Airway Distension Research Articles

Nasal high-flow therapy for Newborn infants in special care nurseries.

Late preterm infants account for a significant majority of preterm infants born in the United States. According to the CDC, 70% of all preterm deliveries occur between 34 and 37 weeks’ gestational age. There is evidence to suggest that short-term morbidities, such as respiratory distress syndrome (RDS), are more prevalent in this population.1 Non-invasive ventilation (NIV) such as CPAP and humidified heated high-flow nasal cannula has been shown to be effective strategies for reducing RDS by optimising pulmonary mechanics, reducing work of breathing and improving oxygenation and ventilation. Increasing use of NIV has reduced intubation in infants with RDS, likely due to the combination of positive airway distension and lack of de-recruitment alveoli and collapse of small airways during exhalation in the surfactant-deficient lung.2 This non-inferiority study of HFNC compared to CPAP by Manley and colleagues is the latest in a series of studies looking at NIV delivery in late preterm RDS. Use of CPAP is well established as the standard of care for preterm infants with respiratory distress. Studies in a late preterm to term population of Caesarean-born infants demonstrated that prophylactic CPAP is helpful in reducing NICU admission by improving lung compliance and uniformity of lung compliance.2 High-flow nasal cannula as an alternative has been demonstrated to have several advantages, including decreased nasal trauma,3 and has been shown in prior surveys to be preferred by parents of admitted infants.4 Despite the possible advantages of HFNC, the main drawback is the variability in pressures that can be generated, leading to possible ‘failure’ of this mode of NIV. Given that many infants of GA 31 weeks or greater are cared for in a non-tertiary NICU, the setting of this study in a similar environment enhances the generalisability of the results. In this setting, when comparing HFNC and CPAP with the goal of preventing respiratory failure, HFNC was shown to be inferior to CPAP, as defined by study parameters. Many of those who failed therapy on HFNC and transferred to CPAP ultimately stabilised, so that in the end, only slightly more than 5% in each group were intubated in the first 72 hours. Given that both groups had similar rates of treatment failure that ultimately required transfer to higher level care, it may be reasonable for centres to offer HFNC as an alternative to CPAP when requested by parents or staff, so long as CPAP is available onsite to rescue these infants should they fail HFNC. https://ebneo.org/2019/07/nasal-high-flow/ None.

Involvement of the epithelial sodium channel in initiation of mechanically evoked swallows in anaesthetized rats.

Afferents carried by the superior laryngeal nerve play a primary role in the initiation of laryngeal mechanically evoked swallows in anaesthetized rats. Amiloride and its analogues inhibit swallowing evoked by mechanical stimulation, but not swallowing evoked by chemical and electrical stimulation. The epithelial sodium channel is probably involved in the initiation of laryngeal mechanically evoked swallows. The swallowing reflex plays a critical role in airway protection. Because impaired laryngeal mechanosensation is associated with food bolus aspiration, it is important to know how the laryngeal sensory system regulates swallowing initiation. This study was performed to clarify the neuronal mechanism of mechanically evoked swallows. Urethane-anaesthetized Sprague-Dawley male rats were used. A swallow was identified by activation of the suprahyoid and thyrohyoid muscles on electromyography. The swallowing threshold was measured by von Frey filament and electrical stimulation of the larynx. The number of swallows induced by upper airway distension and capsaicin application (0.03nmol, 3μl) to the vocal folds was counted. The effects of topical application (0.3-30nmol, 3μl) of the epithelial sodium channel (ENaC) blocker amiloride and its analogues (benzamil and dimethylamiloride), acid-sensing ion channel (ASIC) inhibitors (mambalgine-1 and diminazene) and gadolinium to the laryngeal mucosa on swallowing initiation were evaluated. A nerve transection study indicated that afferents carried by the superior laryngeal nerve play a primary role in the initiation of laryngeal mechanically evoked swallows. The mechanical threshold of swallowing was increased in a dose-dependent manner by amiloride and its analogues and gadolinium, but not by ASIC inhibitors. The number of swallows by upper airway distension was significantly decreased by benzamil application. However, the initiation of swallows evoked by capsaicin and electrical stimulation was not affected by benzamil application. We speculate that the ENaC is involved in the initiation of laryngeal mechanically evoked swallows.

