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Will Mediterranean terrestrial ecosystems be affected by the expected changes in precipitation regimes? If so, by how much and in which direction? These questions are at the basis of the research performed in context of the EU MIND project, whose key objectives were: i) to investigate the potential effects of increasing drought on Mediterranean terrestrial ecosystems at the process, ecosystem and regional scales and ii) to assess ecosystem vulnerability to changes in rainfall patterns. A network of experimental study sites has been created in Portugal, Spain, France and Italy, where field manipulations alter the amount of water available to the ecosystem. The most up-to-date methods of ecophysiology, micrometeorology, soil ecology and remote sensing have been used to elucidate the mechanisms that regulate the response of vegetation and soil to changes in water availability. This information is providing the basis for the implementation and validation of simulation models capable of predicting the drought response of Mediterranean terrestrial ecosystems, and their vulnerability to future climate change, on a larger scale. The out-coming results are elucidating how water availability affects plant ecophysiological processes, the dynamics of soil carbon and the overall exchange of mass and energy between the land and the atmosphere. This paper focuses on some of the important, yet preliminary, results on C and energy fluxes that have been obtained at the large scale troughfall manipulation experiment (Tolfa, Italy), in a forest dominated by Arbutus unedo L.

OBJECTIVES: Plasma membrane disruptions are caused by excessive mechanical stress and thought to be involved in inflammatory mediator upregulation. Presently, plasma membrane disruption formation has been studied only during mechanical ventilation with large tidal volumes and limitedly to subpleural alveoli. No information is available concerning the distribution of plasma membrane disruptions within the lung or the development of plasma membrane disruptions during another modality of injurious mechanical ventilation, i.e., mechanical ventilation with eupneic tidal volume (7 mL · kg) at low end-expiratory lung volume. The aim of this study is to assess whether 1) mechanical ventilation with eupneic tidal volume at low end-expiratory lung volume causes plasma membrane disruptions; and 2) the distribution of plasma membrane disruptions differs from that of mechanical ventilation with large tidal volume at normal end-expiratory lung volume. DESIGN: Experimental animal model. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Plasma membrane disruptions have been detected as red spots in gelatin-included slices of rat lungs stained with ethidium homodimer-1 shortly after anesthesia (control) after prolonged mechanical ventilation with eupneic tidal volume at low end-expiratory lung volume followed or not by the restoration of physiological end-expiratory lung volume and after prolonged mechanical ventilation with large tidal volumes and normal end-expiratory lung volume. MEASUREMENTS AND MAIN RESULTS: Plasma membrane disruptions increased during mechanical ventilation at low end-expiratory lung volume, mainly at the bronchiolar level. Resealing of most plasma membrane disruptions occurred on restoration of normal end-expiratory lung volume. Mechanical ventilation with large tidal volume caused the appearance of plasma membrane disruptions, both bronchiolar and parenchymal, the latter to a much greater extent than with mechanical ventilation at low end-expiratory lung volume. The increase of plasma membrane disruptions correlated with the concomitant increase of airway resistance with both modes of mechanical ventilation. CONCLUSIONS: : Amount and distribution of plasma membrane disruptions between small airways and lung parenchyma depends on the type of injurious mechanical ventilation. This could be relevant to the release of inflammatory mediators. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is characterised by airway obstruction with an increase in airway resistance (R) to airflow in the lungs. An extreme case of expiratory airway resistance is expiratory flow limitation, a common feature of severe COPD. Current analyses quantify expiratory R with linear model-based methods, which do not capture non-linearity's noted in COPD literature. This analysis utilises a simple nonlinear model to describe patient-specific nonlinear expiratory resistance dynamics typical of COPD and assesses its ability to both fit measured data and also to discriminate between severity levels of COPD., Methods: Plethysmographic data, including alveolar pressure and airway flow, was collected from n=100 subjects (40 healthy, 60 COPD) in a previous study. Healthy cohorts included Young (20-32 years) and Elderly (64-85 years) patients. COPD patients were