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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. To explore this, we exposed human lung fibroblasts to 10% static stretch on a background of 5% oscillations for 48 h, with no static stretch considered controls. Collagen I, fibronectin, alpha-smooth muscle actin (α-SMA), and Piezo 1 (PZ1) expression was determined in the presence or absence of Yoda1 (PZ1 agonist) or GsMTx4 (PZ1 inhibitor). Collagen I, fibronectin, and α-SMA expression was increased by stretch and Yoda1, whereas pretreatment with GsMTx4 or knockdown of PZ1 by siRNA blunted this effect. Acute stretch in the presence and absence of Yoda1 demonstrated activation of the ERK pathway but not Smad. Measurement of [Ca2+]i responses to histamine showed significantly greater responses following stretch, effects that were blunted by knockdown of PZ1. Our findings identify an essential role for PZ1 in mechanical stretch-induced production of ECM mediated by ERK phosphorylation and Ca2+ influx in lung fibroblasts. Targeting PZ channels in fibroblasts may constitute a novel approach to ameliorate airway remodeling by decreasing ECM deposition. NEW & NOTEWORTHY: The lung is an inherently mechanosensitive organ that can respond to mechanical forces in adaptive or maladaptive ways, including via remodeling resulting in increased fibrosis. We explored the mechanisms that link mechanical forces to remodeling using human lung fibroblasts. We found that mechanosensitive Piezo channels increase with stretch and mediate extracellular matrix formation and the fibroblast-to-myofibroblast transition that occurs with stretch. Our data highlight the importance of Piezo channels in lung mechanotransduction toward remodeling. [ABSTRACT FROM AUTHOR]

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. Members of the transient receptor potential (TRP) superfamily and Piezo channels are broadly expressed in human tissues and contribute to multiple cellular functions. Both TRP and Piezo channels are thought to play key roles in physiological homeostasis and pathophysiology of disease states including in the lung. Here, we review the current state of knowledge on the expression, regulation, and function of TRP and Piezo channels in the context of the adult lung across the age spectrum, and in lung diseases such as asthma, COPD and pulmonary fibrosis where mechanical forces likely play varied roles in the structural and functional changes characteristic of these diseases. Understanding of TRP and Piezo in the lung can provide insights into new targets for treatment of pulmonary disease. [ABSTRACT FROM AUTHOR]

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. This is of particular importance in the preterm lung, where premature exposure to room air represents a hyperoxic insult that may cause harm to a lung primed to develop in a hypoxic environment. Preterm infants are also subject to increased episodes of hypoxia, which may also result in pulmonary damage and disease. Here, we summarize the current understanding of the effects of oxygen on the developing lung and how low vs. high oxygen may predispose to pulmonary disease that may extend even into adulthood. Better understanding of the underlying mechanisms will help lead to improved care and outcomes in this vulnerable population. Key words: neonatal, bronchopulmonary dysplasia, asthma, hypoxia, hyperoxia. Les maladies pulmonaires telles la dysplasie broncho-pulmonaire, la respiration sifflante et l'asthme, demeurent des causes significatives de morbidite et de mortalite chez la population pediatrique, particulierement dans les cas de naissance prematuree. Les consequences sur le plan pulmonaire chez ces bebes sont fortement influencees par des expositions perinatales incluant l'inflammation prenatale, les soins intensifs postnataux et les agents environnementaux. Il y a ici de fortes preuves que l'administration perinatale d'oxygene d'appoint a des effets significatifs sur le developpement et la sante pulmonaires. Ceci est particulierement important chez le poumon premature, ou l'exposition prematuree a l'air ambiant represente un choc hyperoxique qui pourrait etre dommageable a un poumon habitue a un environnement hypoxique. Les bebes prematures sont aussi sujets a des periodes accrues d'hypoxie, qui peuvent aussi resulter en dommage et maladies pulmonaires. Les auteurs resument ici les connaissances actuelles des effets de l'oxygene sur le poumon en developpement, et discutent comment une concentration elevee d'oxygene, par rapport a une faible concentration, peut predisposer a une maladie pulmonaire qui peut persister meme jusqu'a l'age adulte. Une meilleure comprehension des mecanismes sous-jacents aidera a ameliorer les soins et les consequences chez cette population vulnerable. [Traduit par la Redaction] Mots-cles: neonatal, dysplasie broncho-pulmonaire, asthme, hypoxie, hyperoxie., Introduction Premature birth (defined as birth prior to 37 weeks gestational age) continues to be a significant source of morbidity and mortality in neonatal and pediatric populations. Neonatal lung diseases, [...]

