Airway Smooth Muscle and Asthma.

Airway smooth muscle (ASM) was first described in 1804 by Franz Daniel Reisseisen (as related by Otis (1983)) [...

Childhood asthma diagnoses declined during the COVID-19 pandemic in the United States.

Background: Prior studies have documented declines in pediatric asthma exacerbations and asthma-related health care utilization during the COVID-19 pandemic, but less is known about the incidence of asthma during the pandemic.

Methods: We conducted a retrospective cohort study of children under age 18 without a prior diagnosis of asthma within a large US commercial claims database. Incident asthma was defined using a combination of diagnosis codes, location of services, and medication dispensing.

The role of innate lymphocytes in regulating brain and cognitive function.

Mounting evidence indicates complex interaction between the immune system and the nervous system, challenging the traditional view about the immune privilege of the brain. Innate lymphoid cells (ILCs) and innate-like T cells are unique families of immune cells that functionally mirror traditional T cells but may function via antigen- and T cell antigen receptor (TCR)-independent mechanisms. Recent work indicates that various ILCs and innate-like T cell subsets are present in the brain barrier tissue, where they play important roles in regulating brain barrier integrity, brain homeostasis and cognitive function.

A Par3/LIM Kinase/Cofilin Pathway Mediates Human Airway Smooth Muscle Relaxation by TAS2R14.

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical G-mediated stimulation of Ca release from intracellular stores by activation of PLCβ (phospholipase Cβ). Alone, this [Ca] signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at G-coupled receptors also increase [Ca].

Mechanistic Links Between Obesity and Airway Pathobiology Inform Therapies for Obesity-Related Asthma.

Obesity-related asthma is associated with a high disease burden and a poor response to existent asthma therapies, suggesting that it is a distinct asthma phenotype. The proposed mechanisms that contribute to obesity-related asthma include the effects of the mechanical load of obesity, adipokine perturbations, and immune dysregulation. Each of these influences airway smooth muscle function.

Mucosal-associated invariant T cells restrict reactive oxidative damage and preserve meningeal barrier integrity and cognitive function.

Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood. Mucosal-associated invariant T cells (MAIT cells) are a unique type of innate-like T cell with molecular and functional properties that remain to be better characterized.

Community- Versus Health Care Organization-Based Approaches to Expanding At-Home COVID-19 Testing in Black and Latino Communities, New Jersey, 2021.

At-home COVID-19 testing offers convenience and safety advantages. We evaluated at-home testing in Black and Latino communities through an intervention comparing community-based organization (CBO) and health care organization (HCO) outreach. From May through December 2021, 1100 participants were recruited, 94% through CBOs.

Starving a Cell Promotes Airway Smooth Muscle Relaxation: Inhibition of Glycolysis Attenuates Excitation-Contraction Coupling.

Bronchomotor tone modulated by airway smooth muscle shortening represents a key mechanism that increases airway resistance in asthma. Altered glucose metabolism in inflammatory and airway structural cells is associated with asthma. Although these observations suggest a causal link between glucose metabolism and airway hyperresponsiveness, the mechanisms are unclear.

Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear. We applied Mendelian randomization analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis [AD]). We conducted two-sample bidirectional Mendelian randomization to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies conducted on asthma ( = 56,167) and GERD ( = 71,522).

Crosstalk between CD4 T Cells and Airway Smooth Muscle in Pediatric Obesity-related Asthma.

Pediatric obesity-related asthma is a nonatopic asthma phenotype with high disease burden and few effective therapies. RhoGTPase upregulation in peripheral blood T helper (Th) cells is associated with the phenotype, but the mechanisms that underlie this association are not known. To investigate the mechanisms by which upregulation of CDC42 (Cell Division Cycle 42), a RhoGTPase, in Th cells is associated with airway smooth muscle (ASM) biology.

CEBPD modulates the airway smooth muscle transcriptomic response to glucocorticoids.

Background: CCAAT/Enhancer Binding Protein D (CEBPD), a pleiotropic glucocorticoid-responsive transcription factor, modulates inflammatory responses. Of relevance to asthma, expression of CEBPD in airway smooth muscle (ASM) increases with glucocorticoid exposure. We sought to characterize CEBPD-mediated transcriptomic responses to glucocorticoid exposure in ASM by measuring changes observed after knockdown of CEBPD and its impact on asthma-related ASM function.