divided into those with expiratory flow limitation (FL) and those without (NFL). Inspiratory R was treated as linear (R 1 ,insp ). Expiratory R was modelled with two separate models for a comparison: linear with constant resistance (R 1 ,exp ), and nonlinear time-varying resistance (R 2 ,exp (t)) using b-splines., Results: Model fit to PQ loops show inspiration is typically linear. Linear R 1 ,exp captured expiratory dynamics in healthy cohorts (RMSE 0.3 [0.2 - 0.4] cmH 2 O), but did not capture nonlinearity in COPD patients. COPD cohorts showed PQ-loop ballooning during expiration, which was better captured by non-linear R 2 ,exp (t) (RMSE 1.7[1.3-2.8] vs. 0.3[0.2-0.4] cmH 2 O in FL patients). Airway resistance is higher in COPD than healthy cohorts (mean R 2,exp (t) for Young (1.9 [1.6-2.8]), Elderly (2.4 [1.4-3.5]), NFL (4.9 [3.9-6.6]) and FL (13.5 [10.4-21.9]) cmH 2 O/L/s, with p ≤ 0.0001 between aggregated measures for Young and Elderly healthy subjects and NFL and FL COPD subjects). FL patients showed non-linear R 2 ,exp (t) dynamics during flow deceleration, differentiating them from NFL COPD patients., Conclusions: Linear model metrics describe expiration dynamics well in healthy subjects, but fail to capture nonlinear dynamics in COPD patients. Overall, the model-based method presented shows promise in detecting expiratory flow limitation, as well as describing different dynamics in healthy, COPD, and FL COPD patients. This method may thus be clinically useful in the diagnosis or monitoring of COPD patients using Plethysmography data, without the need for additional expiratory flow limitation confirmation procedures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J. Geoffrey Chase reports financial support was provided by New Zealand Tertiary Education Commission. No further activities to disclose If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Biodegradability standards measure ultimate biodegradation of polymers by exposing the material under test to a natural microbial inoculum. Available tests developed by the International Organization for Standardization (ISO) use inoculums sampled from different environments e.g. soil, marine sediments, seawater. Understanding whether each inoculum is to be considered as microbially unique or not can be relevant for the interpretation of tests results. In this review, we address this question by consideration of the following: (i) the chemical nature of biodegradable plastics (virtually all biodegradable plastics are polyesters) (ii) the diffusion of ester bonds in nature both in simple molecules and in polymers (ubiquitous); (iii) the diffusion of decomposers capable of producing enzymes, called esterases, which accelerate the hydrolysis of esters, including polyesters (ubiquitous); (iv) the evidence showing that synthetic polyesters can be depolymerized by esterases (large and growing); (v) the evidence showing that these esterases are ubiquitous (growing and confirmed by bioinformatics studies). By combining the relevant available facts it can be concluded that if a certain polyester shows ultimate biodegradation when exposed to a natural inoculum, it can be considered biodegradable and need not be retested using other inoculums. Obviously, if the polymer does not show ultimate biodegradation it must be considered recalcitrant, until proven otherwise., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Acute dyspnea represents one of the most frequent symptoms leading to emergency room evaluation. Its significant prognostic value warrants a careful evaluation. The differential diagnosis of dyspnea is complex due to the lack of specificity and the loose association between its intensity and the severity of the underlying pathological condition. The initial assessment of dyspnea calls for prompt diagnostic evaluation and identification of optimal monitoring strategy and provides information useful to allocate the patient to the most appropriate setting of care. In recent years, accumulating evidence indicated that lung ultrasound, along with echocardiography, represents the first rapid and non-invasive line of assessment that accurately differentiates heart, lung or extra-pulmonary involvement in patients with dyspnea. Moreover, non-invasive respiratory support modalities such as high-flow nasal oxygen and continuous positive airway pressure have aroused major clinical interest, in light of their efficacy and practicality to treat patients with dyspnea requiring ventilatory support, without using invasive mechanical ventilation. This clinical review is focused on the pathophysiology of acute dyspnea, on its clinical presentation and evaluation, including ultrasound-based diagnostic workup, and on available non-invasive modalities of respiratory support that may be required in patients with acute dyspnea secondary or associated with respiratory failure., (© 2023. The Author(s).)

