Stéphane Delpierre

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 &mgr;g/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 &agr;. 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.

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.

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.

Long-term exposure of adults to outdoor air pollution is associated with increased airway obstruction and higher prevalence of bronchial hyperresponsiveness.

The authors studied the association between long-term exposure (i.e., > 10 y) to outdoor air pollution and the severity of obstructive pulmonary disease and prevalence of bronchial hyperreactivity to beta2 agonists in two groups of adult patients who were of similar ages and who had similar smoking habits. The subjects lived in downtown districts or in the outer suburbs of Marseilles, the neighborhood that contained air samplers. The regions were similar with respect to sulfur dioxide levels, but levels of nitric oxides and particulate matter (10 millimeters or less) were higher in the downtown area than the suburbs. The authors assessed airway obstruction, as determined by a decrease in forced expiratory volume in 1 s, mean forced expiratory flow measured between 25% and 75% of vital capacity, and an elevated value of central airway resistance. The authors tested the changes in these variables induced by inhalation of a beta2 agonist. Baseline lung function was altered more significantly in both male and female patients who lived in downtown Marseilles than in those who resided in the suburbs, and the differences persisted regardless of the season during which the study occurred. Prevalence of bronchial hyperreactivity and symptoms of asthma (but not of rhinitis) were higher in the downtown than suburban male subjects. The results of this study suggest that an association exists between actual environmental exposure to outdoor air pollution (i.e., nitrogen oxides and/or particulate matter of 10 millimeters or less) and respiratory effects in sensitive adults represented by patients with chronic obstructive pulmonary disease or asthma.

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.

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°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.

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-cmH2O 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.

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 cmH2O high airway pressure injurious ventilation (HV40 and HV25) 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)‐1β 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 HV40 and HV25 that induced the same levels of lung injury and increased lung contents of IL‐1β and IL‐6. They were 90 min and 120 min, respectively. Both HV40 and HV25 increased lung SP, IL‐1β and IL‐6 levels, these effects being markedly reduced by NK‐1 receptor blockade. Bivagotomy reduced to a lesser extent the HV40‐ and HV25‐induced increases in SP but significantly reduced cytokine production. Neither vagotomy nor NK‐1 receptor blockade prevented HV40‐induced lung injury but, in the HV25 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.

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.

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.