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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. This is of particular importance in the preterm lung, where premature exposure to room air represents a hyperoxic insult that may cause harm to a lung primed to develop in a hypoxic environment. Preterm infants are also subject to increased episodes of hypoxia, which may also result in pulmonary damage and disease. Here, we summarize the current understanding of the effects of oxygen on the developing lung and how low vs. high oxygen may predispose to pulmonary disease that may extend even into adulthood. Better understanding of the underlying mechanisms will help lead to improved care and outcomes in this vulnerable population. [ABSTRACT FROM AUTHOR]

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 2+ regulatory protein stromal interaction molecule 1 (STIM1). Expression of Ca 2+ regulatory proteins, including STIM1, Orai1, and caveolin-1, mechanosensitive ion channels Piezo-1 and Piezo-2, and NLRP3 inflammasomes were upregulated by 10% static stretch superimposed on 5% cyclic stretch. These effects were blunted by STIM1 siRNA. Histamine-induced [Ca 2+ ] i responses and inflammasome activation were similarly blunted by STIM1 knockdown. These data show that the effects of mechanical stretch in human ASM cells are mediated through STIM1, which activates multiple pathways, including Piezo channels and the inflammasome, leading to potential downstream changes in contractility and ECM remodeling. NEW & NOTEWORTHY Mechanical forces on the airway can contribute to altered contractility and remodeling in airway diseases, but the mechanisms are not clearly understood. Using human airway smooth muscle cells exposed to cyclic forces with static stretch to mimic breathing and static pressure, we found that the effects of stretch are mediated through STIM1, resulting in the activation of multiple pathways, including Piezo channels and the inflammasome, with potential downstream influences on contractility and remodeling.

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. Using 18-22-wk gestation human fetal airway smooth muscle (fASM) as an in vitro model, we tested the hypothesis that mechanosensitive Piezo (PZ) channels contribute to stretch effects. We found that PZ1 and PZ2 channels are expressed in the smooth muscle of developing airways and that their expression is influenced by stretch. PZ activation via agonist Yoda1 or stretch results in significant [Ca 2+ ] i responses as well as increased extracellular matrix production. These data suggest that functional PZ channels may play a role in detrimental stretch-induced airway changes in the context of prematurity. NEW & NOTEWORTHY Piezo channels were first described just over a decade ago and their function in the lung is largely unknown. We found that piezo channels are present and functional in the developing airway and contribute to intracellular calcium responses and extracellular matrix remodeling in the setting of stretch. This may improve our understanding of the mechanisms behind development of chronic airway diseases, such as asthma, in former preterm infants exposed to respiratory support, such as continuous positive airway pressure (CPAP).

The lung is an inherently mechanosensitive organ, where cells of the airway and parenchyma experience a range of mechanical forces throughout life including shear, stretch, and compression, in both health and disease. In this regard, pediatric and adult lung diseases such as wheezing and asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) all involve macroscopic and cellular changes to the mechanical properties of the bronchial airways and/or parenchyma to varying extents. Accordingly, understanding how mechanical forces are sensed in the lung, and the responses of cells and tissues in the context of normal development and health versus disease conditions becomes highly relevant. There is increasing recognition that transduction of mechanical forces into cellular responses involves a number of channels, some of which are inherently mechanosensitive. Such channels trigger mechanotransduction pathways that may further mediate cellular remodeling, inflammation, and other pathophysiologic mechanisms in response to stretch, stiffness, and inflammatory cascades. Two particularly important channel families have emerged in pulmonary pathophysiology: the transient receptor potential vanilloid family with focus on member TRPV4 and the recently identified Piezo (PZ) channels. Here, we explore current understanding of the contributions of TRPV4 and PZ channels in lung health and disease states, focusing on the interactions between these mechanosensitive channels and their local environment including immune cells, the extracellular matrix, and cellular cytoskeletal elements. We further discuss potential areas for future research to better understand the impact of mechanical channels on pulmonary health and disease. © 2023 American Physiological Society. Compr Physiol 13:5157-5178, 2023., (Copyright © 2023 American Physiological Society. All rights reserved.)

