VRAC Complex Modulates Mechano-Electrical Signal Responses in Human Airway Smooth Muscle Shortening.

Leucine-rich repeat containing 8A (LRRC8A) is an obligatory constituent of the volume-regulated anion channel (VRAC) that is fundamental to a wide range of biological processes, including regulating cell size, proliferation, and migration. Here we explored the physiological role for VRAC in excitation-contraction (E-C) coupling and shortening of human airway smooth muscle (HASM). In HASM cells, pharmacological inhibition of VRAC with DCPIB (0.

Bronchomotor tone imbalance evokes airway hyperresponsiveness.

Introduction: Obstructive airway diseases asthma and COPD represent a significant healthcare burden. Airway hyperresponsiveness (AHR), a salient feature of these two diseases, remains the main therapeutic target. Airway smooth muscle (ASM) cell is pivotal for bronchomotor tone and development of AHR in airway diseases.

An Analysis of Tube Thoracostomy in Combat Implications for Improved Prehospital Recognition and Treatment.

Background: Thoracic trauma occurs frequently in combat and is associated with high mortality. Tube thoracostomy (chest tube) is the treatment for pneumothorax resulting from thoracic trauma, but little data exist to characterize combat casualties undergoing this intervention. We sought to describe the incidence of these injuries and procedures to inform training and materiel development priorities.

Juke Stick: A Case of Pediatric Atraumatic Compartment Syndrome.

Compartment syndrome is usually due to trauma but can also have atraumatic causes. It is defined as a compromise of neurovascular and muscle function that presents symptomatically with the six P's: pain, pallor, paresthesia, paralysis, poikilothermia, and pulselessness. Diagnosis is confirmed by a delta pressure of <30 mmHg (diastolic blood pressure minus the compartment pressure).

The Bronchoprotective Effects of Dual Pharmacology, Muscarinic Receptor Antagonist and β Adrenergic Receptor Agonist Navafenterol in Human Small Airways.

Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β adrenergic receptor (βAR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is a single-molecule, dual pharmacology agent combining muscarinic antagonist and βAR agonist functions, currently in development as a COPD therapeutic.

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.

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.

Helicopter Crashes in the Deployed Combat Setting: The Department of Defense Trauma Registry Experience.

Background: Military helicopter mishaps frequently lead to multiple casualty events with complex injury patterns. Data specific to this mechanism of injury in the deployed setting are limited. We describe injury patterns associated with helicopter crashes.

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.

TGF-β: The missing link in obesity-associated airway diseases?

Obesity is emerging as a global public health epidemic. The co-morbidities associated with obesity significantly contribute to reduced quality of life, mortality, and global healthcare burden. Compared to other asthma comorbidities, obesity prominently engenders susceptibility to inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), contributes to greater disease severity and evokes insensitivity to current therapies.

Inhibition of ABCC1 Decreases cAMP Egress and Promotes Human Airway Smooth Muscle Cell Relaxation.

In most living cells, the second-messenger roles for adenosine 3',5'-cyclic monophosphate (cAMP) are short-lived, confined to the intracellular space, and tightly controlled by the binary switch-like actions of Gα (stimulatory G protein)-activated adenylyl cyclase (cAMP production) and cAMP-specific PDE (cAMP breakdown). Here, by using human airway smooth muscle (HASM) cells in culture as a model, we report that activation of the cell-surface βAR (β-adrenoceptor), a G-coupled GPCR (G protein-coupled receptor), evokes cAMP egress to the extracellular space. Increased extracellular cAMP levels ([cAMP]) are long-lived in culture and are induced by receptor-dependent and receptor-independent mechanisms in such a way as to define a universal response class of increased intracellular cAMP levels ([cAMP]).

Prehospital Intervention Analysis of Helicopter Crashes in Afghanistan.

Background: Based on isolated case reports, military helicopter mishaps often result in multiple critical casualties leading to complicated stabilization and evacuation by healthcare providers. The aim of this retrospective descriptive analysis is to describe the incidence of common prehospital injuries associated with rotary wing crashes in order to improve mission planning and casualty survivability.

Methods: This is a secondary analysis of data from the Prehospital Trauma Registry and the Department of Defense Trauma Registry (DoDTR) from April 2003 through May 2019.

Metabolomics in asthma: A platform for discovery.

Asthma, characterized by airway hyperresponsiveness, inflammation and remodeling, is a chronic airway disease with complex etiology. Severe asthma is characterized by frequent exacerbations and poor therapeutic response to conventional asthma therapy. A clear understanding of cellular and molecular mechanisms of asthma is critical for the discovery of novel targets for optimal therapeutic control of asthma.

Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells.

N-methyl-D-aspartate (NMDA) receptors are widely expressed in the central nervous system. However, their presence and function at extraneuronal sites is less well characterized. In the present study, we examined the expression of NMDA receptor subunit mRNA and protein in human pulmonary artery (HPA) by quantitative polymerase chain reaction (PCR), immunohistochemistry and immunoblotting.

FFAR1 activation attenuates histamine-induced myosin light chain phosphorylation and cortical tension development in human airway smooth muscle cells.

