Endogenous adenosine release is involved in the control of heart rate in rats.

Intravenous (i.v.) injections of adenosine exert marked effects on heart rate (HR) and arterial blood pressure (BP), but the role of an endogenous adenosine release by vagal stimulation has not been evaluated. In anaesthetized rats, we examined HR and BP changes induced by 1 min electrical vagal stimulation in the control condition, and then after i.v. injections of (i) atropine, (ii) propranolol, (iii) caffeine, (iv) 8 cyclopentyl-1,3-dipropylxanthine (DPCPX), or (v) dipyridamole to increase the plasma concentration of adenosine (APC). APC was measured by chromatography in the arterial blood before and at the end of vagal stimulation. The decrease in HR in the controls during vagal stimulation was markedly attenuated, but persisted after i.v. injections of atropine and propranolol. When first administered, DPCPX modestly but significantly reduced the HR response to vagal stimulation, but this disappeared after i.v. caffeine administration. Both the HR and BP responses were significantly accentuated after i.v. injection of dipyridamole. Vagal stimulation induced a significant increase in APC, proportional to the magnitude of HR decrease. Our data suggest that the inhibitory effects of electrical vagal stimulations on HR and BP were partly mediated through the activation of A1 and A2 receptors by an endogenous adenosine release. Our experimental data could help to understand the effects of ischemic preconditioning, which are partially mediated by adenosine.

Home-based respiratory rehabilitation in adult patients with moderate or severe persistent asthma.

OBJECTIVE: We assessed retrospectively the feasibility of a home-based respiratory rehabilitation (RR) program for asthmatics under optimal pharmacological treatment, as this type of care can reduce costs and offer a more patient-friendly approach for subjects with persistent asthma. METHODS: Fifty-two patients with persistent asthma were recruited to the RR program (20 males, 32 females, 54 ± 11 (SD) years, forced expiratory volume in one second 71 ± 33% of predicted mean value, BMI 29.9 ± 7.9 kg/m(2)). This two-month protocol comprised education sessions, respiratory physiotherapy and an exercise training program at home and in groups supervised by an adapted physical activity instructor. RESULTS: Thirty-nine patients completed the whole RR program, i.e. 25% dropout. The dropout rate was significantly higher with respect to younger patients in employment. The number of exacerbations decreased significantly during the year following the program, regardless of whether the patients had dropped out (p < 0.02) or not (p < 0.001). The distance walked during a 6-min walking test increased by 33 m (p < 0.001). Several indices measured during a cycle ergometer test increased significantly after RR: peak oxygen uptake (10%), oxygen uptake at ventilatory threshold (12%) and maximum load (19%), all at a similar maximum heart rate. Concerning quality of life assessment, the Short-Form-36 Item Health Survey revealed a non-significant improvement in the "health change" item after RR (p < 0.07). CONCLUSIONS: This study demonstrates the potential of a home-based program in the treatment and rehabilitation of patients with asthma. Both functional and physiologic indices improved during the follow-up period.

Inter-individual differences in breathing pattern at high levels of incremental cycling exercise in healthy subjects.

Interindividual differences in the rate of changes in tidal volume (V(T)) and respiratory frequency (f(R)) were examined during a maximal incremental cycling exercise. The gain of the inspiratory off-switch reflex was inferred from the V(T) vs. inspiratory duration (T(i)) relationship. Some subjects also executed a static handgrip exercise, used as a "non-dynamic" exercise trial to study patterning of breathing. Above the ventilatory threshold (V(Th)), two patterns of response were identified: in group 1, the rate of change in V(T) significantly increased, while in group 2 the breakpoint of ventilation solely resulted from f(R) increase. After the respiratory compensation point, a tachypnoeic response always occurred. A leftward shift of the V(T) vs. Ti relationship, i.e., an inspiratory off-switch reflex, was measured during the handgrip in group 2 subjects as well as marked f(R) variations. Our study identifies two different patterns of breathing after the V(Th). The subjects who present a tachypnoeic response to exercise above the V(Th) have a higher sensitivity to pulmonary inflation and their tachypnoeic response was ubiquitous during a maximal handgrip test.

Increased asymptomatic airway hyper-responsiveness in obese individuals.