Chronic obstructive pulmonary disease (COPD) patients often experience tidal expiratory flow-limitation (tEFL), a condition causing respiratory and cardiovascular detrimental effects. As the appearance of tEFL should increase expiratory (Rexp) relative to inspiratory (Rins) resistance, we hypothesized that Rexp/Rins can be used to detect tEFL. Rexp/Rins was measured with a commercial plethysmograph in 109 healthy subjects and, before and after bronchodilation (BD), in 64 COPD patients, 36 with and 28 without tEFL according to the NEP technique. Before BD, the median (interquartile range) of Rexp/Rins was significantly greater (P < 0.001) in COPD patients with tEFL (2.47(3.06;7.07)) than in COPD patients without tEFL (1.63(1.44;1.82)) and in healthy subjects (1.52(1.35;1.62)). In COPD patients Rexp/Rins above 1.98 predicted the presence of tEFL with 96 % specificity and 92 % sensitivity, Rexp 2 /Rins performing even better. After BD the predictive ability of Rexp/Rins slightly declined, but remained elevated. The non-invasive measurement of Rexp/Rins is an easy, inexpensive, routinely usable method to detect tEFL in spontaneously breathing COPD subjects., (Copyright © 2021. Published by Elsevier B.V.)

Discovered some 40 years ago, the I f current has since been known as the "pacemaker" current due to its role in the initiation and modulation of the heartbeat and of neuronal excitability. But this is not all, the funny current keeps entertaining the researchers; indeed, several data discovering novel and uncanonical roles of f/HCN channel are quickly accumulating. In the present review, we provide an overview of the expression and cellular functions of HCN/f channels in a variety of systems/organs, and particularly in sour taste transduction, hormones secretion, activation of astrocytes and microglia, inhibition of osteoclastogenesis, renal ammonium excretion, and peristalsis in the gastrointestinal and urine systems. We also analyzed the role of HCN channels in sustaining cellular respiration in mitochondria and their participation to mitophagy under specific conditions. The relevance of HCN currents in undifferentiated cells, and specifically in the control of stem cell cycle and in bioelectrical signals driving left/right asymmetry during zygote development, is also considered. Finally, we present novel data concerning the expression of HCN mRNA in human leukocytes. We can thus conclude that the emerging evidence presented in this review clearly points to an increasing interest and importance of the "funny" current that goes beyond its role in cardiac sinoatrial and neuronal excitability regulation., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We investigated the effects of heliox administration (80% helium in O 2 ) on tidal inspiratory flow limitation (tIFL) occurring in supine anesthetized spontaneously breathing rabbits, regarded as an animal model of obstructive apnea-hypopnea syndrome. 22 rabbits were instrumented to record oro-nasal mask flow, airway opening, tracheal and esophageal pressures, and diaphragm and genioglossus electromyographic activities while breathing either room air or heliox, and, in 12 rabbits, also during the application of continuous positive airway pressure (CPAP; 6 cmH 2 O). For the group, heliox increased peak inspiratory flow, ventilation (18 ± 11%), peak inspiratory tracheal and dynamic transpulmonary pressures, but in no animal eliminated tIFL, as instead CPAP did in all. Muscle activities were unaffected by heliox. In the presence of IFL the increase in flow with heliox (ΔV̇ifl) varied markedly among rabbits (2 to 49%), allowing the distinction between responders and non-responders. None of the baseline variables discriminated responders and non-responders. However, fitting the Rohrer equation ( R  =  K 1 + K 2 V̇) to the tracheal pressure-flow relationship over the first 0.1 s of inspiration while breathing air allowed such discrimination on the basis of larger K 2 in responders (0.005 ± 0.002 versus 0.002 ± 0.001 cmH 2 O·s 2 ·ml -2 ; P < 0.001), suggesting a corresponding difference in the relative contribution of laminar and turbulent flow. The differences in ΔV̇ifl between responders and non-responders were simulated by modeling the collapsible segment of the upper airways as a non-linear resistor and varying its pressure-volume curve, length, and diameter, thus showing the importance of mechanical and geometrical factors in determining the response to heliox in the presence of tIFL. NEW & NOTEWORTHY In an obstructive sleep apnea rabbit model, heliox never abolishes tidal inspiratory flow limitation (IFL), but increases inspiratory flow and tidal volume, substantially in some and nearly nil in other animals. Positive response to heliox cannot be predicted on the basis of breathing pattern characteristics or upper airway resistance that preceded IFL onset, but is related to the mechanical and geometrical features of upper airway collapsible segment, as indicated by model simulation.

Sepsis is the life-threatening organ dysfunction arising from a dysregulated host response to infection. Although the specific mechanisms leading to organ dysfunction are still debated, impaired tissue oxygenation appears to play a major role, and concomitant hemodynamic alterations are invariably present. The hemodynamic phenotype of affected individuals is highly variable for reasons that have been partially elucidated. Indeed, each patient's circulatory condition is shaped by the complex interplay between the medical history, the volemic status, the interval from disease onset, the pathogen, the site of infection, and the attempted resuscitation. Moreover, the same hemodynamic pattern can be generated by different combinations of various pathophysiological processes, so the presence of a given hemodynamic pattern cannot be directly related to a unique cluster of alterations. Research based on endotoxin administration to healthy volunteers and animal models compensate, to an extent, for the scarcity of clinical studies on the evolution of sepsis hemodynamics. Their results, however, cannot be directly extrapolated to the clinical setting, due to fundamental differences between the septic patient, the healthy volunteer, and the experimental model. Numerous microcirculatory derangements might exist in the septic host, even in the presence of a preserved macrocirculation. This dissociation between the macro- and the microcirculation might account for the limited success of therapeutic interventions targeting typical hemodynamic parameters, such as arterial and cardiac filling pressures, and cardiac output. Finally, physiological studies point to an early contribution of cardiac dysfunction to the septic phenotype, however, our defective diagnostic tools preclude its clinical recognition. © 2021 American Physiological Society. Compr Physiol 11:1605-1652, 2021., (Copyright © 2021 American Physiological Society. All rights reserved.)

COPD and asthma have different risk factors and pathogenesis, but they share a pathophysiologic hallmark characterized by small airways disease. Although difficult to explore and measure, modifications of distal airways' pathophysiology and biology represent an early sign of obstructive disease and should be researched and assessed in everyday clinical practice. In the last 15 years, computed microtomography scans have shed light on the anatomy and physiology of the so-called silent zone, and research devoted to investigate the effect of inhaled treatments on small airway pathophysiology has been increasing. This narrative review offers a historical summary of researchers and landmark studies that reported, defined, and advanced the research on small airways. We then discuss the latest findings on the role and characteristics of the small airways' inflammatory and cellular structure, and we describe the assessment tools available to detect small airways dysfunction in COPD and asthma and the effect of bronchodilators and inhaled steroids on functional and biological biomarkers. Finally, we analyze the newest technological therapeutic advances aimed at small airways treatment in terms of inhalation devices and small particle size molecules., Competing Interests: Dr Santus has disclosed relationships with Chiesi Farmaceutici, AirLiquide, Pfizer, Almirall, Astra Zeneca, Boehringer Ingelheim, Novartis, Menarini, Malesci/Guidotti, Mundipharma, and Zambon. Dr Radovanovic has disclosed relationships with Boehringer Ingelheim, Astra Zeneca, and Neopharmed Gentili. Dr Patella has disclosed relationships with Astra Zeneca, Menarini, and the Italian Drug Agency (AIFA). Dr Braido has disclosed relationships with AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, Dompè, GlaxoSmithKline, Lallemand Pharma, Malesci/Guidotti, Menarini Group, Mundipharma, Novartis, Teva, and Zambon. The remaining authors have disclosed no conflicts of interest., (Copyright © 2020 by Daedalus Enterprises.)

