The role of lung volume recruitment therapy in neuromuscular disease: a narrative review.

Respiratory muscle weakness results in substantial discomfort, disability, and ultimately death in many neuromuscular diseases. Respiratory system impairment manifests as shallow breathing, poor cough and associated difficulty clearing mucus, respiratory tract infections, hypoventilation, sleep-disordered breathing, and chronic ventilatory failure. Ventilatory support (i.e., non-invasive ventilation) is an established and key treatment for the latter. As survival outcomes improve for people living with many neuromuscular diseases, there is a shift towards more proactive and preventative chronic disease multidisciplinary care models that aim to manage symptoms, improve morbidity, and reduce mortality. Clinical care guidelines typically recommend therapies to improve cough effectiveness and mobilise mucus, with the aim of averting acute respiratory compromise or respiratory tract infections. Moreover, preventing recurrent infective episodes may prevent secondary parenchymal pathology and further lung function decline. Regular use of techniques that augment lung volume has similarly been recommended (volume recruitment). It has been speculated that enhancing lung inflation in people with respiratory muscle weakness when well may improve respiratory system "flexibility", mitigate restrictive chest wall disease, and slow lung volume decline. Unfortunately, clinical care guidelines are based largely on clinical rationale and consensus opinion rather than level A evidence. This narrative review outlines the physiological changes that occur in people with neuromuscular disease and how these changes impact on breathing, cough, and respiratory tract infections. The biological rationale for lung volume recruitment is provided, and the clinical trials that examine the immediate, short-term, and longer-term outcomes of lung volume recruitment in paediatric and adult neuromuscular diseases are presented and the results synthesised.

Chronic Daily House Dust Mite Exposure in Mice is an Effective Model to Quantify the Effect of Pharmacologic Agents on Discrete Stages of Artery Remodeling in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a heterogenous and incurable disease marked by varying degrees of pulmonary vascular remodeling. This vascular remodeling, which includes thickening of the smooth muscle layer (an early finding) and formation of occlusive neointimal lesions (a late finding) in the pulmonary arteries, is a major driver of morbidity and mortality in PH. Available PH therapies consist of vasodilators that do not specifically target lesion formation or expansion and neither prevent progression nor reverse disease. This paucity of curative treatments highlights the need for new drug discovery targeting crucial steps of artery remodeling in PH. The cell dynamics and molecular signals driving neointimal lesion formation have been difficult to elucidate as classic mouse models of PH do not develop neointima. Here, we detail the methods to generate a robust and non-genetic mouse model of PH with medial thickening and neointimal lesion formation in the pulmonary arteries, through chronic exposure to an inflammatory stimulus-house dust mite (HDM). This model rapidly generates human-like pulmonary arterial lesions following a reproducible time course, allowing scrutiny of the cellular and molecular mechanisms controlling each stage of artery remodeling. Further, we outline optimal tissue handling, sectioning, and staining methodologies for detailed quantitative analysis of artery medial thickening and neointimal lesion formation and expansion. Finally, we present a method for staged pharmacologic intervention to identify molecules and pathways required at each step of the pulmonary arterial remodeling process. The advantages of this mouse model of PH over currently available animal models are five-fold. (i) It allows the use of the full range of genetic and single cell tools available in mice to manipulate and study the process of vascular remodeling seen in human disease, including the formation of neointimal lesions in a controlled and cell specific manner. (ii) The vascular lesions develop in a stereotyped manner with predictable timing, allowing for pharmacologic manipulation at discrete stages of vessel remodeling. (iii) It is rapid, with development of PH and vascular remodeling in a timeframe of two to eight weeks. (iv) It uses simple techniques and requires neither surgery, unusual equipment, or extensive personnel training. (v) The staining and quantitation methodologies we present are a significant improvement over those currently in use in the field. We hope that dissemination of this model and the associated detailed methods will speed up the development of novel and more effective PH therapeutics. Graphic abstract: Chronic perivascular inflammation induces medial thickening and neointima formation in pulmonary arteries, following a stereotyped time course, and allowing staged pharmacologic intervention during specific remodeling events, as well as quantitative assessment of vascular changes.