Smooth muscle in human bronchi is disposed to resist airway distension

Studying airway smooth muscle (ASM) in conditions that emulate the in vivo environment within which the bronchi normally operate may provide important clues regarding its elusive physiological function. The present study examines the effect of lengthening and shortening of ASM on tension development in human bronchial segments. ASM from each bronchial segment was set at a length approximating in situ length (Linsitu). Bronchial tension was then measured during a slow cyclical strain (0.004Hz, from 0.7Linsitu to 1.3Linsitu) in the relaxed state and at graded levels of activation by methacholine. In all cases, tension was greater at longer ASM lengths, and greater during lengthening than shortening. The threshold of methacholine concentration that was required for ASM to account for bronchial tension across the entire range of ASM lengths tested was on average smaller by 2.8 logs during lengthening than during shortening. The length-dependency of ASM tension, together with this lower threshold of methacholine concentration during lengthening versus shortening, suggest that ASM has a greater ability to resist airway dilation during lung inflation than to narrow the airways during lung deflation. More than serving to narrow the airway, as has long been thought, these data suggest that the main function of ASM contraction is to limit airway wall distension during lung inflation.

Nitric oxide synthase promotes distension-induced tracheal venular leukocyte adherence.

The process of leukocyte recruitment to the airways in real time has not been extensively studied, yet airway inflammation persists as a major contributor to lung pathology. We showed previously in vivo, that neutrophils are recruited acutely to the large airways after periods of airway distension imposed by the application of positive end-expiratory pressure (PEEP). Given extensive literature implicating products of nitric oxide synthase (NOS) in lung injury after ventilatory over-distension, we questioned whether similar mechanisms exist in airway post-capillary venules. Yet, endothelial nitric oxide has been shown to be largely anti-inflammatory in other systemic venules. Using intravital microscopy to visualize post-capillary tracheal venules in anesthetized, ventilated mice, the number of adherent leukocytes was significantly decreased in eNOS-/- mice under baseline conditions (2±1 cell/60 min observation) vs wild type (WT) C57BL/6 mice (7±2 cells). After exposure to PEEP (8 cmH2O for 1 min; 5 times), adherent cells increased significantly (29±5 cells) in WT mice while eNOS-/- mice demonstrated a significantly decreased number of adherent cells (11±4 cells) after PEEP. A similar response was seen when thrombin was used as the pro-inflammatory stimulus. In addition, mouse tracheal venular endothelial cells studied in vitro after exposure to cyclic stretch (18% elongation) or thrombin both demonstrated increased p-selectin expression that was significantly attenuated by NG-nitro-L-arginine methyl ester, N-acetylcysteine amide (NACA) and excess BH4. In vivo treatment with the ROS inhibitor NACA or co-factor BH4 abolished completely the PEEP-induced leukocyte adherence. These results suggest that pro-inflammatory stimuli cause leukocyte recruitment to tracheal endothelium in part due to eNOS uncoupling.

Mechanical ventilation causes airway distension with proinflammatory sequelae in mice.