OBJECTIVE: Asymptomatic airway hyper-responsiveness (AHR) represents a risk of further accelerated decline in lung function, and of asthma. Due to the fact that rare and contradictory results exist concerning the impact of obesity on BHR, we re-assessed the prevalence of bronchial hyper-responsiveness (BHR) in a large cohort of 60 lean, 84 overweight, and 360 class 1-3 obese non-asthmatic individuals, by coupled plethysmography and spirometry. METHODS: Baseline-specific airway conductance (SGaw) and spirometric values were measured and then a methacholine challenge testing (MCT) was performed and considered as positive when a ≥200% increase in specific airway resistance (SRaw = 1/SGaw) was reached. RESULTS: Compared to lean and overweight subjects, obese subjects of any class presented about a twice more frequent AHR (∼ 50% in obese vs. 17 and 26% in lean and overweight subjects, respectively). However, the bronchial sensitivity (methacholine dose doubling SRaw) and the shape of the relationship between SGaw and cumulative methacholine doses were the same in the five groups of individuals. CONCLUSION: The present data show a more frequent AHR in obese subjects. The association of plethysmography with spirometry, by taking into account the bronchodilator effect of the lung inflation (preceding the expiratory flow measurement) in some individuals, permitted to include some MCT which would have been otherwise excluded.

Activation of nicotinic cholinergic receptors prevents ventilator-induced lung injury in rats.

Respiratory distress syndrome is responsible for 40 to 60 percent mortality. An over mortality of about 10 percent could result from additional lung injury and inflammation due to the life-support mechanical ventilation, which stretches the lung. It has been recently demonstrated, in vitro, that pharmacological activation of the alpha 7 nicotinic receptors (α7-nAChR) could down regulate intracellular mediators involved in lung cell inflammatory response to stretch. Our aim was to test in vivo the protective effect of the pharmacological activation of the α7-nAChR against ventilator-induced lung injury (VILI). Anesthetized rats were ventilated for two hours with a high stretch ventilation mode delivering a stroke volume large enough to generate 25-cmH(2)O airway pressure, and randomly assigned to four groups: pretreated with parenteral injection of saline or specific agonist of the α7-nAChR (PNU-282987), or submitted to bilateral vagus nerve electrostimulation while pre-treated or not with the α7-nAChR antagonist methyllycaconitine (MLA). Controls ventilated with a conventional stroke volume of 10 mL/kg gave reference data. Physiological indices (compliance of the respiratory system, lung weight, blood oxygenation, arterial blood pressure) and lung contents of inflammatory mediators (IL-6 measured by ELISA, substance P assessed using HPLC) were severely impaired after two hours of high stretch ventilation (sham group). Vagal stimulation was able to maintain the respiratory parameters close to those obtained in Controls and reduced lung inflammation except when associated to nicotinic receptor blockade (MLA), suggesting the involvement of α7-nAChR in vagally-mediated protection against VILI. Pharmacological pre-treatment with PNU-282987 strongly decreased lung injury and lung IL-6 and substance P contents, and nearly abolished the increase in plasmatic IL-6 levels. Pathological examination of the lungs confirmed the physiological differences observed between the groups. In conclusion, these data suggest that the stimulation of α7-nAChR is able to attenuate VILI in rats.

Prevalence rate of exercise-induced bronchoconstriction in Annaba (Algeria) schoolchildren.

BACKGROUND: We studied the prevalence rate of exercise-induced bronchoconstriction (EIB) in Annaba schoolchildren. No previous assessment of this syndrome had ever been done in Algeria. METHODS: EIB was evaluated using the 6 min free running test (6MFRT) on 286 children, 87.4% of whom were 10-12 years old. They performed the test in the morning, during the autumn-winter season. Peak expiratory flow rate (PEFR) was measured before, and then 5 and 10 min after the 6MFRT, a 15% or more decrease in post-exercise PEFR being defined as significant. RESULTS: EIB was much more frequent in asthmatic than in nonasthmatic children (47.0% vs. 13.9%, p < .001) and the drop in PEFR was more marked among the former. EIB was observed more often in a cool temperature (<8°C). There were relatively more children who were either eutrophic or overweight among those presenting an EIB. Past histories of nocturnal wheezing and rhinoconjunctivitis presented respectively the best specificity (96.7%) and sensitivity (84.8%). Children of unemployed workers presented the highest occurrence of EIB. Passive smoking appeared as the only factor being related to EIB among the indoor pollutants. The prevalence rate of asthma (6.7%) was higher than in a previous cross-sectional epidemiological survey study performed in the Maghreb. The prevalence rate of EIB (13.9%) was situated in the upper range of the results given worldwide. CONCLUSIONS: These features of a fairly high bronchial hyperresponsiveness could be facilitated by the polluted environment of the city.

