Piezo channels modulate human lung fibroblast function.

Bronchial airways and lung parenchyma undergo both static and dynamic stretch in response to normal breathing as well as in the context of insults such as mechanical ventilation (MV) or in diseases such as asthma and chronic obstructive pulmonary disease (COPD) which lead to airway remodeling involving increased extracellular matrix (ECM) production. Here, the role of fibroblasts is critical, but the relationship between stretch- and fibroblast-induced ECM remodeling under these conditions is not well-explored. Piezo (PZ) channels play a role in mechanotransduction in many cell and organ systems, but their role in mechanical stretch-induced airway remodeling is not known.

Role of STIM1 in stretch-induced signaling in human airway smooth muscle.

Alteration in the normal mechanical forces of breathing can contribute to changes in contractility and remodeling characteristic of airway diseases, but the mechanisms that mediate these effects in airway cells are still under investigation. Airway smooth muscle (ASM) cells contribute to both contractility and extracellular matrix (ECM) remodeling. In this study, we explored ASM mechanisms activated by mechanical stretch, focusing on mechanosensitive piezo channels and the key Ca regulatory protein stromal interaction molecule 1 (STIM1).

Mechanosensitive channels in lung disease.

Mechanosensitive channels (MS channels) are membrane proteins capable of responding to mechanical stress over a wide dynamic range of external mechanical stimuli. In recent years, it has been found that MS channels play an important role as "sentinels" in the process of cell sensing and response to extracellular and intracellular force signals. There is growing appreciation for mechanical activation of ion channels and their subsequent initiation of downstream signaling pathways.

Interactions between calcium regulatory pathways and mechanosensitive channels in airways.

Introduction: Asthma is a chronic lung disease influenced by environmental and inflammatory triggers and involving complex signaling pathways across resident airway cells such as epithelium, airway smooth muscle, fibroblasts, and immune cells. While our understanding of asthma pathophysiology is continually progressing, there is a growing realization that cellular microdomains play critical roles in mediating signaling relevant to asthma in the context of contractility and remodeling. Mechanosensitive pathways are increasingly recognized as important to microdomain signaling, with Piezo and transient receptor protein (TRP) channels at the plasma membrane considered important for converting mechanical stimuli into cellular behavior.

Piezo channels in stretch effects on developing human airway smooth muscle.

The use of respiratory support strategies such as continuous positive airway pressure in premature infants can substantially stretch highly compliant perinatal airways, leading to airway hyperreactivity and remodeling in the long term. The mechanisms by which stretch detrimentally affects the airway are unknown. Airway smooth muscle cells play a critical role in contractility and remodeling.

Oxygen and mechanical stretch in the developing lung: risk factors for neonatal and pediatric lung disease.

Chronic airway diseases, such as wheezing and asthma, remain significant sources of morbidity and mortality in the pediatric population. This is especially true for preterm infants who are impacted both by immature pulmonary development as well as disproportionate exposure to perinatal insults that may increase the risk of developing airway disease. Chronic pediatric airway disease is characterized by alterations in airway structure (remodeling) and function (increased airway hyperresponsiveness), similar to adult asthma.

Definitive Closure of the Patent Ductus Arteriosus in Preterm Infants and Subsequent Short-Term Respiratory Outcomes.

A persistent patent ductus arteriosus (PDA) can have significant clinical consequences in preterm infants, depending on the degree of left-to-right shunting, its impact on cardiac performance, and associated perinatal risk factors that can mitigate or exacerbate the shunt. Although the best management strategy remains contentious, PDAs that have contraindications to, or have failed medical management have historically undergone surgical ligation. Recently smaller occluder devices and delivery systems have allowed for minimally invasive closure in the catheterization laboratory even in extremely premature infants.

Dosing of Opioid Medications During and After Pediatric Cardiac Surgery for Children With Down Syndrome.

Objective: To determine whether children with Down syndrome (DS) receive higher doses of opioid medications compared with children without DS for repair of complete atrioventricular canal (CAVC).

Design: A retrospective chart review of children with and without DS who underwent primary repair of CAVC. The exclusion criteria included unbalanced CAVC and patients undergoing biventricular staging procedures.

Cigarette Smoke Exposure, Pediatric Lung Disease, and COVID-19.

The detrimental effects of tobacco exposure on children's health are well known. Nonetheless, the prevalence of secondhand or direct cigarette smoke exposure (CSE) in the pediatric population has not significantly decreased over time. On the contrary, the rapid incline in use of e-cigarettes among adolescents has evoked public health concerns since increasing cases of vaping-induced acute lung injury have highlighted the potential harm of these new "smoking" devices.