The pathogenesis of ventilator-induced lung injury has predominantly been attributed to overdistension or mechanical opening and collapse of alveoli, whereas mechanical strain on the airways is rarely taken into consideration. Here, we hypothesized that mechanical ventilation may cause significant airway distension, which may contribute to the pathological features of ventilator-induced lung injury. C57BL/6J mice were anesthetized and mechanically ventilated at tidal volumes of 6, 10, or 15 ml/kg body wt. Mice were imaged by flat-panel volume computer tomography, and central airways were segmented and rendered in 3D for quantitative assessment of airway distension. Alveolar distension was imaged by intravital microscopy. Functional dead space was analyzed in vivo, and proinflammatory cytokine release was analyzed in isolated, ventilated tracheae. CT scans revealed a reversible, up to 2.5-fold increase in upper airway volume during mechanical ventilation compared with spontaneous breathing. Airway distension was most pronounced in main bronchi, which showed the largest volumes at tidal volumes of 10 ml/kg body wt. Conversely, airway distension in segmental bronchi and functional dead space increased almost linearly, and alveolar distension increased even disproportionately with higher tidal volumes. In isolated tracheae, mechanical ventilation stimulated the release of the early-response cytokines TNF-α and IL-1β. Mechanical ventilation causes a rapid, pronounced, and reversible distension of upper airways in mice that is associated with an increase in functional dead space. Upper airway distension is most pronounced at moderate tidal volumes, whereas higher tidal volumes redistribute preferentially to the alveolar compartment. Airway distension triggers proinflammatory responses and may thus contribute relevantly to ventilator-induced pathologies.

Airway distension during lung inflation in healthy and allergic-sensitised mice in vivo

We evaluated the airway distention during lung inflation of varying size in healthy and allergic-sensitised mice in vivo. Computed tomography (CT) images of healthy and ovalbumin-treated mice were acquired using a synchrotron in vivo CT system when lung pressures was 0 and 20cmH2O, and the morphometric distension (diameter, length, and volume) and the compliance of airway segments (to as small as ∼150μm internal diameter) were calculated. With respect to airway size, in healthy mice, the changes in airway diameter and compliance were larger in the small-airway group. In contrast, in allergic-sensitised mice, there were no significant differences in the changes in airway distension or compliance. Airway wall thickness in allergic-sensitised mice increased significantly in all airway groups, but the change was much larger in the small than in the large-airway group. Compared with healthy airways, the changes in diameter and airway compliance of the allergic-sensitised mice were significantly smaller in the small-airway group.

Regulatable stiffness in relaxed airway smooth muscle: a target for asthma treatment?

The airway smooth muscle (ASM) layer within the airway wall modulates airway diameter and distensibility. Even in the relaxed state, the ASM layer possesses finite stiffness and limits the extent of airway distension by the radial force generated by parenchymal tethers and transmural pressure. Airway stiffness has often been attributed to passive elements, such as the extracellular matrix in the lamina reticularis, adventitia, and the smooth muscle layer that cannot be rapidly modulated by drug intervention such as ASM relaxation by β-agonists. In this study, we describe a calcium-sensitive component of ASM stiffness mediated through the Rho-kinase signaling pathway. The stiffness of ovine tracheal smooth muscle was assessed in the relaxed state under the following conditions: 1) in physiological saline solution (Krebs solution) with normal calcium concentration; 2) in calcium-free Krebs with 2 mM EGTA; 3) in Krebs with calcium entry blocker (SKF-96365); 4) in Krebs with myosin light chain kinase inhibitor (ML-7); and 5) in Krebs with Rho-kinase inhibitor (Y-27632). It was found that a substantial portion of the passive stiffness could be abolished when intracellular calcium was removed; this calcium-sensitive stiffness appeared to stem from intracellular source and was not sensitive to ML-7 inhibition of myosin light chain phosphorylation, but was sensitive to Y-27632 inhibition of Rho kinase. The results suggest that airway stiffness can be readily modulated by targeting the calcium-sensitive component of the passive stiffness within the muscle layer.

Pulmonary stretch receptor spike time precision increases with lung inflation amplitude and airway smooth muscle tension