Lung Inflation With Hydrogen During the Cold Ischemia Phase Alleviates Lung Ischemia-Reperfusion Injury by Inhibiting Pyroptosis in Rats.

Background: Lung inflation with hydrogen is an effective method to protect donor lungs from lung ischemia-reperfusion injury (IRI). This study aimed to examine the effect of lung inflation with 3% hydrogen during the cold ischemia phase on pyroptosis in lung grafts of rats. Methods: Adult male Wistar rats were randomly divided into the sham group, the control group, the oxygen (O2) group, and the hydrogen (H2) group. The sham group underwent thoracotomy but no lung transplantation. In the control group, the donor lungs were deflated for 2 h. In the O2 and H2 groups, the donor lungs were inflated with 40% O2 + 60% N2 and 3% H2 + 40% O2 + 57% N2, respectively, at 10 ml/kg, and the gas was replaced every 20 min during the cold ischemia phase for 2 h. Two hours after orthotopic lung transplantation, the recipients were euthanized. Results: Compared with the control group, the O2 and H2 groups improved oxygenation indices, decreases the inflammatory response and oxidative stress, reduced lung injury, and improved pressure-volume (P-V) curves. H2 had a better protective effect than O2. Furthermore, the levels of the pyroptosis-related proteins selective nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), cysteinyl aspartate specific proteinase (caspase)-1 p20, and the N-terminal of gasdermin D (GSDMD-N) were decreased in the H2 group. Conclusion: Lung inflation with 3% hydrogen during the cold ischemia phase inhibited the inflammatory response, oxidative stress, and pyroptosis and improved the function of the graft. Inhibiting reactive oxygen species (ROS) production may be the main mechanism of the antipyroptotic effect of hydrogen.

Sustained Lung Inflation in Pre-term Infants at Birth: A Randomized Controlled Trial.

BACKGROUND: Invasive mechanical ventilation (IMV) of pre-term infants may be associated with high rate of mortality and iatrogenic complications in low- and middle-income countries. Sustained lung inflation (SLI) may help to reduce their need for IMV. METHODS: This randomized controlled trial included 160 infants with gestational age (GA) ≥27 and ≤32 weeks who were randomly assigned to receive either SLI; using a pressure of 20 cmH2O for 15 s followed by nasal continuous positive airway pressure (CPAP) of 5 cmH2O or nasal CPAP alone, through an appropriate mask and a T-piece resuscitator. Primary outcome was the need for IMV in the first 72 h of life. RESULTS: There was no difference in the primary outcome between SLI group; 55% (44 out of 80) and the control group; 65% (52 out of 80) [odds ratio (OR): 0.623, 95% confidence interval (CI): 0.33-1.18; p = 0.145]. However, SLI significantly reduced the primary outcome in the sicker infants; who had clinical eligibility criteria (CEC; OR: 0.224, 95% CI: 0.076-0.663; p = 0.005) and in the smaller babies; whose GA was <30 weeks (OR: 0.183, 95% CI: 0.053-0.635; p = 0.005). CONCLUSION: SLI was not harmful. Although, it did not lead to reduction in the need for IMV in the first 72 h of life in pre-term infants with GA ≥27 and ≤32 weeks, SLI reduced this outcome in the subgroup of infants with CEC and those with GA <30 weeks. Future trials are needed to investigate the effect of SLI on these two subgroups. TRIAL REGISTRATION: Clinical trials.gov, NCT03518762. https://www.clinicaltrials.gov/ct2/show/NCT03518762?term=NCT03518762&rank=1.

Modulation of glycinergic inhibition on respiratory rhythmic hypoglossal bursting in the rat.

