Macrophages Orchestrate Airway Inflammation, Remodeling, and Resolution in Asthma.

Asthma is a heterogenous chronic inflammatory lung disease with endotypes that manifest different immune system profiles, severity, and responses to current therapies. Regardless of endotype, asthma features increased immune cell infiltration, inflammatory cytokine release, and airway remodeling. Lung macrophages are also heterogenous in that there are separate subsets and, depending on the environment, different effector functions.

Aging-Related Mechanisms Contribute to Corticosteroid Insensitivity in Elderly Asthma.

Asthma in elderly populations is an increasing health problem that is accompanied by diminished lung function and frequent exacerbations. As potent anti-inflammatory drugs, corticosteroids are commonly used to reduce lung inflammation, improve lung function, and manage disease symptoms in asthma. Although effective for most individuals, older patients are more insensitive to corticosteroids, making it difficult to manage asthma in this population.

Impact of elexacaftor-tezacaftor-ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis.

Background: Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF).

In Vitro Screening Method for Characterization of Macrophage Activation Responses.

Macrophage activation refers to the enhanced functionality of macrophages in response to endogenous or exogenous stimuli. Due to the existence of limitless stimuli and a multitude of receptors on macrophage surfaces, the nature of activation (or acquired functioning) can be specific to the encountering stimulus. This article describes a macrophage-activation screening platform in a 96-well format.

Th1 cytokines synergize to change gene expression and promote corticosteroid insensitivity in pediatric airway smooth muscle.

Background: Corticosteroids remain a key therapy for treating children with asthma. Patients with severe asthma are insensitive, resistant, or refractory to corticosteroids and have poorly controlled symptoms that involve airway inflammation, airflow obstruction, and frequent exacerbations. While the pathways that mediate corticosteroid insensitivity in asthma remain poorly defined, recent studies suggest that enhanced Th1 pathways, mediated by TNFα and IFNγ, may play a role.

PRMT5 in T Cells Drives Th17 Responses, Mixed Granulocytic Inflammation, and Severe Allergic Airway Inflammation.

Severe asthma is characterized by steroid insensitivity and poor symptom control and is responsible for most asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding of mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in human asthmatic lungs.

Corticosteroid insensitivity persists in the absence of STAT1 signaling in severe allergic airway inflammation.

Corticosteroid insensitivity in asthma limits the ability to effectively manage severe asthma, which is characterized by persistent airway inflammation, airway hyperresponsiveness (AHR), and airflow obstruction despite corticosteroid treatment. Recent reports indicate that corticosteroid insensitivity is associated with increased interferon-γ (IFN-γ) levels and T-helper (Th) 1 lymphocyte infiltration in severe asthma. Signal transducer and activator of transcription 1 (STAT1) activation by IFN-γ is a key signaling pathway in Th1 inflammation; however, its role in the context of severe allergic airway inflammation and corticosteroid sensitivity remains unclear.

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD.

Corticosteroid insensitivity is a key characteristic of patients with severe asthma and COPD. These individuals experience greater pulmonary oxidative stress and inflammation, which contribute to diminished lung function and frequent exacerbations despite the often and prolonged use of systemic, high dose corticosteroids. Reactive oxygen and nitrogen species (RONS) promote corticosteroid insensitivity by disrupting glucocorticoid receptor (GR) signaling, leading to the sustained activation of pro-inflammatory pathways in immune and airway structural cells.

Myeloid-IL4Rα is an indispensable link in IL-33-ILCs-IL-13-IL4Rα axis of eosinophil recruitment in murine lungs.

Increased eosinophil recruitment is a hallmark feature of eosinophilic disorders. Here, we delineated the key molecular and cellular players involved in physiological eosinophilic recruitment during normal postnatal lung development in mice. Physiological eosinophilic recruitment was consistently present in 7-, 10-, and 15-day-old neonatal mice, but not in 42-day-old mice.

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice.

Tristetraprolin (TTP) is a mRNA binding protein that binds to adenylate-uridylate-rich elements within the 3' untranslated regions of certain transcripts, such as tumor necrosis factor () mRNA, and increases their rate of decay. Modulation of TTP expression is implicated in inflammation; however, its role in acute lung inflammation remains unknown. Accordingly, we tested the role of TTP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.

The Innate Lymphoid System Is a Critical Player in the Manifestation of Mucoinflammatory Airway Disease in Mice.

Innate lymphoid and adaptive immune cells are known to regulate epithelial responses, including mucous cell metaplasia (MCM), but their roles in mucoinflammatory airway diseases, such as cystic fibrosis, remain unknown. transgenic (-Tg) mice, which recapitulate cystic fibrosis-like mucoinflammatory airway disease, deficient in innate lymphoid ( knockout mice [ ]), adaptive immune ( knockout mice [ ]), or both systems ( / ), were employed to investigate their respective contributions in the pathogenesis of mucoinflammatory airway disease. As previously reported, immunocompetent Tg juveniles exhibited spontaneous neonatal bacterial infections with robust mucoinflammatory features, including elevated expression of -associated markers accompanied by MCM, elevated MUC5B expression, and airway mucus obstruction.

Ablation of IL-33 Suppresses Responses but Is Accompanied by Sustained Mucus Obstruction in the Transgenic Mouse Model.

Cystic fibrosis is characterized by dehydration of the airway surface liquid layer with persistent mucus obstruction. immune responses are often manifested as increased mucous cell density (mucous cell metaplasia) associated with mucus obstruction. IL-33 is a known inducer of immune responses, but its roles in mucus obstruction and related phenotypes in a cystic fibrosis-like lung disease model (i.

Immunopathology of Airway Surface Liquid Dehydration Disease.

The primary purpose of pulmonary ventilation is to supply oxygen (O) for sustained aerobic respiration in multicellular organisms. However, a plethora of abiotic insults and airborne pathogens present in the environment are occasionally introduced into the airspaces during inhalation, which could be detrimental to the structural integrity and functioning of the respiratory system. Multiple layers of host defense act in concert to eliminate unwanted constituents from the airspaces.

Effect of LysM+ macrophage depletion on lung pathology in mice with chronic bronchitis.

Macrophages (MΦ) are key sentinels of respiratory exposure to inhaled environmental stimuli. In normal "healthy" tissues, MΦ are believed to be a dormant cell type that, upon exposure to stress-causing stimuli, may get activated to exhibit pro- or anti-inflammatory roles. To test whether stress present in chronic bronchitic (CB) airways triggers MΦ to manifest protective or detrimental responses, the DTA+ (LysM-regulated Diphtheria Toxin A expressing) strain with partial MΦ-deficiency was crossed with the Scnn1b-Tg mouse model of CB and the progenies were studied at 4-5 weeks of age.

Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease.

Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed transgenic (-Tg) mice to SHS from postnatal day (PND) 3-21 and lung phenotypes were examined at PND22.