Slowly adapting pulmonary stretch receptors (SARs) respond to different lung inflation volumes with distinct spike counts and patterns, conveying information regarding the rate and depth of breathing to the cardiovascular and respiratory control systems. Previous studies demonstrated that SARs respond to repetitions of the same lung inflation faithfully, suggesting the possibility of modeling an SAR's discrete response pattern to a stimulus using a statistically based method. Urethane-anesthetized rabbit SAR spike trains were recorded in response to repeated 9-, 12-, and 15-ml lung inflations, and used to construct model spike trains using K-means clustering. Analysis of the statistics of the responses to different lung inflation volumes revealed that SARs fire with more temporal precision in response to larger lung inflations, because the standard deviations of real spikes clustered around the modeled spike times of responses to 15-ml stimuli were smaller than those produced by 12 or 9 ml, even at the same absolute firing frequencies. This implied that the mechanical coupling of SAR endings with pulmonary tissue is critical in determining spike time reliability. To test this, we collected SAR responses during bronchial constriction, compared them with those produced by the same SARs under normal airway resistance, and found that their firing reliability improved during bronchial constriction. These results suggest that airway distension and mechanical coupling of the receptor endings with the airway wall (partially determined by smooth muscle tone) are important determinants of SAR spike time reliability.

Evolution of tidal volume requirement during the first 3 weeks of life in infants

Background:Volume-targeted ventilation is used in neonates to reduce volutrauma and inadvertent hyperventilation. Little is known about appropriate tidal volume (VT) settings in extremely low birthweight (ELBW) infants who remain intubated...

Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema

Background:Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, plays a role in the pathophysiology of smoking-related pulmonary emphysema. Expression of several antioxidant proteins, such...

Alterations of the Beneficial Effect of Deep Inspiration in Scleroderma: Relationships between Lung Function and Imaging

Background: It has been postulated that the beneficial effects of deep inspiration are dependent on the magnitude of airway distension by virtue of airway to parenchyma interdependence. Objective: This study was designed to examine whether the changes that occur in pulmonary fibrosis affect the beneficial effect of deep inspiration. Methods: Thirty-one subjects with scleroderma underwent lung volume and diffusion capacity assessment as well as high-resolution computed tomography. To assess the effect of deep inspiration, each subject underwent methacholine provocations in the absence of deep breaths. When the targeted change in lung function was achieved, subjects were asked to take 4 consecutive deep inspirations after which lung function measurements were repeated. The inspiratory vital capacity (IVC) was used as primary outcome. Results: Only 19 subjects attained the desired reduction in IVC in the absence of deep breaths. In those subjects, deep inspiration reversed the effect of methacholine on IVC by 48 ± 8.4%. The effect of deep inspiration correlated with DLCO% predicted (r = 0.55, p = 0.01), but not with high-resolution computed tomography abnormalities or baseline lung function measurements. When all subjects were considered, responsiveness to methacholine in the absence of deep inspiration was progressively lower with decreasing DLCO% predicted values (r = 0.51, p = 0.003). Conclusions: In systemic scleroderma, pulmonary abnormalities resulting in mild to moderate reduction in the diffusion capacity are associated with reduced ability of deep inspiration to reverse methacholine-induced early airway closure and bronchoconstriction. When diffusion capacity is severely affected, methacholine fails to produce obstructive airway changes.

Effects of airway distension on leukocyte recruitment in the mouse tracheal microvasculature

We have shown previously that excessive distention of the rat trachea during mechanical ventilation results in enhanced leukocyte recruitment to the airway (Lim LH and Wagner EM. Am J Respir Crit Care Med 168:1068-1074, 2003). The objectives of this study were to develop a mouse model of positive end-expiratory pressure (PEEP)-induced leukocyte recruitment to the airway and begin to pursue molecular mechanisms that may contribute to the in vivo observation of increased leukocyte adhesion after PEEP exposure. We studied C57BL/6 wild-type mice and mice deficient in P-selectin or intercellular adhesion molecule-1 (ICAM-1) exposed to intermittent PEEP (8 cmH(2)O) applied five times for a 1-min duration, at 10-min intervals. After the imposed ventilatory stress, during normal ventilation (0.2 ml/breath, no PEEP), leukocyte adhesion in tracheal postcapillary venules was determined using intravital microscopy. PEEP induced a time-dependent increase in leukocyte adhesion that was significantly increased between 0 and 60 min (P < 0.01). Furthermore, PEEP-induced leukocyte adhesion at 60 min was ablated in P-selectin- and ICAM-1-deficient mice. These findings demonstrate the essential nature of both P-selectin and ICAM-1 within airway postcapillary venular endothelium for leukocyte recruitment after airway distension.