The hypoglossal nerve displays respiratory rhythmic bursting and is composed of preinspiratory and inspiratory activity which is important in maintaining upper airway patency. The present study was designed to examine the modulatory role of glycinergic inhibition in respiratory rhythmic hypoglossal bursting. The activity of the phrenic nerve, as well as the medial and lateral branches of the hypoglossal nerve, was recorded simultaneously in urethane-anesthetized and mechanically ventilated adult rats in response to moderate and high levels of sustained lung inflation. The results demonstrated that inspiratory activity of the phrenic nerve gradually reduced with increasing lung inflation. The burst amplitude and discharge onset of the hypoglossal nerve branches were enhanced during moderate lung inflation but inhibited by high levels of lung inflation. These lung volume-mediated respiratory reflexes were abolished following a bilateral cervical vagotomy. In addition, intravenous administration of a glycine receptor antagonist (strychnine, 1 µmole/kg) attenuated preceding onset of rhythmic hypoglossal bursting but enhanced inspiratory hypoglossal burst amplitude during the baseline. Moreover, both excitatory and inhibitory effects of lung inflation on hypoglossal nerve activity were attenuated following a glycine transmission blockade. These results suggest that glycinergic inhibition modulated rhythmic hypoglossal bursting and was involved in mediating lung volume-induced respiratory reflexes.

Comparison of breathing patterns, pressure, volume, and flow characteristics of three breathing techniques to encourage lung inflation in healthy older people.

Background: It is important to encourage lung inflation to prevent postsurgical pulmonary complications and we compared three breathing techniques that place different emphasis on inspiratory flow and breath-holding. Methods: Fourteen healthy older people (69 ± 3.6 yrs) used diaphragmatic breathing (DB), Triflo II (TF), and a water pressure threshold device (BreatheMAX; BM) in a randomized and balanced crossover design. Outcome measures were inspiratory flow and pressure, inspiratory time (Ti), tidal volume (Vt), and breathing frequency. Results: Inspiratory flow with TF was significantly faster than DB and BM (p < 0.001: 0.96 ± 0.1; 0.43 ± 0.20 and 0.28 ± 0.1 L.s-1, respectively) and pressures greater (p < 0.001: -1.3 ± 0.6, -5.5 ± 1.2 and -2.8 ± 3.6 cm H2O). However, Ti was shorter (TF, 1.16 ± 0.21s; DB, 3.31 ± 0.97 s, p < 0.001; BM, 5.53 ± 1.92 s, p < 0.001), resulting in smaller Vt (TF, 1.12 ± 0.29 L; DB, 1.28 ± 0.29L, p = 0.003; BM, 1.37 ± 0.43L, p = 0.016). Breathing frequency was faster with TF compared to DB and BM (p < 0.001). Conclusions: Substantial lung inflation could be achieved with any of the above-mentioned methods, although Vt was smaller with TF and the high inspiratory flow with this method may not inflate the lower lung. The high pressures and rapid breathing with TF could increase the sense of effort. Trials are needed to determine the clinical value of the different breathing exercises.

Fine Tuning Non-invasive Respiratory Support to Prevent Lung Injury in the Extremely Premature Infant.

Within the last decades, therapeutic advances, such as antenatal corticosteroids, surfactant replacement, monitored administration of supplemental oxygen, and sophisticated ventilatory support have significantly improved the survival of extremely premature infants. In contrast, the incidence of some neonatal morbidities has not declined. Rates of bronchopulmonary dysplasia (BPD) remain high and have prompted neonatologists to seek effective strategies of non-invasive respiratory support in high risk infants in order to avoid harmful effects associated with invasive mechanical ventilation. There has been a stepwise replacement of invasive mechanical ventilation by early continuous positive airway pressure (CPAP) as the preferred strategy for initial stabilization and for early respiratory support of the premature infant and management of respiratory distress syndrome. However, the vast majority of high risk babies are mechanically ventilated at least once during their NICU stay. Adjunctive therapies aiming at the prevention of CPAP failure and the support of functional residual capacity have been introduced into clinical practice, including alternative techniques of administering surfactant as well as non-invasive ventilation approaches. In contrast, the strategy of applying sustained lung inflations in the delivery room has recently been abandoned due to evidence of higher rates of death within the first 48 h of life.

[Application of Intermittent Lung Inflation Combined with Rigid Ureteroscopy in Treating Upper Ureteral Stones That Were Not Fully Visible].