During spontaneous breathing at rest, the alveolar pressure (P alv )-flow (V̇) relation exhibits a prominent expiratory loop in many chronic obstructive pulmonary disease (COPD) patients. Among the possible determinants of the loop, tidal expiratory flow limitation (tEFL) may be the main responsible. To compare the characteristics of the expiratory loop in COPD patients with flow limitation (FL) and without flow limitation (NFL), tEFL was assessed with the negative expiratory pressure technique in stable mild to very severe COPD patients undergoing body plethysmography before and after bronchodilation (BD), an intervention that is able to reduce mechanical heterogeneity, recruitment/derecruitment, and gas trapping but rarely abolishes tEFL. The magnitude of the expiratory loop was indexed by the integral of P alv on V̇ during expiration ( A exp ). Before BD, A exp was 360% greater in FL ( n = 35) than in NFL ( n = 25) patients ( P < 0.001). After BD, A exp was unchanged in NFL patients (Δ A exp 0%, P = 0.882) and slightly decreased in FL patients who remained FL ( n = 32, Δ A exp -17%, P = 0.064). Three FL patients became NFL after BD, and their A exp decreased markedly (Δ A exp -61%), reaching values similar to those observed in NFL patients at baseline. In conclusion, the greater A exp measured in FL relative to NFL COPD patients, its relative invariance after BD when flow limitation persists, and its fall when flow limitation is abolished indicate that tEFL is a major determinant of the magnitude of the expiratory loop. Furthermore, A exp can be used as a predictor of the presence of tEFL. NEW & NOTEWORTHY In stable chronic obstructive pulmonary disease (COPD) patients spontaneously breathing at rest, tidal expiratory flow limitation is the major determinant of the occurrence of expiratory looping in the plethysmographic flow-alveolar pressure diagram. In these patients the magnitude and the characteristics of the loop can be used as predictors of the presence of tidal expiratory flow limitation.

Sixty-three, open-chest normal rats were subjected to mechanical ventilation (MV) with tidal volumes (V T ) ranging from 7.5-39.5ml kg -1 and PEEP 2.3 cmH 2 O. Arterial blood gasses and pressure, and lung mechanics were measured during baseline ventilation (V T  = 7.5ml kg -1 ) before and after test ventilation, when cytokine, von Willebrand factor (vWF), and albumin concentration in serum and broncho-alveolar lavage fluid (BALF), wet-to-dry weight ratio (W/D), and histologic injury scores were assessed. Elevation of W/D and serum vWF and cytokine concentration occurred with V T  > 25ml kg -1 . With V T  > 30ml kg -1 cytokine and albumin concentration increased also in BALF, arterial oxygen tension decreased, lung mechanics and histology deteriorated, while W/D and vWF and cytokine concentration increased further. Hence, the initial manifestation of injurious MV consists of damage of extra-alveolar vessels leading to interstitial edema, as shown by elevated vWF and cytokine levels in serum but not in BALF. Failure of the endothelial-epithelial barrier occurs at higher stress-strain levels, with alveolar edema, small airway injury, and mechanical alterations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A growing body of evidence implicates the human microbiome as a potentially influential player actively engaged in shaping the pathogenetic processes underlying the endotypes and phenotypes of chronic respiratory diseases, particularly of the airways. In this article, we specifically review current evidence on the characteristics of lung microbiome, and specifically the bacteriome, the modes of interaction between lung microbiota and host immune system, the role of the "lung-gut axis", and the functional effects thereof on asthma pathogenesis. We also attempt to explore the possibilities of therapeutic manipulation of the microbiome, aiming at the establishment of asthma prevention strategies and the optimization of asthma treatment.

The airway epithelium stretches and relaxes during the normal respiratory cycle, and hyperventilation exaggerates this effect, resulting in changes in lung physiology. In fact, stretching of the airways influences lung function and the secretion of airway mediators, which in turn may cause a potentially injurious inflammatory response. This aim of the present narrative review was to illustrate the current evidence on the importance of mechanical stress in the pathophysiology of lung diseases with a particular focus on chronic obstructive pulmonary disease (COPD) and to discuss how this may influence pharmacological treatment strategies. Overall, treatment selection should be tailored to counterpart the effects of mechanical stress, which influences inflammation both in asthma and COPD. The most suitable treatment approach between a long-acting β 2-agonists/long-acting antimuscarinic-agonist (LABA/LAMA) alone or with the addition of inhaled corticosteroids should be determined based on the underlying mechanism of inflammation. Noteworthy, the anti-inflammatory effects of the glycopyrronium/indacaterol combination on hyperinflation and mucociliary clearance may decrease the rate of COPD exacerbations, and it may synergistically improve bronchodilation with a double action on both the cyclic adenosine monophosphate (cAMP) and the acetylcholine pathways., Competing Interests: PS reports research grants from Chiesi Farmaceutici, Air Liquide, Pfizer, Almirall, and Boehringer Ingelheim and honoraria for lectures and consultancy from AstraZeneca, Boehringer Ingelheim, Novartis, Guidotti, Berlin-Chemie, Mundipharma, Zambon Italia, and Valeas. DR received honoraria for lectures from Boehringer Ingelheim, AstraZeneca, and Neopharmed Gentili and personal fees for participating to advisory boards from AstraZeneca. MP, MS, VV, and FT declare no competing or financial interests., (Copyright © 2019 Pierachille Santus et al.)

