofloxacin from these formulations: (i) membrane diffusion, (ii) air interface Calu-3 cells and (iii) isolated perfused rat lungs. The data from these models were compared to the performance of the formulations in vivo. The solution formulation provided the highest rate of absorptive transport followed by the mixture formulation, with the liposomal formulation providing substantially slower drug release. The rank order of drug release/transport from the different formulations was consistent across the in vitro andex vivo methods, and this was predictive of the profiles in vivo. The use of complimentary in vitro and ex vivo methodologies provided a robust analysis of formulation behaviour, including mechanistic insights, and predicted in vivo pharmacokinetics.© 2013 Elsevier B.V. All rights reserved

Exploring the Transcriptomic Data of the Australian Paralysis Tick, Ixodes Holocyclus

Ixodes holocyclus is the paralysis tickcommonly found in Australia. I. holocyclus does notcause paralysis in the primary host – bandicoots, butmarkedly affects secondary hosts such as companionanimals, livestock and humans. Holocyclotoxins are theneurotoxin molecules in I. holocyclus responsible forparalysis symptoms. There is a limited understanding ofholocyclotoxins due to the difficulties in purifying andexpressing these toxins in vitro. Next-generationsequencing technologies were utilised for the first time togenerate transcriptome data from two cDNA samples –salivary glands samples collected from female adult ticksengorged on paralysed companion animals and onbandicoots. Contig-encoded proteins in each librarywere annotated according to their best BLAST matchagainst several databases and functionally assigned intosix protein categories: housekeeping, transposableelements, pathogen-related, hypothetical, secreted andnovel. The “secreted protein” category is comprised often protein families: enzymes, protease inhibitors,antigens, mucins, immunity-related, lipocalins, glycinerich,putative secreted, salivary and toxin-like.Comparisons of contig representation between the twolibraries reveal the differential expression of tickproteins collected from different hosts. This studyprovides a preliminary description of the I. holocyclustick salivary gland transcriptome

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract.

Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases

Large enhancement of the thermopower in Nax_xCoO2_2 at high Na doping

Research on the oxide perovskites has uncovered electronic properties that are strikingly enhanced compared with those in conventional metals. Examples are the high critical temperatures of the cuprate superconductors and the colossal magnetoresistance in the manganites. The conducting layered cobaltate $\rm Na_xCoO_2$ displays several interesting electronic phases as $x$ is varied including water-induced superconductivity and an insulating state that is destroyed by field. Initial measurements showed that, in the as-grown composition, $\rm Na_xCoO_2$ displays moderately large thermopower $S$ and conductivity $\sigma$. However, the prospects for thermoelectric cooling applications faded when the figure of merit $Z$ was found to be small at this composition (0.6$<x<$0.7). Here we report that, in the poorly-explored high-doping region $x>$0.75, $S$ undergoes an even steeper enhancement. At the critical doping $x_p\sim$ 0.85, $Z$ (at 80 K) reaches values $\sim$40 times larger than in the as-grown crystals. We discuss prospects for low-temperature thermoelectric applications.Comment: 6 pages, 7 figure

Hypoxia increases neutrophil-driven matrix destruction after exposure to Mycobacterium tuberculosis.

The importance of neutrophils in the pathology of tuberculosis (TB) has been recently established. We demonstrated that TB lesions in man are hypoxic, but how neutrophils in hypoxia influence lung tissue damage is unknown. We investigated the effect of hypoxia on neutrophil-derived enzymes and tissue destruction in TB. Human neutrophils were stimulated with M. tuberculosis (M.tb) or conditioned media from M.tb-infected monocytes (CoMTB). Neutrophil matrix metalloproteinase-8/-9 and elastase secretion were analysed by luminex array and gelatin zymography, gene expression by qPCR and cell viability by flow cytometry. Matrix destruction was investigated by confocal microscopy and functional assays and neutrophil extracellular traps (NETs) by fluorescence assay. In hypoxia, neutrophil MMP-8 secretion and gene expression were up-regulated by CoMTB. MMP-9 activity and neutrophil elastase (NE) secretion were also increased in hypoxia. Hypoxia inhibited NET formation and both neutrophil apoptosis and necrosis after direct stimulation by M.tb. Hypoxia increased TB-dependent neutrophil-mediated matrix destruction of Type I collagen, gelatin and elastin, the main structural proteins of the human lung. Dimethyloxalylglycin (DMOG), which stabilizes hypoxia-inducible factor-1α, increased neutrophil MMP-8 and -9 secretion. Hypoxia in our cellular model of TB up-regulated pathways that increase neutrophil secretion of MMPs that are implicated in matrix destruction

Sliding charge density wave in manganites

The so-called stripe phase of the manganites is an important example of the complex behaviour of metal oxides, and has long been interpreted as the localisation of charge at atomic sites. Here, we demonstrate via resistance measurements on La_{0.50}Ca_{0.50}MnO_3 that this state is in fact a prototypical charge density wave (CDW) which undergoes collective transport. Dramatic resistance hysteresis effects and broadband noise properties are observed, both of which are typical of sliding CDW systems. Moreover, the high levels of disorder typical of manganites result in behaviour similar to that of well-known disordered CDW materials. Our discovery that the manganite superstructure is a CDW shows that unusual transport and structural properties do not require exotic physics, but can emerge when a well-understood phase (the CDW) coexists with disorder.Comment: 13 pages; 4 figure