Objective To analyze the effectiveness and safety of intermittent lung inflation combined with rigid ureteroscopy in the treatment of upper ureteral stones that were not fully visible. Methods The clinical and imaging data of 56 patients with upper ureteral stone undergoing rigid ureteroscopic lithotripsy combined with intermittent lung inflation in Zhejiang Quhua Hospital from March 2016 to October 2017 were retrospectively analyzed.Intermittentt lung inflation was used to change and stabilize the position of ureteral calculi during the operation,so as to ensure the visual field of ureteroscopy.Holmium laser lithotripsy was performed to remove the stones.Urinary tract abdominal plain X-ray or CT urography was performed 1 and 3 months after the operation to evaluate the residual stones and the clinical efficacy. Results Stones were successfully removed after a single attempt in 48 patients.In 5 patients,stones escaped into the kidney during ureteroscopic lithotripsy,and thus flexible ureteroscopy were performed.In 3 patients,a second session of auxiliary procedure was required,among whom 2 patients received extracorporeal shock wave lithotripsy and 1 patient underwent extracorporeal shock wave lithotripsy+ureteroscopic lithotripsy.The stone-free rates 1 and 3 months after surgery were 94.6%(53/56)and 100%(56/56),respectively.No severe complication such as ureter perforation,gross hematuria,septic shock,or pneumothorax occurred during and after surgery. Conclusions Intermittent lung inflation in tracheal intubation under general anesthesia in patients with proximal ureteral stones that can not be fully visible during rigid ureteroscopic lithotripsy was feasible and reliable.It can effectively change the location of stones and thus enable safe and effective lithotripy.It expands the indications of rigid ureteroscopy for treating upper ureteral stones.

Application of Intermittent Lung Inflation Combined with Rigid Ureteroscopy in Treating Upper Ureteral Stones That Were Not Fully Visible / 中国医学科学院学报

To analyze the effectiveness and safety of intermittent lung inflation combined with rigid ureteroscopy in the treatment of upper ureteral stones that were not fully visible. The clinical and imaging data of 56 patients with upper ureteral stone undergoing rigid ureteroscopic lithotripsy combined with intermittent lung inflation in Zhejiang Quhua Hospital from March 2016 to October 2017 were retrospectively analyzed.Intermittentt lung inflation was used to change and stabilize the position of ureteral calculi during the operation,so as to ensure the visual field of ureteroscopy.Holmium laser lithotripsy was performed to remove the stones.Urinary tract abdominal plain X-ray or CT urography was performed 1 and 3 months after the operation to evaluate the residual stones and the clinical efficacy. Stones were successfully removed after a single attempt in 48 patients.In 5 patients,stones escaped into the kidney during ureteroscopic lithotripsy,and thus flexible ureteroscopy were performed.In 3 patients,a second session of auxiliary procedure was required,among whom 2 patients received extracorporeal shock wave lithotripsy and 1 patient underwent extracorporeal shock wave lithotripsy+ureteroscopic lithotripsy.The stone-free rates 1 and 3 months after surgery were 94.6%(53/56)and 100%(56/56),respectively.No severe complication such as ureter perforation,gross hematuria,septic shock,or pneumothorax occurred during and after surgery. Intermittent lung inflation in tracheal intubation under general anesthesia in patients with proximal ureteral stones that can not be fully visible during rigid ureteroscopic lithotripsy was feasible and reliable.It can effectively change the location of stones and thus enable safe and effective lithotripy.It expands the indications of rigid ureteroscopy for treating upper ureteral stones.

Sustained lung inflation at birth via short binasal prong in very low birth weight preterm infants: A retrospective study.