In 9 anesthetized, paralyzed dogs lung and chest-wall standard (viscous resistance, Rint, and quasi-static elastance, Est) and viscoelastic parameters (resistance, Rvel, and time constant, τvel) were measured in the supine posture before and after rib-cage block, after application of an expiratory threshold load, and after 75° head-up tilting before and after wide chest opening. Lung and chest-wall τvel were the same under all conditions. Rvel was independent of volume and posture, and greater for the lung. Chest-wall Rint was independent of flow, volume, and posture. Lung Rint decreased with increasing volume. Chest-wall Rint, Est and Rvel increased with rib-cage block, allowing the assessment of both abdominal-wall and rib-cage characteristics. When chest opening did not elicit bronchoconstriction, the decrease of Rvel was ∼6%. Main conclusions: lung and chest-wall exhibit linear tissue viscoelasticity within the range studied; rib-cage and abdomen characteristics are similar, and asynchronous motion is not expected at physiological respiratory rates; in normal lungs, heterogeneity of parallel time constants plays a marginal role., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Plethysmographic alveolar pressure-flow ( P alv - F ) loops contain potentially relevant information about the pathophysiology of chronic obstructive pulmonary disease (COPD), but no quantitative analysis of these loops during spontaneous breathing has ever been performed. The area of the loop's inspiratory ( A ins ) and expiratory portion ( A exp ), and the difference between the end-expiratory and end-inspiratory alveolar pressure (Δ P alv ) were measured in 20 young, 20 elderly healthy subjects, and 130 stable COPD patients. A ins and Δ P alv increased by 55 and 78% from young to elderly subjects, and by 107 and 122% from elderly subjects to COPD patients, reflecting changes in mechanical heterogeneity, lung-units recruitment/derecruitment, and possibly air trapping occurring with aging and/or obstructive disease. A exp increased by 38% from young to elderly subjects, and by 198% from elderly subjects to COPD patients, consistent with the additional contribution of tidal expiratory flow-limitation, which occurs only in COPD patients and affects A exp only. In COPD patients, A exp and Δ P alv showed a significant negative correlation with VC, FEV 1 , IC, and a significant positive correlation with RV/TLC. The results suggest that the analysis of plethysmographic P alv -F loops provides an insight of the pathophysiological factors, especially tidal expiratory flow-limitation, that affect lung function in COPD patients.

Introduction: Exercise intolerance is the most predominant symptom in patients with COPD. Nevertheless, it is unclear whether walking economy and gait variability are altered in these patients. Thus, our main objective was to compare the cost of transport and gait variability as a function of speed, including the self-selected walking speed, in subjects with COPD relative to healthy subjects., Methods: 22 subjects, 11 with COPD (FEV 1 = 45 ± 17% of predicted) and 11 age- and sex-matched healthy subjects undertook an evaluation that involved walking on a treadmill at 6 speeds (at 3.2 km/h, at a self-selected walking speed, and at 2 speeds below and 2 speeds above the self-selected walking speed) and measuring the cost of transport (the oxygen consumption normalized by mass and distance), gait variability, perceived dyspnea, and leg fatigue., Results: In subjects with COPD, the cost of transport decreased with increasing walking speed, contrary to healthy subjects, who presented a minimum at the self-selected walking speed. No difference was found in cost of transport between the experimental groups at the same absolute velocity ( P = .62). In subjects with COPD, dyspnea sensation rose above the self-selected walking speed, doubling at the maximal walking velocity ( P = .03), and gait variability was higher at low speeds., Conclusion: Subjects with COPD choose their walking speed so as to keep the dyspnea sensation tolerable and to keep gait variability and cost of transport at an acceptable level. These outcomes suggest that interventions acting on dyspnea and gait pattern may increase patients' self-selected walking speed and improve their quality of life., (Copyright © 2018 by Daedalus Enterprises.)

Small airways represent the key factor of chronic obstructive pulmonary disease (COPD) pathophysiology. The effect of different classes of bronchodilators on small airways is still poorly understood and difficult to assess. Hence the acute effects of tiotropium (18 µg) and indacaterol (150 µg) on closing volume (CV) and ventilation inhomogeneity were investigated and compared in 51 stable patients (aged 70 ± 7 yr, mean ± SD; 82% men) with moderate to very severe COPD. Patients underwent body plethysmography, arterial blood gas analysis, tidal expiratory flow limitation (EFL), dyspnea assessment, and simultaneous recording of single-breath N 2 test and transpulmonary pressure-volume curve (P L -V), before and 1 h after drug administration. The effects produced by indacaterol on each variable did not differ from those caused by tiotropium, independent of the severity of disease, assessed according to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) scale and the presence of EFL. Bronchodilators significantly decreased the slope of phase III and CV (-5 ± 4 and -2.5 ± 2.1%, respectively, both P < 0.001), with an increase in both slope and height of phase IV and of the anatomical dead space. Arterial oxygen pressure and saturation significantly improved (3 ± 3 mmHg and 2 ± 2%, respectively, both P < 0.001); their changes negatively correlated with those of phase III slope ( r  = -0.659 and r  = -0.454, respectively, both P < 0.01). The vital capacity (VC) increased substantially, but the P L -V/VC curve above CV was unaffected. In conclusion, bronchodilators reduce the heterogeneity of peripheral airway mechanical properties and the extent of their closure, with minor effects on critical closing pressure. This should lessen the risk of small-airway damage and positively affect gas exchange. NEW & NOTEWORTHY This is the first study investigating in stable chronic obstructive pulmonary disease patients the acute effects of two long-acting bronchodilators, a β-agonist and a muscarinic antagonist, on peripheral airways using simultaneous lung pressure-volume curve and single-breath N 2 test. By lessening airway mechanical property heterogeneity, both drugs similarly reduced ventilation inhomogeneity and extent of small-airway closure, as indicated by the decrease of phase III slope, increased oxygen saturation, and fall of closing volume, often below expiratory reserve volume., (Copyright © 2017 the American Physiological Society.)