Substance P receptor blockade decreases stretch-induced lung cytokines and lung injury in rats.

Overdistension of lung tissue during mechanical ventilation causes cytokine release, which may be facilitated by the autonomic nervous system. We used mechanical ventilation to cause lung injury in rats, and studied how cervical section of the vagus nerve, or substance P (SP) antagonism, affected the injury. The effects of 40 or 25 cmH(2)O high airway pressure injurious ventilation (HV(40) and HV(25)) were studied and compared with low airway pressure ventilation (LV) and spontaneous breathing (controls). Lung mechanics, lung weight, gas exchange, lung myeloperoxidase activity, lung concentrations of interleukin (IL)-1 beta and IL-6, and amounts of lung SP were measured. Control rats were intact, others were bivagotomized, and in some animals we administered the neurokinin-1 (NK-1) receptor blocking agent SR140333. We first determined the durations of HV(40) and HV(25) that induced the same levels of lung injury and increased lung contents of IL-1 beta and IL-6. They were 90 min and 120 min, respectively. Both HV(40) and HV(25) increased lung SP, IL-1 beta and IL-6 levels, these effects being markedly reduced by NK-1 receptor blockade. Bivagotomy reduced to a lesser extent the HV(40)- and HV(25)-induced increases in SP but significantly reduced cytokine production. Neither vagotomy nor NK-1 receptor blockade prevented HV(40)-induced lung injury but, in the HV(25) group, they made it possible to maintain lung injury indices close to those measured in the LV group. This study suggests that both neuronal and extra-neuronal SP might be involved in ventilator-induced lung inflammation and injury. NK-1 receptor blockade could be a pharmacological tool to minimize some adverse effects of mechanical ventilation.

Role of proinflammatory activity contained in gastric juice from intensive care unit patients to induce lung injury in a rabbit aspiration model.

OBJECTIVE: Although aspiration pneumonitis is a severe complication in patients hospitalized in intensive care units, its pathogenesis is poorly understood. The aim of this study was to determine whether the intensity of lung injury and inflammation developing after aspiration during mechanical ventilation differed depending on the inflammatory activity of intensive care unit patients' gastric fluid. DESIGN: In vitro study on human gastric juice and randomized controlled animal study. SETTING: Research laboratories of academic institutions. SUBJECTS: Male New-Zealand white rabbits. INTERVENTIONS: Proinflammatory activity of gastric juice from 17 intensive care unit patients and 12 controls undergoing elective surgery was measured based on a target cell activation assay. Two gastric juices from intensive care unit patients with similar pH but differing for their in vitro proinflammatory activity (high and low) were further instilled into the trachea of ventilated rabbits. Lung function, mechanics, pathology, leukocyte infiltration, and local cytokine levels were measured after 6 hrs. MEASUREMENTS AND MAIN RESULTS: Gastric juice from intensive care unit patients, even buffered at pH 7.4, stimulated human type II-like A549 epithelial cells to up-regulate intercellular adhesion molecule-1 and interleukin-8, significantly more than juice obtained in controls. Gastric juice from an intensive care unit patient supporting high proinflammatory activity in vitro also induced a more severe and persistent drop in PaO2/FIO2 and respiratory system compliance in ventilated rabbits, a worse histologic score, higher lung lavage concentrations of inflammatory cells, interleukin-8 (p < 0.01), and growth-related oncogene-alpha (p < 0.01) than one fluid with low proinflammatory activity. CONCLUSION: Gastric juice from critically ill patients is proinflammatory and stimulates human pulmonary cells in vitro. A human gastric juice with high proinflammatory activity is more "toxic" to the lung than one with low proinflammatory activity in a ventilated rabbit model, an effect that is independent of pH and particulate matter content.

High-frequency percussive ventilation attenuates lung injury in a rabbit model of gastric juice aspiration.