BACKGROUND AND OBJECTIVES: It is believed, that sustained lung inflation (SLI) at birth in preterm infants reduces the need for mechanical ventilation (MV) and improves respiratory outcomes. The aim of this study was to compare need for MV in preterm infants at high risk for respiratory distress syndrome (RDS) after prophylactic SLI via short binasal prongs at birth combined with early nasal continuous positive airway pressure (nCPAP) versus nCPAP alone. METHODS: Medical records of infants born at 260/7 to 296/7 weeks gestation through 2015 and 2017 were retrospectively assessed. Infants who get sustained inflations at 25 cmH2 O pressure for 15 s following delivery via binasal short prongs comprised the study group. Gestational age matched infants who was supported solely with nCPAP (6 cmH2 O PEEP) comprised the control group. Early rescue surfactant (200 mg/kg poractant alfa) was delivered using the less invasive surfactant administration technique in infants with established RDS. RESULTS: A total of 215 infants were analyzed. Fewer infants in the SLI group required MV within the first 72 h of life compared to the control group (25.7% vs 56.9%, P < 0.001). In multiple logistic regression analysis, SLI emerged as an independent factor for reduced MV need. Bronchopulmonary dysplasia (BPD) incidence including mild BPD was significantly lower in the SLI group (31.9% vs 48%, P = 0.01); however, moderate and severe BPD rates did not reach to a statistical significance (11.5% vs 20.6%, P = 0.06). CONCLUSION: Prophylactic SLI maneuver at birth for preterm infants with impending RDS reduces the need for MV with no adverse effects.

Preventing Continuous Positive Airway Pressure Failure: Evidence-Based and Physiologically Sound Practices from Delivery Room to the Neonatal Intensive Care Unit.

Routine use of continuous positive airway pressure (CPAP) to support preterm infants with respiratory distress is an evidenced-based strategy to decrease incidence of bronchopulmonary dysplasia. However, rates of CPAP failure remain unacceptably high in very premature neonates, who are at high risk for developing bronchopulmonary dysplasia. Using the GRADE framework to assess the quality of available evidence, this article reviews strategies aimed at decreasing CPAP failure, starting with delivery room interventions and followed through to system-based efforts in the neonatal intensive care unit. Despite best efforts, some very premature neonates fail CPAP. Also reviewed are predictors of CPAP failure in this vulnerable population.

Sustained lung inflation at birth for preterm infants at risk of respiratory distress syndrome: The proper pressure and duration.

BACKGROUND: Variations exist among the administered pressure and duration of sustained lung inflation (SLI) in the delivery room (DR). We aimed to evaluate the appropriate pressure and duration needed for SLI in preterm infants with respiratory distress syndrome. METHODS: We prospectively randomized 100 preterm (<32 weeks) infants to receive either conventional therapy of continuous positive airway pressure (CPAP) at 5 cm H2O, or four groups of CPAP plus a single maneuver of SLI at four regimens based on administered pressures and durations; P20D20 (Pressure of 20 cm H2O for a duration of 20 seconds), P20D10 (20 cm H2O for 10 seconds), P15D20 (15 cm H2O for 20 seconds), and P15D10 (15 cm H2O for 10 seconds) using a T-piece ventilator. The primary outcome was the need for endotracheal intubation (ETT) in the DR. Broncho-alveolar lavage (BAL) was obtained from intubated infants for interleukin-10 (IL-10) assessment. RESULTS: SLI decreased the need for ETT in the DR (21% versus 55%, p < 0.01) compared to conventional therapy. ETT requirement was significantly lower in P20D10 (20%), P15D20 (20%), and P15D10 (20%) groups, but not P20D20 (25%) compared to the conventional group (55%, p < 0.05). Group P20D20 had significant higher BAL levels of IL-10 [713.8 (IQR 611-874) versus 535.4 (IQR 480-563) pg/ml, p < 0.05] compared to the conventional group, and to other SLI groups. Pneumothorax was not significantly different among studied groups. CONCLUSION: SLI for a pressure and duration ≥20 cm H2O for 20 seconds is not superior to lower pressures for shorter duration and may be injurious to lungs.

The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model.

BACKGROUND: Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH2O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain). METHODS: Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + HDS, n = 6) and (2) over-distension + low dynamic strain (OD + LDS, n = 6). OD was caused by setting the inspiratory pressure at 40 cmH2O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy. RESULTS: In normal tissue (NT), OD + LDS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + HDS. In acutely injured tissue (ALIT), OD + LDS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + HDS. CONCLUSIONS: Both NT and ALIT are resistant to VILI caused by OD alone, but when combined with a HDS, significant tissue injury develops.