Mechanisms of limited airway dimension with lung inflation

Airways distend with each inspiration, while a sigh or deep inspiration (DI) leads to a significant or a maximum distension of the airways. Distension of the airways is thought to play an important role in maintaining airway patency. Limited distension of the airways with lung inflation may be a major factor in certain lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). High resolution computed tomography (HRCT) has gained wide acceptance as a diagnostic and investigational radiological tool for the evaluation of airway function. HRCT has been used to measure dynamic changes in airway caliber in vivo that are not detectable by conventional global lung measurements such as airway and lung resistance. HRCT is uniquely capable of imaging and quantifying airway size at different lung volumes. The current paper reviews the use of HRCT to examine the role of lung inflation on airway distension in animal models, and discusses potential mechanisms for limited distension of the airways with lung inflation in individuals with asthma and COPD.

Effect of bronchial thermoplasty on airway distensibility

Recent studies have reported that the application of thermal energy delivered through a bronchoscope (bronchial thermoplasty) impairs the ability of airways to narrow in response to methacholine. How such altered smooth muscle affects the response of airways to lung inflation may have important clinical implications, particularly as it relates to the abnormal response of asthmatic subjects to lung inflation and deep inspiration. The aim of this study was to examine whether bronchial thermoplasty affected airway distension with lung inflation in relaxed and contracted airways. A total of 230 airways were studied, ranging 2.5-15 mm, in six dogs. These airways were divided into two groups: an untreated (control) population and a bronchial thermoplasty-treated population. Prior to treatment, the airway pressure-area curves in the two groups of airways were identical. In contrast, the relaxed and contracted airway pressure-area curves in treated airways were shifted upward at all points, showing increased airway area at both 3 and 5 weeks post-treatment. In conclusion, these results show that reducing that amount of functional smooth muscle with bronchial thermoplasty leads to increased airway size in both relaxed and contracted states over a normal range of inflation pressures.

Images in Anesthesia: Airway obstruction after peanut aspiration — air trapping is due to airway distension and narrowing

ing cough and mild fever 15 hr after choking and transiently turning cyanotic while eating peanuts. Chest auscultation revealed decreased air entry, and the chest x-ray showed hyperinflation on the left. The patient underwent rigid bronchoscopy under general anesthesia. Spontaneous respiration (with gentle assistance) with 100% oxygen was maintained. After lidocaine topicalization of the larynx and trachea, a bronchoscopy revealed a peanut in the left mainstem bronchus. On real time video, the peanut was seen immobilized. Dilatation and contraction of the bronchial lumen with inspiration and expiration, respectively, led to air trapping. The peanut was not bobbing up and down like a ball, as the term “ballvalve” effect may suggest (Figure 1A and 1B). Figure 2 shows partial obstruction of the tracheal lumen after the peanut was dropped accidentally by the retrieving forceps. Again, one witnesses the role of airway distention and narrowing during respiration as the mechanism of air trapping in intrathoracic airway obstruction. CARDIOTHORACIC ANESTHESIA, RESPIRATION AND AIRWAY 205

How to ventilate patients with acute lung injury and acute respiratory distress syndrome