OBJECTIVE: To test the effects of high-frequency percussive ventilation (HFPV) compared with high-frequency oscillatory ventilation (HFOV) and low-volume conventional mechanical ventilation (LVCMV), on lung injury course in a gastric juice aspiration model. DESIGN: Prospective, randomized, controlled, in-vivo animal study. SETTING: University animal research laboratory. SUBJECTS: Forty-three New Zealand rabbits. INTERVENTIONS: Lung injury was induced by intratracheal instillation of human gastric juice in order to achieve profound hypoxaemia (PaO2/FIO2< or =50). Animals were ventilated for 4h after randomization in one of the following four groups: HFPV (median pressure 15cmH2O); LVCMV (VT 6mlkg(-1) and PEEP set to reach 15cmH2O plateau pressure); HFOV (mean pressure 15cmH2O); and a high-volume control group HVCMV (VT 12ml kg(-1) and ZEEP). MEASUREMENTS AND RESULTS: Static respiratory compliance increased after the ventilation period in the HFPV, LVMCV and HFOV groups, in contrast with the HVCMV group. PaO2/FIO2 improved similarly in the HFPV, LVCMV and HFOV groups, and remained lower in the HVCMV group than in the three others. Lung oedema, myeloperoxidase and histological lung injury score were higher in the HVCMV group, but not different among all others. Arterial lactate markedly increased after 4h of ventilation in the HVCMV group, while lower but similar levels were observed in the three other groups. CONCLUSION: HFPV, like HFOV and protective CMV, improves respiratory mechanics and oxygenation, and attenuates lung damage. The HFPV provides attractive lung protection, but further studies should confirm these results before introducing HFPV into the clinical arena.

Hemodynamics in experimental gastric juice induced aspiration pneumonitis.

OBJECTIVE: To characterize hemodynamic changes during experimental aspiration pneumonitis, paying special attention to echocardiographic assessment. DESIGN AND SETTING: Animal study in a university-based research laboratory. SUBJECTS: Fourteen mechanically ventilated New Zealand white rabbits INTERVENTIONS: We instilled 1 ml/kg human gastric juice (mean pH: 4.1+0.2) intratracheally. Hemodynamic and respiratory parameters were measured every hour for 4 h, associated with a transthoracic echocardiography. MEASUREMENTS AND RESULTS: Lung injury occurred within 1 hour with a marked decrease in PaO(2)/FIO(2) and an increase in plateau pressure; after this initial drop the ratio remained stable throughout the experiment. Seven rabbits experienced only a mild to moderate alteration in lung oxygenation function as defined by a PaO(2)/FIO(2) ratio above 200 (group A), while the other seven developed a severe alteration with a ratio below 200 (group B). At the end of the experiment pH and cardiac output were lower in group B than in group A. Using a PaO(2)/FIO(2) threshold value of 150, pH, mean arterial pressure, and cardiac output were lower in the animals with the more severe hypoxemia. Neither left nor right ventricular dysfunction occurred during the experiment, and no animal experienced circulatory failure CONCLUSION: Experimental aspiration pneumonitis after intratracheal infusion of human gastric juice is characterized by a stable fall in PaO(2)/FIO(2). Animals with the most severe lung injury experienced a lower systemic arterial pressure, cardiac output, and metabolic acidosis without circulatory failure or cardiac dysfunction.

Respiratory and circulatory effects of parietal pleural afferent stimulation in rabbits.

Respiratory symptoms accompanying pleural diseases combine dyspnea, tachypnea, rapid shallow breathing, and sometimes hypotension. There are no experimental data on the changes in respiratory and circulatory functions elicited by the activation of pleural afferents. After removal of all muscles covering the 5th to 10th intercostal spaces, we investigated in paralyzed, vagotomized rabbits the changes in phrenic discharge, transpulmonary pressure, and systemic arterial pressure in response to an outwardly directed force exerted on the parietal pleura or the local application of solutions containing lactic acid or inflammatory mediators. Mechanical stimulation of the pleura induced an immediate decrease in both integrated phrenic discharge and arterial blood pressure, the responses being positively correlated with the magnitude of force applied on the pleura. No accompanying changes in ventilatory timing, transpulmonary pressure, or heart rate were measured. Lactic acid solution also elicited an inhibition of phrenic activity and a fall in blood pressure. Section of the internal intercostal nerves supplying the stimulated intercostal spaces totally abolished the responses to mechanical stimulation or lactic acid. An inflammatory mixture elicited only modest respiratory and circulatory effects. We concluded that an acute mechanical distension of the parietal pleura as well as its chemical stimulation by lactic acid elicit a marked inhibition of phrenic motoneurons combined to a reduction of the sympathetic outflow to the circulatory system.

