Mesenchymal stromal cells reduce inflammation and improve lung function in a mouse model of cystic fibrosis lung disease.

Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which possess immunomodulatory and repair capabilities. In this study, we investigated whether MSC therapy could modulate inflammation and lung damage in the lungs of Scnn1b-transgenic mice overexpressing the β-subunit of the epithelial sodium channel (β-ENaC), a model with features of Cystic Fibrosis lung disease. Human bone marrow derived MSC cells were intravenously delivered to mice, prior to collection of bronchoalveolar lavage (BALF) and tissue.

PROTECTION OF MICE AGAINST CECAL LIGATION AND PUNCTURE-INDUCED POLYMICROBIAL SEPSIS BY A FASCIOLA HEPATICA HELMINTH DEFENSE MOLECULE.

Sepsis results from a dysregulated host immune response to infection and is responsible for ~11 million deaths each year. In the laboratory, many aspects of sepsis can be replicated using a cecal ligation and puncture model, which is considered the most clinically relevant rodent model of sepsis. In the present study, histological and biomarker multiplex analyses revealed that the cecal ligation and puncture model initiated a large-scale inflammatory response in mice by 24 h, with evidence of acute organ damage by 48-72 h.

Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects.

Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function.

Bacterial Outer Membrane Vesicles: Role in Pathogenesis and Host-Cell Interactions.

Outer membrane vesicles (OMVs) are small, spherical structures released from the outer membranes of Gram-negative bacteria into the surrounding environment. Investigations into OMVs range from their biogenesis and cargo composition to their ability to transfer virulence factors and modulate host immune responses. This emerging understanding of OMVs has unveiled their pivotal role in the pathogenicity of infectious diseases, shedding light on their interactions with host cells, their contributions to inflammation, their potential involvement in antimicrobial resistance, and their promising use for the development of novel treatments and therapies.

Diminished airway host innate response in people with cystic fibrosis who experience frequent pulmonary exacerbations.

Rationale: Pulmonary exacerbations are clinically impactful events that accelerate cystic fibrosis (CF) lung disease progression. The pathophysiological mechanisms underlying an increased frequency of pulmonary exacerbations have not been explored.

Objectives: To compare host immune response during intravenous antibiotic treatment of pulmonary exacerbations in people with CF who have a history of frequent infrequent exacerbations.

The relationship between plasma cystatin C, mortality and acute respiratory distress syndrome subphenotype in the HARP-2 trial.

To evaluate the performance of cystatin C as a prognostic and predictive marker in a trial of patients with acute respiratory distress syndrome (ARDS). A retrospective analysis was performed on plasma samples from patients included in the HARP-2 (hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction) trial - a multicentre, phase 2b trial carried out in general intensive care units across 40 hospitals in the United Kingdom and Ireland. Cystatin C concentrations in plasma obtained from 466 patients with ARDS (before they were randomly assigned in the trial) were quantified by ELISA (enzyme-linked immunosorbent assay).

Airway Epithelium Senescence as a Driving Mechanism in COPD Pathogenesis.

Cellular senescence is a state of permanent cell cycle arrest triggered by various intrinsic and extrinsic stressors. Cellular senescence results in impaired tissue repair and remodeling, loss of physiological integrity, organ dysfunction, and changes in the secretome. The systemic accumulation of senescence cells has been observed in many age-related diseases.

Vascular risk factors for COVID-19 ARDS: endothelium, contact-kinin system.

SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and obesity-conditions linked by the presence of endothelial pathology. Viral infection in this setting causes increased conversion of circulating Factor XII to its active form (FXIIa).

Valaciclovir for Epstein-Barr Virus Suppression in Moderate-to-Severe COPD: A Randomized Double-Blind Placebo-Controlled Trial.

Background: Epstein-Barr virus (EBV) frequently is measured at high levels in COPD using sputum quantitative polymerase chain reaction, whereas airway immunohistochemistry analysis has shown EBV detection to be common in severe disease.

Research Question: Is valaciclovir safe and effective for EBV suppression in COPD?

Study Design And Methods: The Epstein-Barr Virus Suppression in COPD (EViSCO) trial was a randomized double-blind placebo-controlled trial conducted at the Mater Hospital Belfast, Northern Ireland. Eligible patients had stable moderate-to-severe COPD and sputum EBV (measured using quantitative polymerase chain reaction) and were assigned randomly (1:1) to valaciclovir (1 g tid) or matching placebo for 8 weeks.

