Motor control of the diaphragm in anesthetized rabbits

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

Plasma membrane disruptions with different modes of injurious mechanical ventilation in normal rat lungs

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[middle dot]kg-1) 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

Reversibility of airflow obstruction by hypoglossus nerve stimulation in anesthetized rabbits

Rationale: Anesthesia-induced uncoupling of upper airway dilating and inspiratory pump muscles activation may cause inspiratory flow limitation, thereby mimicking obstructive sleep apnea/hypopnea. Objectives: Determine whether inspiratory flow limitation occurs in spontaneously breathing anesthetized rabbits and whether this can be reversed by direct hypoglossal nerve stimulation and by the application of continuous positive airway pressure. Methods: Ten New Zealand White rabbits were anesthetized, instrumented, and studied supine while breathing spontaneously at ambient pressure or during the application of positive or negative airway pressure. Under each of these conditions, the effect of unilateral or bilateral hypoglossal nerve stimulation was investigated. Measurements: Inspiratory flow and tidal volume were measured together with esophageal pressure and the electromyographic activity of diaphragm, alae nasi, and genioglossus muscles. Main results: Anesthesia caused a marked increase in inspiratory resistance, snoring, and in eight rabbits, inspiratory flow limitation. Hypoglossus nerve stimulation was as effective as continuous positive airway pressure in reversing inspiratory flow limitation and snoring. Its effectiveness increased progressively as airway opening pressure was lowered, reached a maximum at -5 cm H2O, but declined markedly at lower pressures. With negative airway opening pressure, airway collapse eventually occurred during inspiration that could be prevented by hypoglossus nerve stimulation. The recruitment characteristics of hypoglossus nerve fibers was steep, and significant upper airway dilating effects already obtained with stimulus intensities 36 to 60% of maximum. Conclusion: This study supports hypoglossus nerve stimulation as a treatment option for obstructive sleep apnea

The airways' mechanical stress in lung disease: Implications for COPD pathophysiology and treatment evaluation

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 \u3b22-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

Cytokine release, small airway injury, and parenchymal damage during mechanical ventilation in normal open-chest rats

Lung morpho-functional alterations and inflammatory response to various types of mechanical ventilation (MV) have been assessed in normal, anesthetized, open-chest rats. Measurements were taken during protective MV [tidal volume (Vt) = 8 ml/kg; positive end-expiratory pressure (PEEP) = 2.6 cmH(2)O] before and after a 2- to 2.5-h period of ventilation on PEEP (control group), zero EEP without (ZEEP group) or with administration of dioctylsodiumsulfosuccinate (ZEEP-DOSS group), on negative EEP (NEEP group), or with large Vt (26 ml/kg) on PEEP (Hi-Vt group). No change in lung mechanics occurred in the Control group. Relative to the initial period of MV on PEEP, airway resistance increased by 33 +/- 4, 49 +/- 9, 573 +/- 84, and 13 +/- 4%, and quasi-static elastance by 19 +/- 3, 35 +/- 7, 248 +/- 12, and 20 +/- 3% in the ZEEP, NEEP, ZEEP-DOSS, and Hi-Vt groups. Relative to Control, all groups ventilated from low lung volumes exhibited histologic signs of bronchiolar injury, more marked in the NEEP and ZEEP-DOSS groups. Parenchymal and vascular injury occurred in the ZEEP-DOSS and Hi-Vt groups. Pro-inflammatory cytokine concentration in the bronchoalveolar lavage fluid (BALF) was similar in the Control and ZEEP group, but increased in all other groups, and higher in the ZEEP-DOSS and Hi-Vt groups. Interrupter resistance was correlated with indexes of bronchiolar damage, and cytokine levels with vascular-alveolar damage, as indexed by lung wet-to-dry ratio. Hence, protective MV from resting lung volume causes mechanical alterations and small airway injury, but no cytokine release, which seems mainly related to stress-related damage of endothelial-alveolar cells. Enhanced small airway epithelial damage with induced surfactant dysfunction or MV on NEEP can, however, contribute to cytokine production

The fall in exhaled nitric oxide with ventilation at low lung volumes in rabbits : an index of small airway injury