Background: Activation of free fatty acid receptors (FFAR1 and FFAR4) which are G protein-coupled receptors (GPCRs) with established (patho)physiological roles in a variety of obesity-related disorders, induce human airway smooth muscle (HASM) cell proliferation and shortening. We reported amplified agonist-induced cell shortening in HASM cells obtained from obese lung donors. We hypothesized that FFAR1 modulate excitation-contraction (EC) coupling in HASM cells and play a role in obesity-associated airway hyperresponsiveness.

The odorant receptor OR2W3 on airway smooth muscle evokes bronchodilation via a cooperative chemosensory tradeoff between TMEM16A and CFTR.

The recent discovery of sensory (tastant and odorant) G protein-coupled receptors on the smooth muscle of human bronchi suggests unappreciated therapeutic targets in the management of obstructive lung diseases. Here we have characterized the effects of a wide range of volatile odorants on the contractile state of airway smooth muscle (ASM) and uncovered a complex mechanism of odorant-evoked signaling properties that regulate excitation-contraction (E-C) coupling in human ASM cells. Initial studies established multiple odorous molecules capable of increasing intracellular calcium ([Ca]) in ASM cells, some of which were (paradoxically) associated with ASM relaxation.

Melon with a Twist: A Case of Nicotine Overdose After Ingestion and Aspiration of Vape Liquid.

We present the case of an active duty 21-year-old male with severe hypoxic respiratory failure after accidentally ingesting, and subsequently aspirating, vaping liquid while intoxicated. Because of the increasing prevalence of vaping devices, this case highlights a unique risk of vape liquids with concentrated nicotine levels and appetizing labels and aromas. Vaping-associated pulmonary injury has been previously described in multiple publications, but unlike those patients with pathology after inhaling vaping products, our patient ingested and subsequently aspirated the highly nicotinic substance.

Role of CD38/cADPR signaling in obstructive pulmonary diseases.

The worldwide socioeconomical burden associated with chronic respiratory diseases is substantial. Enzymes involved in the metabolism of nicotinamide adenine dinucleotide (NAD) are increasingly being implicated in chronic airway diseases. One such enzyme, CD38, utilizes NAD to produce several metabolites, including cyclic ADP ribose (cADPR), which is involved in calcium signaling in airway smooth muscle (ASM).

RGS4 promotes allergen- and aspirin-associated airway hyperresponsiveness by inhibiting PGE2 biosynthesis.

Background: Allergens elicit host production of mediators acting on G-protein-coupled receptors to regulate airway tone. Among these is prostaglandin E2 (PGE2), which, in addition to its role as a bronchodilator, has anti-inflammatory actions. Some patients with asthma develop bronchospasm after the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs, a disorder termed aspirin-exacerbated respiratory disease.

Salicylic acid amplifies Carbachol-induced bronchoconstriction in human precision-cut lung slices.

Background: Asthma exacerbations evoke emergency room visits, progressive loss of lung function and increased mortality. Environmental and industrial toxicants exacerbate asthma, although the underlying mechanisms are unknown. We assessed whether 3 distinct toxicants, salicylic acid (SA), toluene diisocyanate (TDI), and 1-chloro-2,4-dinitrobenzene (DNCB) induced airway hyperresponsiveness (AHR) through modulating excitation-contraction coupling in human airway smooth muscle (HASM) cells.

Obesity increases airway smooth muscle responses to contractile agonists.

The asthma-obesity syndrome represents a major public health concern that disproportionately contributes to asthma severity and induces insensitivity to therapy. To date, no study has shown an intrinsic difference between human airway smooth muscle (HASM) cells derived from nonobese subjects and those derived from obese subjects. The objective of this study was to address whether there is a greater response to agonist-induced calcium mobilization, phosphorylation of myosin light chain (MLC), and greater shortening in HASM cells derived from obese subjects.

Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking.

Neutrophils are white blood cells that are mobilized to damaged tissues and to sites of pathogen invasion, providing the first line of host defense. Chemokines displayed on the surface of blood vessels promote migration of neutrophils to these sites, and tissue- and pathogen-derived chemoattractant signals, including -formylmethionylleucylphenylalanine (fMLP), elicit further migration to sites of infection. Although nearly all chemoattractant receptors use heterotrimeric G proteins to transmit signals, many of the mechanisms lying downstream of chemoattractant receptors that either promote or limit neutrophil motility are incompletely defined.

Gα facilitates shortening in human airway smooth muscle by modulating phosphoinositide 3-kinase-mediated activation in a RhoA-dependent manner.

Background And Purpose: PI3K-dependent activation of Rho kinase (ROCK) is necessary for agonist-induced human airway smooth muscle cell (HASMC) contraction, and inhibition of PI3K promotes bronchodilation of human small airways. The mechanisms driving agonist-mediated PI3K/ROCK axis activation, however, remain unclear. Given that G family proteins activate ROCK pathways in other cell types, their role in M muscarinic acetylcholine receptor-stimulated PI3K/ROCK activation and contraction was examined.