Interaction entre ventilation mécanique et traumatisme à la moelle épinière : réponses inflammatoires pulmonaires et médullaires

Le traumatisme de la moelle épinière est à l’origine d’une inflammation locale importante caractérisée par l’augmentation massive des cellules inflammatoires et la présence de réactions oxydatives. Cette inflammation locale peut déclencher une réponse inflammatoire systémique par voie hématogène. Au niveau cervical, les lésions médullaires peuvent entraîner des faiblesses ou la paralysie des muscles respiratoires. Le patient, qui ne peut plus respirer de façon autonome, doit avoir recours à un support respiratoire. Bien que la ventilation mécanique soit la thérapie traditionnellement appliquée aux blessés médullaires souffrant d’insuffisance respiratoire, les études ont démontré qu’elle pouvait contribuer à promouvoir une réponse inflammatoire ainsi que des dommages pulmonaires. L’interaction entre le traumatisme médullaire et la ventilation mécanique, indispensable au maintien de l’équilibre des échanges respiratoires, est inconnue à ce jour. En voulant protéger les tissus, cellules et organes, l’organisme met en œuvre toute une panoplie de réponses inflammatoires à différents endroits. Nous pensons que ces réponses peuvent être altérées via l’interaction entre ce traumatisme et cette ventilation mécanique, sous l’influence de la principale source cellulaire de cytokines pour la défense de l’hôte, le macrophage, récemment classé en deux phénotypes principaux: 1) l’activation classique de type M1 et 2) l’activation alternative de type M2. Le phénotype M1 est conduit par le facteur GM-CSF et induit par l’interféron IFN-ɣ ainsi que le lipopolysaccharide. Le phénotype M2 quant à lui, est conduit par le facteur M-CSF et induit par les interleukines IL-4, IL-13 ou IL-21. M1 relâche principalement IL-1β, IL-6, TNF-α et MIP-1α tandis que M2 principalement IL-10 et MCP-1. Toutefois, nous ignorons actuellement par quel type d’activation se manifestera cette réponse immunitaire et si l’application de support respiratoire pourrait entraîner un risque inflammatoire additionnel au site du traumatisme. Nous ignorons également si la ventilation mécanique affecterait, à distance, les tissus de la moelle épinière via une inflammation systémique et amplifierait alors le dommage initial. Il n’existe pas à ce jour, de thérapie qui ait montré d’effet bénéfique réel envers une récupération fonctionnelle des patients blessés médullaires. Il paraît donc essentiel de déterminer si la ventilation mécanique peut moduler l’inflammation post-traumatique à la fois au niveau pulmonaire et au site de la lésion. Ce travail visait à caractériser les liens entre l’inflammation issue du traumatisme médullaire et celle issue de la ventilation, dans le but de fournir une meilleure compréhension des mécanismes inflammatoires activés dans ce contexte. L’étude a été menée sur un modèle animal. Elle consistait à évaluer : 1) si le traumatisme médullaire influençait les réponses inflammatoires pulmonaires induites par la ventilation mécanique, y compris le phénotype des macrophages alvéolaires et 2) si la ventilation pouvait altérer à distance, les tissus de la moelle épinière. L’impact de la blessure médullaire sur l’inflammation pulmonaire et locale, induite par la ventilation fut interprété grâce à l’analyse des cellules inflammatoires dans les lavages broncho-alvéolaires et dans les tissus prélevés à l’endroit de la blessure après 24 heures. Ces analyses ont démontré un profil spécifique des cytokines pulmonaires et médullaires. Elles ont révélé que la ventilation mécanique a engendré un environnement pro-inflammatoire en faveur d’un phénotype M1 chez les animaux ayant bénéficié de la thérapie respiratoire. Inversement, l’atteinte thoracique chez les animaux sans ventilation, a montré qu’une réponse immunitaire avait été activée en faveur d’un environnement anti-inflammatoire de phénotype M2. La lésion cervicale quant à elle a induit un profil de cytokines différent et les réponses au stress oxydatif dans le poumon induites par la ventilation ont été réduites significativement. De plus, une lésion médullaire a augmenté l’expression d’IL-6 et la ventilation a diminué l’IL-1β et augmenté le TNF-α dans les tissus de la moelle. Finalement, ces données ont fourni les premières évidences que la ventilation a induit d’avantage à un phénotype pulmonaire M1 et que le traumatisme médullaire a impacté spécifiquement les réponses inflammatoires et oxydatives dans le poumon. La ventilation a contribué non seulement à distance à une inflammation des tissus médullaires lésés mais aussi des tissus sains.Spinal cord injury is a major cause of excessive local inflammation characterized by a massive increase in inflammatory cells and oxidative reactions. It can also enhance systemic inflammatory response through the bloodstream. Cervical spinal cord lesions can result in respiratory failure due to weakness or paralysis of respiratory muscles and may lead a patient to require respiratory support. Although mechanical ventilation is the current therapy of choice applied to injured patients for respiratory insufficiency, evidence has shown that it can directly contribute to inflammatory response and lung damage. Currently, interplay between spinal cord injury and mechanical ventilation, essential to maintain the balance of respiratory exchanges, is unknown. To protect tissues, cells and organs, the body implements a wide range of inflammatory responses in various locations. We believe that the immune response can be modulated by this interplay under the influence of the main cellular source of cytokines for host defense; the macrophage. Macrophages have recently been classified into two phenotypes: 1) classical activation (M1) and 2) alternative activation (M2) and, as of today, it is unknown through which activation profile the immune response manifests itself. M1 phenotype is GM-CSF-driven, and also induced or primed by interferon-ɣ and lipopolysaccharide. In contrast, M2 phenotype is M-CSF-driven and induced also by IL-4 and IL-13 or IL-21. M1 release mainly IL-1β, IL-6, TNF-α and MIP-1α whereas M2 produce mainly IL-10 and MCP-1.The application of respiratory support may lead to an additional inflammatory risk to the injury site that may affect distal spinal cord tissues via the systemic inflammatory responses thus amplifying damage to the spine. There is currently no therapy which has shown beneficial effects towards a real functional recovery of spinal cord injury. It seems important to determine if and how mechanical ventilation may affect the post-traumatic inflammation in both lung and at injury site. This work was aimed to better characterize the relationship between inflammation induced by a spinal cord injury and ventilation thus providing a deeper understanding of the activated inflammatory mechanisms in this context. The study was conducted in an animal model and we wanted to evaluate: 1) if spinal cord injury impacts lung inflammatory responses induced by mechanical ventilation including alveolar macrophage phenotype and 2) determine whether mechanical ventilation may alter inflammatory responses of distal spine tissues. Interplay between spinal cord injury and inflammation-induced by mechanical ventilation on lung and local spine was interpreted through analyses of inflammatory cells in broncho-alveolar lavages and spinal cord tissues after 24 hours. These analyses have shown a specific cytokines profiles both in the lung and at local site of injury. It also revealed that the application of mechanical ventilation induced a pro-inflammatory environment favoring the M1 phenotype. Conversely, a thoracic spinal cord injury in non-ventilated animals, showed that an immune response had been activated favoring an anti-inflammatory environment M2 phenotype in the lung. Cervical lesion also induced a different cytokine profile and oxidative stress responses in the lung induced by ventilation have been reduced significantly. In addition, spinal cord injury induced pro-inflammatory cytokines IL-6 expression and mechanical ventilation has been decreased IL-1β and increased TNF-α in spine tissues. In retrospect, this work provide the first evidence that ventilation induced a predominant M1 phenotype and that spinal cord injury modulated specific inflammatory and oxidative stress responses in the lung. In addition, mechanical ventilation not only contributed to local inflammation in distal spinal injured tissues but also in healthy tissues