Randomised controlled trial of sustained lung inflation for resuscitation of preterm infants in the delivery room.

AIM: To compare the effects of sustained lung inflation (SLI) vs. standard resuscitation on physiologic responses of preterm infants during resuscitation. METHODS: Preterm infants (25-32 weeks gestational age) requiring positive-pressure ventilation or continuous positive airway pressure were randomly assigned to either the SLI group (SLI at 25cmH2O for 15s) or Non-SLI group (standard resuscitation alone). The heart rate (HR), oxygen saturation (SpO2), oxygen requirement, and intubation rate in the delivery room were evaluated. RESULTS: Eighty-one infants were enrolled (SLI group, 43; Non-SLI group, 38). The use of SLI effectively reduced the oxygen requirement. The mean fraction of inspired oxygen 10min after birth was 0.28 (95% CI, 0.26-0.30) in the SLI group and 0.47 (95% CI, 0.43-0.52) in the Non-SLI group (p<0.001). During the first 5min, infants in the SLI group trended towards a higher HR and SpO2 than those in the Non-SLI group. The intubation rate in the delivery room was not different between the two groups; however, among infants ≤28 weeks gestational age, the intubation rate was lower in the SLI than Non-SLI group (5 of 17 [29%] vs. 10 of 16 [63%], respectively; p=0.05). The duration of respiratory support, survival without bronchopulmonary dysplasia, and the occurrence of pneumothorax were not different between the groups. CONCLUSION: SLI in infants who require respiratory support appears to be effective in facilitating postnatal transition as determined by HR and SpO2 responses, resulting in less oxygen supplementation. Further studies are needed to confirm the benefits of SLI.

Application of sustained lung inflations for neonatal resuscitation / 中华实用儿科临床杂志

Application of sustained lung inflation (SLI)during neonatal resuscitation can increase alveolar opening,promote lung fluid absorption and maintain the appropriate functional residual capacity (FRC) which can complete the transition from fetal phase of respiratory system to neonatal period.In recent years,SLI has also been confirmed by a large number of animal experiments and clinical studies,and it is expected to be practically applied in the resuscitation of newborns.However,more randomized controlled trials with a large number of samples is required for exploring suitable populations,methods of operation,and recent or long-term effects on newborns.Now,the application and research of SLI in neonatal resuscitation are described.

Noninvasive Support: Does It Really Decrease Bronchopulmonary Dysplasia?

Noninvasive support of preterm infants with respiratory distress is an evidenced-based strategy to decrease the incidence of bronchopulmonary dysplasia. Continuous positive airway pressure (CPAP) is the only noninvasive strategy with sufficient evidence to support its use in acute respiratory distress syndrome. It is unclear if one method for delivering CPAP is superior to another. Future research will focus on strategies (eg, sustained lung inflation, and administration of surfactant using a thin plastic catheter) that increase the likelihood of success with CPAP, especially in infants with a gestational age of less than 26 weeks.

Real-time imaging of inflation-induced ATP release in the ex vivo rat lung.

Extracellular ATP and other nucleotides are important autocrine/paracrine mediators that regulate diverse processes critical for lung function, including mucociliary clearance, surfactant secretion, and local blood flow. Cellular ATP release is mechanosensitive; however, the impact of physical stimuli on ATP release during breathing has never been tested in intact lungs in real time and remains elusive. In this pilot study, we investigated inflation-induced ATP release in rat lungs ex vivo by real-time luciferin-luciferase (LL) bioluminescence imaging coupled with simultaneous infrared tissue imaging to identify ATP-releasing sites. With LL solution introduced into air spaces, brief inflation of such edematous lung (1 s, ∼20 cmH2O) induced transient (<30 s) ATP release in a limited number of air-inflated alveolar sacs during their recruitment/opening. Released ATP reached concentrations of ∼10-6 M, relevant for autocrine/paracrine signaling, but it remained spatially restricted to single alveolar sacs or their clusters. ATP release was stimulus dependent: prolonged (100 s) inflation evoked long-lasting ATP release that terminated upon alveoli deflation/derecruitment while cyclic inflation/suction produced cyclic ATP release. With LL introduced into blood vessels, inflation induced transient ATP release in many small patchlike areas the size of alveolar sacs. Findings suggest that inflation induces ATP release in both alveoli and the surrounding blood capillary network; the functional units of ATP release presumably consist of alveolar sacs or their clusters. Our study demonstrates the feasibility of real-time ATP release imaging in ex vivo lungs and provides the first direct evidence of inflation-induced ATP release in lung air spaces and in pulmonary blood capillaries, highlighting the importance of purinergic signaling in lung function.