Purpose: To determine whether the analysis of the slow expiratory transpulmonary pressure-volume (P L -V) curve provides an alternative to the single-breath nitrogen test (SBN) for the assessment of the closing volume (CV)., Methods: SBN test and slow deflation P L -V curve were simultaneously recorded in 40 healthy subjects and 43 COPD patients. Onset of phase IV identified CV in SBN test (CV SBN ), whereas in the P L -V curve CV was identified by: a) deviation from the exponential fit (CV exp ), and b) inflection point of the interpolating sigmoid function (CV sig )., Results: In the absence of phase IV, COPD patients exhibited a clearly discernible inflection in the P L -V curve. In the presence of phase IV, CV SBN and CV exp coincided (CV SBN /CV exp =1.04±0.04 SD), whereas CV sig was systematically larger (CV sig /CV exp =2.1±0.86)., Conclusion: The coincidence between CV SBN and CV exp , and the presence of the inflection in the absence of phase IV indicate that the deviation of the P L -V curve from the exponential fit reliably assesses CV., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Lung diffusing capacity (DLCO) and lung volume distribution predict exercise performance and are altered in COPD patients. If pulmonary rehabilitation (PR) can modify DLCO parameters is unknown., Objectives: To investigate changes in DLCO and ventilation inhomogeneity following a PR program and their relation with functional outcomes in patients with COPD., Methods: This was a prospective, observational, multicentric study. Patients were evaluated before and after a standardized 3-week PR program. Functional assessment included body plethysmography, DLCO, transfer factor (KCO) and alveolar volume (VA), gas exchange, the 6-min walking test (6MWT) and exercise-related dyspnea. Patients were categorized according to the severity of airflow limitation and presence of ventilation inhomogeneity, identified by a VA/TLC <0.8., Results: Two hundred and fifty patients completed the study. Baseline forced expiratory volume in 1 s (FEV1) % predicted (mean ± SD) was 50.5 ± 20.1 (76% males); 137 patients had a severe disease. General study population showed improvements in 6MWT (38 ± 55 m; p < 0.01), DLCO (0.12 ± 0.63 mmol × min-1 kPa-1; p < 0.01), lung function and dyspnea. Comparable improvements in DLCO were observed regardless of the severity of disease and the presence of ventilation inhomogeneity. While patients with VA/TLC <0.8 improved the DLCO increasing their VA (177 ± 69 ml; p < 0.01), patients with VA/TLC >0.8 improved their KCO (8.1 ± 2.8%; p = 0.019). The latter had also better baseline lung function and higher improvements in 6MWT (14.6 ± 6.7 vs. 9.0 ± 1.8%; p = 0.015). Lower DLCO at baseline was associated with lower improvements in 6MWT, the greatest difference being between subjects with very severe and mild DLCO impairment (2.7 ± 7.4 vs. 14 ± 2%; p = 0.049)., Conclusions: In COPD patients undergoing a PR program, different pathophysiological mechanisms may drive improvements in DLCO, while ventilation inhomogeneity may limit improvements in exercise tolerance., (© 2016 S. Karger AG, Basel.)