In vitro evaluation of the potential use of snake-derived peptides in the treatment of respiratory infections using inhalation therapy: A proof of concept study.

Inhalation therapy using nebulisers is an attractive non-invasive route for drug delivery, particularly for the treatment of lung infections with anti-inflammatory and anti-microbial compounds. This study evaluated the suitability of three snake-derived peptides (termed Sn1b, SnE1 and SnE1-F), which we have recently shown have potent anti-inflammatory and bacteriostatic activities, for nebulisation using a vibrating mesh nebuliser (VMN). The effect of nebulisation on peptide concentration, stability and function were assessed, prior to progression to aerodynamic particle size distribution, and in vitro drug delivery in simulated adult spontaneous breathing and mechanical ventilated patient models.

Secretory Leucoprotease Inhibitor (SLPI) Promotes Survival during Acute Infection by Suppression of Inflammation Rather Than Microbial Killing.

Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary infection. Mice lacking SLPI were highly susceptible to infection, however there was no difference in bacterial burden.

The Effect of CFTR Modulators on Airway Infection in Cystic Fibrosis.

The advent of Cystic fibrosis transmembrane receptor (CFTR) modulators in 2012 was a critical event in the history of cystic fibrosis (CF) treatment. Unlike traditional therapies that target downstream effects of CFTR dysfunction, CFTR modulators aim to correct the underlying defect at the protein level. These genotype-specific therapies are now available for an increasing number of CF patients, transforming the way we view the condition from a life-limiting disease to one that can be effectively managed.

Altered Differentiation and Inflammation Profiles Contribute to Enhanced Innate Responses in Severe COPD Epithelium to Rhinovirus Infection.

Background: Respiratory viral infections are closely associated with COPD exacerbations, hospitalisations, and significant morbidity and mortality. The consequences of the persisting inflammation and differentiation status in virus associated severe disease is not fully understood. The aim of this study was to evaluate barrier function, cellular architecture, the inflammatory response in severe COPD bronchial epithelium to human rhinovirus (HRV) induced pathological changes and innate immune responses.

Cathepsin S Contributes to Lung Inflammation in Acute Respiratory Distress Syndrome.

Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments. To characterize the status of cathepsin S in acute lung inflammation and examine the role of cathepsin S in disease pathogenesis. Human and mouse model BAL fluid samples were analyzed for the presence and activity of cathepsin S and its endogenous inhibitors.

Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium.

COPD is a chronic lung disorder characterized by a progressive and irreversible airflow obstruction, and persistent pulmonary inflammation. It has become a global epidemic affecting 10% of the population, and is the third leading cause of death worldwide. Respiratory viruses are a primary cause of COPD exacerbations, often leading to secondary bacterial infections in the lower respiratory tract.

The Impact of Lung Proteases on Snake-Derived Antimicrobial Peptides.

Respiratory infections are a leading cause of global morbidity and mortality and are of significant concern for individuals with chronic inflammatory lung diseases. There is an urgent need for novel antimicrobials. Antimicrobial peptides (AMPs) are naturally occurring innate immune response peptides with therapeutic potential.

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease.

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline.

Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult ENaC-Tg Mice.

Background: Elevated levels of the cysteine protease cathepsin S (CatS) are associated with chronic mucoobstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). We have previously demonstrated that prophylactic treatment with a CatS inhibitor from birth reduces inflammation, mucus plugging, and lung tissue damage in juvenile -epithelial Na+ channel-overexpressing transgenic (ENaC-Tg) mice with chronic inflammatory mucoobstructive lung disease. In this study, we build upon this work to examine the effects of therapeutic intervention with a CatS inhibitor in adult ENaC-Tg mice with established disease.

Coinfection with and in cystic fibrosis.

Objectives: Cystic fibrosis (CF) lung disease is characterised by mucus stasis, chronic infection and inflammation, causing progressive structural lung disease and eventual respiratory failure. CF airways are inhabited by an ecologically diverse polymicrobial environment with vast potential for interspecies interactions, which may be a contributing factor to disease progression. and are the most common bacterial and fungal species present in CF airways respectively and coinfection results in a worse disease phenotype.

-Derived Molecules as Regulators of the Host Immune Response.

Helminths (worms) are one of the most successful organisms in nature given their ability to infect millions of humans and animals worldwide. Their success can be attributed to their ability to modulate the host immune response for their own benefit by releasing excretory-secretory (ES) products. Accordingly, ES products have been lauded as a potential source of immunomodulators/biotherapeutics for an array of inflammatory diseases.