Identification and properties of parietal pleural afferents in rabbits.

Although pain and dyspnoea are common symptoms in pleural diseases, there are few studies on the sensory innervation of the pleura. Using rabbits, after removal of all muscles in the intercostal space to be studied, we investigated the afferents of the internal intercostal nerve by applying to the internal thoracic wall pieces of gauze soaked in warmed (37 degrees C), buffered saline (mechanical stimulation) or solutions containing lactic acid, inflammatory mediators or capsaicin (chemical stimulation). The afferent conduction velocity ranged from 0.5 to 14 m s(-1). Most units (97%) were activated by mechanical stimulation of the pleura (local positive pressure range = 4.5-8.5 cmH2O) and we found a linear relationship between the discharge rate of afferents and the force applied to the thoracic wall. The majority of mechanosensitive units (70%) also responded to one or several chemical agents. Thus, the afferents were activated by lactic acid (49%) and/or a mixture of inflammatory mediators (50%). Local application of capsaicin elicited an initial increased or decreased background afferent activity in 57% of the afferents, a delayed decrease in firing rate being noted in some units initially activated by capsaicin. Capsaicin blocked the afferent response to a further application of inflammatory mediators but did not affect the mechanosensitive units. Thus, sensory endings connected with thin myelinated and unmyelinated fibres in the internal intercostal nerve detect the mechanical and chemical events of pleural diseases.

Mechanical ventilation affects lung function and cytokine production in an experimental model of endotoxemia.

BACKGROUND: Mechanical ventilation using tidal volumes around 10 ml/kg and zero positive end-expiratory pressure is still commonly used in anesthesia. This strategy has been shown to aggravate lung injury and inflammation in preinjured lungs but not in healthy lungs. In this study, the authors investigated whether this strategy would result in lung injury during transient endotoxemia in the lungs of healthy animals. METHODS: Volume-controlled ventilation with a tidal volume of 10 ml/kg and zero positive end-expiratory pressure was applied in two groups of anesthetized-paralyzed rabbits receiving either intravenous injection of 5 mug/kg Escherichia coli lipopolysaccharide (n = 10) or saline (n = 10) 2 h after the start of mechanical ventilation. The third group consisted of 10 spontaneously breathing anesthetized animals receiving lipopolysaccharide. Anesthesia was then continued for 4 h in the three groups while the ventilatory modes were maintained unchanged. Lung injury was studied using blood gases, respiratory physiologic variables, analysis of the bronchoalveolar lavage cell counts, and cytokine concentrations and lung pathologic examination. RESULTS: Significant histologic lung alterations, hypoxemia, and altered lung mechanics were observed in rabbits treated with mechanical ventilation and intravenous lipopolysaccharide but not in the mechanically ventilated animals injected with saline or in spontaneously breathing animals treated with lipopolysaccharide. Endotoxemic ventilated animals also had significantly more lung inflammation as assessed by the alveolar concentration of neutrophils, and the concentrations of the chemokines interleukin 8 and growth-related oncogen alpha. CONCLUSIONS: These results showed that positive-pressure mechanical ventilation using a tidal volume of 10 ml/kg and zero positive end-expiratory pressure was harmful in the setting of endotoxemia, suggesting that the use of this ventilator strategy in the operating room may predispose to lung injury when endotoxemia occurs.

Persistence of diaphragmatic contraction influences the pulmonary inflammatory response to mechanical ventilation.