To verify the hypothesis that by enmeshing lubricants, microvilli reduce the coefficient of kinetic friction (μ) of pleural mesothelium, μ was measured during reciprocating sliding of rabbit's visceral against parietal pleura before and after addition of hyaluronan, and related to the morphological features of the microvillar network. Because no relation was found between μ or μ changes after hyaluronan and microvillar characteristics, the latter are not determinants of the frictional forces which oppose sliding of normal mesothelial surfaces under physiological conditions, nor of the effects of hyaluronan. Addition of hyaluronan increased μ slightly but significantly in normal specimens, probably by altering the physiological mix of lubricants, but decreased μ of damaged mesothelia, suggesting protective, anti-abrasion properties. Indeed, while sliding of an injured against a normal pleura heavily damaged the latter and increased μ when Ringer was interposed between the surfaces, both effects were limited or prevented when hyaluronan was interposed between the injured and normal pleura before onset of sliding., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: In COPD patients, reversibility is currently evaluated from the changes of forced expiratory volume at 1s (ΔFEV1) and forced vital capacity (ΔFVC). By lowering peripheral airway smooth muscle tone, bronchodilators should decrease dynamic hyperinflation, gas trapping, and possibly dyspnea at rest. Hence, we hypothesize that specific airway resistance changes (ΔsRAW) should better characterize the acute response to bronchodilators., Methods: On two days, 60 COPD patients underwent dyspnea evaluation (VAS score) and pulmonary function testing at baseline and one hour after placebo or 300μg indacaterol administration., Results: Spirographic and ΔsRAW-based criteria identified as responders 24 and 45 patients, respectively. ΔsRAW correlated with changes of intrathoracic gas volume (ΔITGV) (r=0.61; p<0.001), residual volume (ΔRV) (r=0.60; p<0.001), ΔFVC (r=0.44; p=0.001), and ΔVAS (r=0.73; p<0.001), while ΔFEV1 correlated only with ΔFVC (r=0.34; p=0.008). Significant differences in terms of ΔITGV (p=0.002), ΔRV (p=0.023), and ΔVAS (p<0.001) occurred only if patients were stratified according to ΔsRAW., Conclusions: In assessing the acute functional effect of bronchodilators, ΔsRAW-based criterion is preferable to FEV1-FVC-based criteria, being more closely related to bronchodilator-induced improvements of lung mechanics and dyspnea at rest., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Recent studies in healthy mice and rats have reported that positive pressure ventilation delivered with physiological tidal volumes at normal end-expiratory volume worsens lung mechanics and induces cytokine release, thus suggesting that detrimental effects are due to positive pressure ventilation per se. The aim of this study in healthy animals is to assess whether these adverse outcomes depend on the mode of mechanical ventilation., Methods: Rats were subjected to 4 h of spontaneous, positive pressure, and whole-body or thorax-only negative pressure ventilation (N = 8 per group). In all instances the ventilatory pattern was that of spontaneous breathing. Lung mechanics, cytokines concentration in serum and broncho-alveolar lavage fluid, lung wet-to-dry ratio, and histology were assessed. Values from eight animals euthanized shortly after anesthesia served as control., Results: No evidence of mechanical ventilation-dependent lung injury was found in terms of lung mechanics, histology, or wet-to-dry ratio. Relative to control, cytokine levels and recruitment of polymorphonuclear leucocytes increased slightly, and to the same extent with spontaneous, positive pressure, and whole-body negative pressure ventilation. Thorax-only negative pressure ventilation caused marked chest and lung distortion, reversible increase of lung elastance, and higher polymorphonuclear leucocyte count and cytokine levels., Conclusion: Both positive and negative pressure ventilation performed with tidal volumes and timing of spontaneous, quiet breathing neither elicit an inflammatory response nor cause morpho-functional alterations in normal animals, thus supporting the notion of the presence of a critical volume threshold above which acute lung injury ensues. Distortion of lung parenchyma can induce an inflammatory response, even in the absence of volotrauma.

Pressure-volume curves of the lungs and chest wall require knowledge of an effective 'average' pleural pressure (Pplav), and are usually estimated using esophageal pressure as Ples-V and Pwes-V curves. Such estimates could be misleading when Ppl becomes spatially non-uniform with lung lavage or shape distortion of the chest. We therefore measured Ples-V and Pwes-V curves in conditions causing spatial non-uniformity of Ppl in rats. Ples-V curves of normal lungs were unchanged by chest removal. Lung lavage depressed PLes-V but not Pwes-V curves to lower volumes, and chest removal after lavage increased volumes at PL≥15cmH2O by relieving distortion of the mechanically heterogeneous lungs. Chest wall distortion by ribcage compression or abdominal distension depressed Pwes-V curves and Ples-V curves of normal lungs only at Pl≥3cmH2O. In conclusion, Pes reflects Pplav with normal and mechanically heterogeneous lungs. With chest wall distortion and dependent deformation of the normal lung, changes of Ples-V curves are qualitatively consistent with greater work of inflation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Coefficient of kinetic friction (μ) of pleural mesothelium blotted with filter paper, and rewetted with Ringer solution markedly increases; this increase is removed if a sufficient amount of sialomucin or hyaluronan is added to Ringer (Bodega et al., 2012. Respiratory Physiology and Neurobiology 180, 34-39). In this research we found that μ of pleural mesothelium blotted, rewetted, and sliding at physiological velocities and loads, decreased with increase of velocity, mainly at low velocities. Despite this decrease, μ at highest velocity was still double that before blotting. With small concentration of sialomucin or hyaluronan μ was markedly smaller at each velocity, decreased less with increase of velocity, and at highest velocity approached preblotting value. These findings indicate a regime of mixed lubrication in post-blotting Ringer, at variance with boundary lubrication occurring before blotting or postblotting with sufficient macromolecule addition. Greater roughness of mesothelial surface, caused by blotting, likely induces zones of elastohydrodynamic lubrication, which increase with velocity, while contact area decreases., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Coefficient of kinetic friction (μ) between rabbit visceral and parietal pleura, sliding in vitro at physiological velocities and load, increases markedly after blotting mesothelial surface with filter paper; this increase is only partially reduced by wetting blotted mesothelium with Ringer solution. Given that mesothelial surface is covered by a thick coat with sialomucin and hyaluronan, we tested whether addition of sialomucin or hyaluronan solution after blotting lowers μ more than Ringer alone. Actually, these macromolecules lowered μ more than Ringer, so that μ was no longer significantly higher than its preblotting value. Moreover, Ringer addition, after washout of macromolecule solution, increased μ, in line with their dilution. These findings indicate that mesothelial blotting removes part of these molecules from the coat covering mesothelial surface, and their relevance for pleural lubrication. Transmission electron micrographs of pleural specimens after mesothelial blotting showed that microvilli were partially or largely removed from mesothelium, consistent with a substantial loss of macromolecules normally entrapped among them., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Heliox has been administered to stable chronic obstructive pulmonary disease (COPD) patients at rest and during exercise on the assumption that this low density mixture would have reduced work of breathing, dynamic hyperinflation, and, consequently, dyspnea sensation. Contrary to these expectations, beneficial effects of heliox in these patients at rest have been reported only sporadically, and the majority of the studies performed until now suggests that heliox is not a therapeutic option in spontaneously breathing resting COPD patients. On the other hand, when it is administered to COPD patients exercising at a constant work rate, heliox systematically decreases dyspnea sensation, and, often but not always, increases exercise tolerance. For these reasons, heliox has been evaluated as a non pharmacological tool to power rehabilitation programs. The conflicting results provided by the published trials probably point at a substantial heterogeneity of the COPD patients population in terms of respiratory mechanics and gas exchange. Therefore, further studies, aimed to the identification of mechanisms conditioning the response of exercising COPD patients to heliox, are warranted, before heliox administration, which is costly and cumbersome, can be routinely used in rehabilitation programs.