The purpose of this paper is to review the mechanisms of ventilator-induced lung injury as a basis for providing the less damaging mechanical ventilation in patients with acute respiratory failure. In normal lungs, high tidal volume causes an immediate gene upregulation and downregulation. Although the importance of alveolar inflammatory reaction is well known, recent findings suggest the potential role of airway distension in causing ventilator-induced lung injury. The initial activation has been shown to occur in the airways, accounting for the damages induced by high peak flow. The healthier lung regions are more exposed to the injury, since they may be subjected to strain. Challenge with endotoxin enhances in a synergistic manner the pulmonary inflammation induced by mechanical ventilation. However, mechanical strain and endotoxin seem to trigger lung inflammation through two different pathways. Despite convincing experimental and clinical evidences of lung injury, the clinical implementation of low tidal volume ventilation is still limited and has not yet become part of standard clinical practice. Setting positive end-expiratory pressure remains an open problem because the ALVEOLI study did not provide any exhaustive answers, likely because of methodologic problems and, unphysiologic design. Gentle lung ventilation must be standard practice. Because stress and strain are the triggers of ventilator-induced lung injury, their clinical equivalents should be measured (transpulmonary pressure and the ratio between tidal volume and end-expiratory lung volume). For a rational application of positive end-expiratory pressure, the potential for recruitment in any single patient should be estimated.

Control and regulation of pulmonary hypoplasia associated with congenital diaphragmatic hernia

Control of fetal lung growth and development is exquisitely orchestrated and regulated. Branching morphogenesis is carefully choreographed with cell growth, proliferation, differentiation, and apoptosis in a spatially and temporally dependent manner. Some of the signals and pathways mediating these events have recently been uncovered, but much remains unknown. The precise etiologic derangements that give rise to pulmonary hypoplasia in congenital diaphragmatic hernia remain elusive. Some clues have been discovered in developmental and signaling pathways that include receptor tyrosine kinase growth factors, homeobox genes, transcription factors, airway distension, retinoid signaling, and oxidation-reduction.

Airway distension with lung inflation measured by HRCT 1

Airways dilate with each inspiration. This normal rhythmic dilation, and even more so, the dilation that occurs with deep inspirations (DI) such as sighing, are thought to play an important role in maintaining airway patency. For example, in the absence of deep inspirations, healthy individuals develop airway obstruction to inhaled stimuli such as methacholine or histamine, whereas, when the inhalation challenge is performed with conventional spirometry (which involves multiple deep inspiration maneuvers), no obstruction takes place (1). Lung disease such as asthma may be related to an inability to sufficiently distend the airways with lung inflation. This defect might result from several factors, including increased stiffness of the airways secondary to increased airway smooth muscle forces preventing airway distension, or secondary to airway remodeling and deposition of nondistensible elements such as collagen in the airway wall (2). Another factor that could affect airway distensibility is air trapping, which results in increased lung volume at functional residual capacity (FRC). If the lung operates at a higher FRC, the magnitude of distention from FRC to total lung capacity (TLC) is necessarily decreased.

4P-1113 IL-5 links adaptive and innate atheroprotective immunity specific for OxLDL

This chapter describes the primary structure, enzymatic characteristics, inhibitor sensitivity, and gene expression of PDE9A, a cGMP-specific PDE with the lowest Km value among all PDEs. Several intracellular small molecules, including cyclic nucleotides (cAMP and cGMP) and ions, act as second messengers to regulate various cellular functions. For instance, cGMP, which is produced by extracellular molecules via activation of guanylyl cyclases, activates cGMP-dependent protein kinases (PKG) and cGMP-gated ion channels. This activation can lead to relaxation of vascular smooth muscle, airway distension, inhibition of cell proliferation, inhibition of platelet aggregation, neuronal transmission, visual signaling, and apoptosis. Cyclic nucleotide phosphodiesterases (PDEs), which comprise 11 families classified on the basis of amino acid sequence homology and substrate specificity, are known to hydrolyze cyclic nucleotides. PDE9A inhibitors improve long-term potentiation in several animal models of cognition. Specific inhibitors of each PDE are used as drugs to treat a variety of diseases. For instance, PDE5 inhibitors, such as sildenafil, vardenafil, tadalafil, and udenafil, are prescribed for erectile dysfunction. On the other hand, cilostazol, a PDE3 inhibitor, is used to treat intermittent claudication. Several PDE4 inhibitors are also being developed for treatment of allergies, including asthma and chronic obstructive pulmonary disease. Thus, PDE families are considered to be drug targets, and many pharmaceutical companies are developing new PDE inhibitors.

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