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. Here, we investigated the impact of clinically relevant moderate hyperoxia (50% O 2 ) on airway remodeling and caveolar protein expression in a neonatal mouse model. Within 12 h of birth, litters of B6129SF2J mice were randomized to room air (RA) or 50% hyperoxia exposure for 7 days with or without caveolin-1 scaffolding domain peptide (CSD; caveolin-1 mimic; 10 µl, 0.25 mM daily via intraperitoneal injection) followed by 14 days of recovery in normoxia. Moderate hyperoxia significantly increased airway reactivity and decreased pulmonary compliance at 3 wk. Histologic assessment demonstrated airway wall thickening and increased ASM mass following hyperoxia. RNA from isolated ASM demonstrated significant decreases in CAV1 and cavin-1 in hyperoxia-exposed animals while cavin-3 was increased. Supplementation with intraperitoneal CSD mitigated both the physiologic and histologic changes observed with hyperoxia. Overall, these data show that moderate hyperoxia is detrimental to developing airway and may predispose to airway reactivity and remodeling. Loss of CAV1 is one mechanism through which hyperoxia produces these deleterious effects. Supplementation of CAV1 using CSD or similar analogs may represent a new therapeutic avenue for blunting hyperoxia-induced pulmonary damage in neonates.

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. In our study, we used human fetal ASM cells as an in vitro model to examine the effect of Toll-like receptor (TLR) agonists on chemokine secretion. We found that fetal ASM express multiple TLRs, including TLR3 and TLR4, which are implicated in the pathogenesis of respiratory syncytial virus and rhinovirus infection. Cells were treated with TLR agonists, polyinosinic-polycytidylic acid [poly(I:C)] (TLR3 agonist), lipopolysaccharide (TLR4 agonist), or R848 (TLR7/8 agonist), and IL-8 and chemokine (C-C motif) ligand 5 (CCL5) secretion were evaluated. Interestingly, poly(I:C), but neither lipopolysaccharide nor R848, increased IL-8 and chemokine (C-C motif) ligand 5 secretion. Examination of signaling pathways suggested that the poly(I:C) effects in fetal ASM involve TLR and ERK signaling, in addition to another major inflammatory pathway, NF-κB. Moreover, there are variations between fetal and adult ASM with respect to poly(I:C) effects on signaling pathways. Pharmacological inhibition suggested that ERK pathways mediate poly(I:C) effects. Overall, our data show that poly(I:C) initiates activation of proinflammatory pathways in developing ASM, which may contribute to immune responses to infection and exacerbation of asthma., (Copyright © 2016 the American Physiological Society.)

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. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca(2+) responses to bronchoconstrictor agonists. Treatment with BAY 41-2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2 did not alter sGCα1 or sGCβ1 expression, BAY 60-2770 did increase sGCβ1 expression. BAY 41-2272 and BAY 60-2770 blunted Ca(2+) responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia-induced increases in Ca(2+) responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants., (Copyright © 2015 the American Physiological Society.)

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. In this study, we used canalicular-stage (18-20 wk gestational age) human fetal airway smooth muscle (fASM) cells as an in vitro model of the immature airway. fASM cells were exposed to cigarette smoke extract (CSE; 0.5-1.5% for 24-72 h), and cell proliferation, ECM deposition, and intracellular calcium ([Ca(2+)]i) responses to agonist (histamine 10 μM) were used to evaluate effects on remodeling and hyperreactivity. CSE significantly increased cell proliferation and deposition of ECM molecules collagen I, collagen III, and fibronectin. In contrast, [Ca(2+)]i responses were not significantly affected by CSE. Analysis of key signaling pathways demonstrated significant increase in extracellular signal-related kinase (ERK) and p38 activation with CSE. Inhibition of ERK or p38 signaling prevented CSE-mediated changes in proliferation, whereas only ERK inhibition attenuated the CSE-mediated increase in ECM deposition. Overall, these results demonstrate that cigarette smoke may enhance remodeling in developing human ASM through hyperplasia and ECM production, thus contributing to development of neonatal and pediatric airway disease., (Copyright © 2014 the American Physiological Society.)