Objective: To see whether in acute lung injury 1) compression of the lungs caused by thoracoabdominal constriction degrades lung function and worsens ventilator-induced lung injury; and 2) maintaining end-expiratory transpulmonary pressure by increasing positive end-expiratory pressure reduces the deleterious effects of chest wall constriction., Design: Experimental study in rats., Setting: Physiology laboratory., Interventions: Acute lung injury was induced in three groups of nine rats by saline lavage. Nine animals immediately killed served as a control group. Group L had lavage only, group LC had the chest wall constricted with an elastic binder, and group LCP had the same chest constriction but with positive end-expiratory pressure raised to maintain end-expiratory transpulmonary pressure. After lavage, all groups were ventilated with the same pattern for 1½ hrs., Measurements and Main Results: Transpulmonary pressure, measured with an esophageal balloon catheter, lung volume changes, arterial blood gasses, and pH were assessed during mechanical ventilation. Lung wet-to-dry ratio, albumin, tumor necrosis factor-α, interleukin-1β, interleukin-6, interleukin-10, and macrophage inflammatory protein-2 in serum and bronchoalveolar lavage fluid and serum E-selectin and von Willebrand Factor were measured at the end of mechanical ventilation. Lavage caused hypoxemia and acidemia, increased lung resistance and elastance, and decreased end-expiratory lung volume. With prolonged mechanical ventilation, lung mechanics, hypoxemia, and wet-to-dry ratio were significantly worse in group LC. Proinflammatory cytokines except E-selectin were elevated in serum and bronchoalveolar lavage fluid in all groups with significantly greater levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in group LC, which also exhibited significantly worse bronchiolar injury and greater heterogeneity of airspace expansion at a fixed transpulmonary pressure than other groups., Conclusions: Chest wall constriction in acute lung injury reduces lung volume, worsens hypoxemia, and increases pulmonary edema, mechanical abnormalities, proinflammatory mediator release, and histologic signs of ventilator-induced lung injury. Maintaining end-expiratory transpulmonary pressure at preconstriction levels by adding positive end-expiratory pressure prevents these deleterious effects.

Diaphragmatic regions are recruited in a specialized manner either as part of a central motor program during non-respiratory maneuvers, e.g. vomiting, or because of reflex responses, e.g. esophageal distension. Some studies in cats and dogs suggest that crural and costal diaphragm may be differentially activated also in response to respiratory stimuli from chemoreceptors or lung and chest wall mechanoreceptors. To verify whether this could occur also in other species, the EMG activity from the sternal, costoventral, costodorsal, and crural diaphragm was recorded in 42 anesthetized rabbits in response to various respiratory maneuvers, such as chemical stimulation, mechanical loading, lung volume and postural changes before and after vagotomy, or a non-respiratory maneuver such as esophageal distension. Regional activity was evaluated from timing of the raw EMG signal, and amplitude and shape of the moving average EMG. In all animals esophageal distension caused greater inhibition of the crural than sternal and costal diaphragm, whereas under all the other conditions differential diaphragmatic activation never occurred. These results indicate that in response to respiratory stimuli the rabbit diaphragm behaves as a single unit under the command of the central respiratory control system., (Copyright 2009 Elsevier B.V. All rights reserved.)

In 26 stable patients with chronic obstructive pulmonary disease, tidal expiratory flow-limitation (TEFL), inspiratory capacity, breathing pattern and dyspnea sensation were assessed during air and heliox (20% O(2) in He) breathing at rest and during exercise up to 2/3 maximal work rate. Breathing air, the 13 patients with TEFL at rest remained flow-limited also during exercise, while 7 of the non-flow-limited patients became flow-limited; tidal volume increased more in non-flow-limited patients, whereas inspiratory capacity decreased in flow-limited and increased in the non-flow-limited patients. Heliox did not abolish flow-limitation, had no effect on breathing pattern, reduced exercise dynamic hyperinflation in 25% of the flow-limited patients, depending on the degree of the dynamic hyperinflation on air, and lessened dyspnea sensation in all patients. Hence, the presence of TEFL has no systematic effects on the respiratory response to heliox, and the heliox-induced decrease of exercise dyspnea is not mainly due to changes in dynamic hyperinflation or TEFL.