Development of an aerosol intervention for COVID-19 disease: Tolerability of soluble ACE2 (APN01) administered via nebulizer.

As ACE2 is the critical SARS-CoV-2 receptor, we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung, and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here, after demonstrating in vitro neutralization of SARS-CoV-2 by APN01, and after obtaining preliminary evidence of its tolerability and preventive efficacy in a mouse model, we pursued development of an aerosol formulation. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization.

Obesity elicits a unique metabolomic signature in human airway smooth muscle cells.

Obesity can aggravate asthma by enhancing airway hyperresponsiveness (AHR) and attenuating response to treatment. However, the precise mechanisms linking obesity and asthma remain unknown. Human airway smooth muscle (HASM) cells exhibit amplified excitation-contraction (EC) coupling and force generation in obesity.

Epinephrine evokes shortening of human airway smooth muscle cells following β adrenergic receptor desensitization.

Epinephrine (EPI), an endogenous catecholamine involved in the body's fight-or-flight responses to stress, activates α-adrenergic receptors (αARs) expressed on various organs to evoke a wide range of physiological functions, including vasoconstriction. In the smooth muscle of human bronchi, however, the functional role of EPI on αARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating β-adrenergic receptors (βARs).

Biologic use and outcomes among adults with severe asthma treated by US subspecialists.

Background: Multiple biologics are now available for severe asthma (SA) treatment and can improve outcomes for patients. However, few available data describe the real-world use and effectiveness of multiple approved biologics, including biologic switching, among subspecialists in the United States.

Objective: To evaluate biologic use and associated exacerbation outcomes in a large cohort of subspecialist-treated US adults with SA.

Selective Signal Capture from Multidimensional GPCR Outputs with Biased Agonists: Progress Towards Novel Drug Development.

G protein coupled receptors (GPCRs) are a superfamily of transmembrane-spanning receptors that are activated by multiple endogenous ligands and are the most common target for agonist or antagonist therapeutics across a broad spectrum of diseases. Initial characterization within the superfamily suggested that a receptor activated a single intracellular pathway, depending on the G protein to which it coupled. However, it has become apparent that a given receptor can activate multiple different pathways, some being therapeutically desirable, while others are neutral or promote deleterious signaling.

Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma.

Background: As asthma symptoms worsen, patients typically rely on short-acting β-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation.

Methods: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial.

G Protein-Coupled Receptor Kinase 2 (GRK2) Regulates T Cell Response in a Murine Model of House Dust Mite-Induced Asthma.

G protein-coupled receptor kinase 2 (GRK2) is an adapter protein that modulates G protein-coupled receptor (GPCR) signaling. It also regulates the functions and activity of other intracellular proteins in many cell types. Accordingly, GRK2 is thought to contribute to disease progression by a variety of mechanisms related to its multifunctional roles.

Abi1 mediates airway smooth muscle cell proliferation and airway remodeling via Jak2/STAT3 signaling.

Asthma is a complex pulmonary disorder with multiple pathological mechanisms. A key pathological feature of chronic asthma is airway remodeling, which is largely attributed to airway smooth muscle (ASM) hyperplasia that contributes to thickening of the airway wall and further drives asthma pathology. The cellular processes that mediate ASM cell proliferation are not completely elucidated.

Identifying a reference list of respiratory sensitizers for the evaluation of novel approaches to study respiratory sensitization.

The induction of immunological responses that trigger bio-physiological symptoms in the respiratory tract following repeated exposure to a substance, is known as respiratory sensitization. The inducing compound is known as a respiratory sensitizer. While respiratory sensitization by high molecular weight (HMW) materials is recognized and extensively studied, much less information is available regarding low molecular weight (LMW) materials as respiratory sensitizers.

Experiences of Black and Latinx health care workers in support roles during the COVID-19 pandemic: A qualitative study.

Black and Latinx individuals, and in particular women, comprise an essential health care workforce often serving in support roles such as nursing assistants and dietary service staff. Compared to physicians and nurses, they are underpaid and potentially undervalued, yet play a critical role in health systems. This study examined the impact of the coronavirus disease 2019 (COVID-19) pandemic from the perspective of Black and Latinx health care workers in support roles (referred to here as HCWs).