Because we already showed (Brégeon, F., Roch, A., Delpierre, S., Ghigo, E., Autillo-Touati, A., Kajikawa, O., Martin, T., Pugin, J., Portugal, H., Auffray, J., Jammes, Y., 2002. Conventional mechanical ventilation of healthy lungs induced pro-inflammatory cytokine gene transcription, Respir. Physiol. Neurobiol. 132, 191-203) that non-injurious mechanical ventilation (MV) elicited inflammatory signal in paralyzed rabbits having normal lungs, we examined the role of neuromuscular blockade in the pulmonary inflammatory response. In the bronchoalveolar lavage fluid (BALF), leukocyte count, MCP-1 and IL-8 cytokine concentrations (ELISA) and mRNAs (reverse transcription polymerase chain reaction, RT-PCR) were measured in paralyzed (P) or non-paralyzed (NP) rabbits ventilated for a 6-h period. Compared to the P group and despite the tidal volume was the same, we measured in the NP one a lower compliance of the respiratory system (Crs,stat), a longer inspiratory time (Ti), a negative inspiratory tracheal pressure (Ptr) wave preceding the pump-induced positive pressure wave, and a higher peak tracheal pressure. Moreover, in NP animals, gross autopsy showed negligible lung abnormalities, and marked reduction of leukocyte count and lung cytokines (P < 0.05). Thus, the absence of neuromuscular blockade decreased the pulmonary chemotactic response to MV suggesting that the total suppression of negative pressure waves elicited by the diaphragmatic (di) contractions could be involved in this lung response to positive pressure MV.

Conventional mechanical ventilation of healthy lungs induced pro-inflammatory cytokine gene transcription.

We investigated the potential inflammatory reaction induced by mechanical ventilation (MV) using 10 ml/kg tidal volume and no positive end-expiratory pressure (PEEP) in control (C, n = 8), spontaneously breathing (SB, n = 12) and mechanically ventilated (MV, n = 12) rabbits with normal lungs. After 6 h (MV and SB groups) or immediately (C group), lungs were removed for measurement of wet-to-dry (W/D) weight ratio and for bronchoalveolar lavage (BAL). Pulmonary mechanics were also studied. MV animals developed a modest but significant (P < 0.01) impairment of arterial blood oxygenation and had higher W/D lung weight ratio than C ones. In MV group, BAL macrophage count was greater (P < 0.05) than in SB one. MV induced an upregulation of MCP-1, TNF-alpha, and IL-1beta gene transcription (mRNAs), without significant elevation of the corresponding protein cytokines in the BAL supernatant, except for MCP-1 (P < 0.05). These data suggest that MV, even using moderate tidal volume, elicits a pro-inflammatory stimulus to the lungs.

High prevalence of reversible airway obstruction in asbestos-exposed workers.

In this retrospective study of 97 male workers exposed to asbestos for 2-50 yr, data were collected on chest x-ray findings and lung function, including lung volumes, forced expiratory flow rates (i.e., forced expiratory volume in 1 sec [FEV1.0], forced expiratory flow measured between 25% and 75% of forced vital capacity [FEF(25-75%)]), airway resistance (R(aw)), carbon monoxide (CO)-diffusing capacity, and the existence of airway obstruction reversible by a beta-adrenergic agonist (RAO). The authors performed multiple-regression analyses to correlate the variations in lung function data with age, smoking habits, duration of asbestos exposure, and time since last exposure. Occupational activities of subjects that might induce specific lung abnormalities were also considered. No significant decrease was seen in lung volumes or CO-diffusing capacity; however, a decrease in FEV1.0 and an increase in R(aw) were measured in 65% of the subjects, and an isolated decrease in FEF(25-75%) occurred in only 18%. There was no difference in lung-function data between subjects who had chest x-ray signs of abnormalities (n = 59) and those who did not (n = 38). A significant relationship was found between the decrease in FEV1.0 and age; however, no correlation was noted between altered lung function and cigarette smoking, duration of asbestos exposure, or time since last exposure. RAO prevalence was higher (34%) than previously reported (9%) in subjects with chronic obstructive pulmonary disease (COPD) who were not exposed to asbestos or outdoor pollution. The RAO prevalence in asbestos-exposed workers was nearly the same as that measured in COPD subjects who lived downtown and who were exposed to outdoor pollution (36%). The high RAO prevalence in asbestos-exposed workers was found in 43% of subjects who were exposed only to asbestos, and in 33% of subjects who were also exposed to air pollution due to their occupational activities. It is hoped that the observations in this study will encourage practitioners to check for RAO in asbestos workers who use inhaled bronchodilators.