The mechanisms involved in the fall of exhaled nitric oxide (NOe) concentration occurring in normal, anesthetized open chest rabbits with prolonged mechanical ventilation (MV) at low lung volume have been investigated. NOe, pH of exhaled vapor condensate, serum prostaglandin E(2), and F(2alpha), tumor necrosis factor (TNF-alpha), PaO(2), PaCO(2), pHa, and lung mechanics were assessed before, during, and after 3-4h of MV at zero end-expiratory pressure (ZEEP), with fixed tidal volume (9 ml kg(-1)) and frequency, as well as before and after 3-4h of MV on PEEP only. Lung histology and wet-to-dry ratio (W/D), and prostaglandin and TNF-alpha in bronchoalveolar lavage fluid (BALF) were also assessed. While MV on PEEP had no effect on the parameters above, MV on ZEEP caused a marked fall (45%) of NOe, with a persistent increase of airway resistance (45%) and lung elastance (12%). Changes in NOe were independent of prostaglandin and TNF-alpha levels, systemic hypoxia, hypercapnia and acidosis, bronchiolar and alveolar interstitial edema, and pH of exhaled vapor condensate. In contrast, there was a significant relationship between the decrease in NOe and bronchiolar epithelial injury score. This indicates that the fall in NOe, which occurs in the absence of an inflammatory response, is due to the epithelial damage caused by the abnormal stresses related to cyclic opening and closing of small airways with MV on ZEEP, and suggests its use as a sign of peripheral airway injury

Effects of mechanical ventilation at low lung volume on respiratory mechanics and nitric oxide exhalation in normal rabbits

Lung mechanics, exhaled NO (NOe), and TNF-(alpha) in serum and bronchoalveolar lavage fluid were assessed in eight closed and eight open chest, normal anesthetized rabbits undergoing prolonged (3-4 h) mechanical ventilation (MV) at low volume with physiological tidal volumes (10 ml/kg). Relative to initial MV on positive end-expiratory pressure (PEEP), MV at low volume increased lung quasi-static elastance (+267 and +281%), airway (+471 and +382%) and viscolelastic resistance (+480 and +294%), and decreased NOe (-42 and -25%) in closed and open chest rabbits, respectively. After restoration of PEEP, viscoelastic resistance returned to control, whereas airway resistance remained elevated (+120 and +31%) and NOe low (-25 and -20%) in both groups of rabbits. Elastance remained elevated (+23%) only in closed-chest animals, being associated with interstitial pulmonary edema, as reflected by increased lung wet-to-dry weight ratio with normal albumin concentration in bronchoalveolar lavage fluid. In contrast, in 16 additional closed- and open-chest rabbits, there were no changes of lung mechanics or NOe after prolonged MV on PEEP only. At the end of prolonged MV, TNF-(alpha) was practically undetectable in serum, whereas its concentration in bronchoalveolar lavage fluid was low and similar in animals subjected or not subjected to ventilation at low volume (62 vs. 43 pg/ml). These results indicate that mechanical injury of peripheral airways due to their cyclic opening and closing during ventilation at low volume results in changes in lung mechanics and reduction in NOe and that these alterations are not mediated by a proinflammatory process, since this is expressed by TNF-(alpha) levels

Still air resistance during walking and running

: In everyday life during terrestrial locomotion our body interacts with two media opposing the forward movement of the body: the ground and the air. Whereas the work done to overcome the ground reaction force has been extensively studied, the work done to overcome still air resistance has been only indirectly estimated by means of theoretical studies and by measurements of the force exerted on puppets simulating the geometry of the human body. In this study, we directly measured the force exerted by still air resistance on eight male subjects during walking and running on an instrumented treadmill with a belt moving at the same speed of a flow of laminar air facing the subject. Overall, the coefficient of proportionality between drag and velocity squared (Aeff) was smaller during running than walking. During running Aeff decreased progressively with increasing average velocity up to an apparently constant, velocity independent value, similar to that predicted in the literature using indirect methods. A predictive equation to estimate drag as a function of the speed and the height of the running subject is provided

Effect of heliox breathing on flow limitation in chronic heart failure patients

Patients with chronic heart failure (CHF) exhibit orthopnoea and tidal expiratory flow limitation in the supine position. It is not known whether the flow-limiting segment occurs in the peripheral or central part of the tracheobronchial tree. The location of the flow-limiting segment can be inferred from the effects of heliox (80% helium/20% oxygen) administration. If maximal expiratory flow increases with this low-density mixture, the choke point should be located in the central airways, where the wave-speed mechanism dominates. If the choke point were located in the peripheral airways, where maximal flow is limited by a viscous mechanism, heliox should have no effect on flow limitation and dynamic hyperinflation. Tidal expiratory flow limitation, dynamic hyperinflation and breathing pattern were assessed in 14 stable CHF patients during air and heliox breathing at rest in the sitting and supine position. No patient was flow-limited in the sitting position. In the supine posture, eight patients exhibited tidal expiratory flow limitation on air. Heliox had no effect on flow limitation and dynamic hyperinflation and only minor effects on the breathing pattern. The lack of density dependence of maximal expiratory flow implies that, in CHF patients, the choke point is located in the peripheral airways

Lubricating effect of sialomucin and hyaluronan on pleural mesothelium

Coefficient of kinetic friction (m) 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 m more than Ringer alone. Actually, these macromolecules lowered m more than Ringer, so that m was no longer significantly higher than its preblotting value. Moreover, Ringer addition, after washout of macromolecule solution, increased m, 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