Protection of donor lung inflation in the setting of cold ischemia against ischemia-reperfusion injury with carbon monoxide, hydrogen, or both in rats.

AIMS: Lung ischemia-reperfusion injury (IRI) may be attenuated through carbon monoxide (CO)'s anti-inflammatory effect or hydrogen (H2)'s anti-oxidant effect. In this study, the effects of lung inflation with CO, H2, or both during the cold ischemia phase on graft function were observed. MATERIALS AND METHODS: Rat donor lungs, inflated with 40% oxygen (control group), 500ppm CO (CO group), 3% H2 (H2 group) or 500ppm CO+3% H2 (COH group), were kept at 4°C for 180min. After transplantation, the recipients' artery blood gas and pressure-volume (P-V) curves were analyzed. The inflammatory response, oxidative stress and apoptosis in the recipients were assessed at 180min after reperfusion. KEY FINDINGS: Oxygenation in the CO and H2 groups were improved compared with the control group. The CO and H2 groups also exhibited significantly improved P-V curves, reduced lung injury, and decreased inflammatory response, malonaldehyde content, and cell apoptosis in the grafts. Furthermore, the COH group experienced enhanced improvements in oxygenation, P-V curves, inflammatory response, lipid peroxidation, and graft apoptosis compared to the CO and H2 groups. SIGNIFICANCE: Lung inflation with CO or H2 protected against IRI via anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms in a model of lung transplantation in rats, which was enhanced by combined treatment with CO and H2.

In vivo imaging of the spectral line broadening of the human lung in a single breathhold.

PURPOSE: To present a technique, which allows for the in vivo quantification of the spectral line broadening of the human lung in a single breathhold. The line broadening is an interesting parameter of the lung because it can provide information about important lung properties, namely: inflation and oxygen uptake. The proposed technique integrates the asymmetric spin-echo (ASE) approach, which is commonly used to quantify the line broadening, with a single shot turbo spin-echo pulse sequence with half-Fourier acquisition (HASTE), to reduce the acquisition times. MATERIALS AND METHODS: Imaging experiments were performed at 1.5 Tesla on 14 healthy volunteers, using a ASE-prepared HASTE sequence. The line broadening was quantified using a two-points method. Data were acquired at different breathing states: functional residual capacity (FRC) and total lung capacity (TLC), and with different breathing gases: room-air and pure-oxygen. Image acquisition was accomplished within a single breathhold of approximately 15 s duration. The violation of the Carr-Purcell-Meiboom-Gill conditions, deriving from inhomogeneities of the static magnetic field, was overcome by means of radiofrequency-phase cycling and generalized autocalibrating partially parallel acquisitions (GRAPPA) reconstruction. RESULTS: Significant increase of the line broadening was observed with both lung inflation and oxygen concentration (P < 0.0001). Values of the line broadening obtained within the lung parenchyma at different breathing states (1.48 ± 0.29 ppm at FRC and 1.95 ± 0.43 ppm at TLC) are in agreement with previous reports and show excellent reproducibility, with a coefficient of variation <0.03. The mean relative difference observed with oxygen-enhancement was approximately 14%. CONCLUSION: The presented technique offers a robust way to quantify the spectral line broadening of the human lung in vivo. Image acquisition can be accomplished in a single breathhold, which could be suitable for clinical applications on patients with lung diseases. J. Magn. Reson. Imaging 2016;44:745-757.