Caveolin-1 scaffolding domain peptide prevents hyperoxia-induced airway remodeling in a neonatal mouse model.

Reactive airway diseases are significant sources of pulmonary morbidity in neonatal and pediatric patients. Supplemental oxygen exposure in premature infants contributes to airway diseases such as asthma and promotes development of airway remodeling, characterized by increased airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition. Decreased plasma membrane caveolin-1 (CAV1) expression has been implicated in airway disease and may contribute to airway remodeling and hyperreactivity.

Moderate hyperoxia induces extracellular matrix remodeling by human fetal airway smooth muscle cells.

Background: Premature infants are at increased risk for airway diseases, such as wheezing and asthma, because of early exposure to risk factors including hyperoxia. As in adult asthma, airway remodeling and increased extracellular matrix (ECM) deposition is involved.

Methods: We assessed the impact of 24-72 h of moderate hyperoxia (50%) on human fetal airway smooth muscle (fASM) ECM deposition through western blot, modified in-cell western, and zymography techniques.

TLR3 activation increases chemokine expression in human fetal airway smooth muscle cells.

Viral infections, such as respiratory syncytial virus and rhinovirus, adversely affect neonatal and pediatric populations, resulting in significant lung morbidity, including acute asthma exacerbation. Studies in adults have demonstrated that human airway smooth muscle (ASM) cells modulate inflammation through their ability to secrete inflammatory cytokines and chemokines. The role of ASM in the developing airway during infection remains undefined.

Effects of antenatal lipopolysaccharide and postnatal hyperoxia on airway reactivity and remodeling in a neonatal mouse model.

Background: Antenatal inflammation and preterm birth are associated with the development of airway diseases such as wheezing and asthma. Utilizing a newborn mouse model, we assessed the effects of maternal inflammation and postnatal hyperoxia on the neonatal airway.

Methods: Pregnant C57/Bl6 dams were injected with lipopolysaccharide (LPS) or saline on embryonic day 16.

Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle.

Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca(2+) ([Ca(2+)]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca(2+)/contractility are not known.

Perinatal oxygen in the developing lung.

Lung diseases, such as bronchopulmonary dysplasia (BPD), wheezing, and asthma, remain significant causes of morbidity and mortality in the pediatric population, particularly in the setting of premature birth. Pulmonary outcomes in these infants are highly influenced by perinatal exposures including prenatal inflammation, postnatal intensive care unit interventions, and environmental agents. Here, there is strong evidence that perinatal supplemental oxygen administration has significant effects on pulmonary development and health.

Cigarette smoke enhances proliferation and extracellular matrix deposition by human fetal airway smooth muscle.

Cigarette smoke is a common environmental insult associated with increased risk of developing airway diseases such as wheezing and asthma in neonates and children. In adults, asthma involves airway remodeling characterized by increased airway smooth muscle (ASM) cell proliferation and increased extracellular matrix (ECM) deposition, as well as airway hyperreactivity. The effects of cigarette smoke on remodeling and contractility in the developing airway are not well-elucidated.

Vitamin D attenuates cytokine-induced remodeling in human fetal airway smooth muscle cells.

Asthma in the pediatric population remains a significant contributor to morbidity and increasing healthcare costs. Vitamin D3 insufficiency and deficiency have been associated with development of asthma. Recent studies in models of adult airway diseases suggest that the bioactive Vitamin D3 metabolite, calcitriol (1,25-dihydroxyvitamin D3 ; 1,25(OH)2 D3 ), modulates responses to inflammation; however, this concept has not been explored in developing airways in the context of pediatric asthma.

Effect of position on valsalva maneuver: supine versus 20 degree position.

Blood pressure changes in response to the Valsalva maneuver (VM), which reflect the integrity of the baroreflex that regulates blood pressure. Performing this maneuver in the standard supine position often prevents adequate venous preload reduction, resulting in a rise rather than a fall in blood pressure, the "flat-top" Valsalva response. We determined whether performing the VM at a 20 degree angle of head-up tilt (20 degrees ) improves preload reduction, thereby reducing the frequency of flat-top responses, improving reflex vasoconstriction, and increasing the Valsalva ratio.

Blood pressure recovery from Valsalva maneuver in patients with autonomic failure.

Background: Blood pressure (BP) changes in response to the Valsalva maneuver (VM) reflect the integrity of the baroreflex that regulates BP, and the phases of VM are widely used indices of adrenergic evaluation.

Objective: To study the BP recovery time (PRT) following termination of VM back to baseline to determine if it could be an additional and better indicator of adrenergic function.

Methods: The authors evaluated three groups of patients with increasing degrees of adrenergic failure and an age-matched control group.