Spinal Cord Injury Modulates the Lung Inflammatory Response in Mechanically Ventilated Rats: A Comparative Animal Study

Mechanical ventilation (MV) is widely used in spinal injury patients to compensate for respiratory muscle failure. MV is known to induce lung inflammation, while spinal cord injury (SCI) is known to contribute to local inflammatory response. Interaction between MV and SCI was evaluated in order to assess the impact it may have on the pulmonary inflammatory profile. Sprague Dawley rats were anesthetized for 24 h and randomized to receive either MV or not. The MV group included C4–C5 SCI, T10 SCI and uninjured animals. The nonventilated (NV) group included T10 SCI and uninjured animals. Inflammatory cytokine profile, inflammation related to the SCI level, and oxidative stress mediators were measured in the bronchoalveolar lavage (BAL). The cytokine profile in BAL of MV animals showed increased levels of TNF-α, IL-1β, IL-6 and a decrease in IL-10 (P = 0.007) compared to the NV group. SCI did not modify IL-6 and IL-10 levels either in the MV or the NV groups, but cervical injury induced a decrease in IL-1β levels in MV animals. Cervical injury also reduced MV-induced pulmonary oxidative stress responses by decreasing isoprostane levels while increasing heme oxygenase-1 level. The thoracic SCI in NV animals increased M-CSF expression and promoted antioxidant pulmonary responses with low isoprostane and high heme oxygenase-1 levels. SCI shows a positive impact on MV-induced pulmonary inflammation, modulating specific lung immune and oxidative stress responses. Inflammation induced by MV and SCI interact closely and may have strong clinical implications since effective treatment of ventilated SCI patients may amplify pulmonary biotrauma

Mechanical Ventilation Modulates Pro-Inflammatory Cytokine Expression in Spinal Cord Tissue After Injury in Rats

Rationale: Spinal cord injury (SCI) may induce significant respiratory muscle weakness and paralysis, which in turn may cause a patient to require ventilator support. Central nervous system alterations can also exacerbate local inflammatory responses with immune cell infiltration leading to additional risk of inflammation at the injury site. Although mechanical ventilation is the traditional treatment for respiratory insufficiency, evidence has shown that it may directly affect distant organs through systemic inflammation. Objectives: This study aimed to better understand the impact of invasive mechanical ventilation on local spinal cord inflammatory responses following cervical or thoracic SCI. Methods: Five groups of female Sprague-Dawley rats were anesthetised for 24 h. Three groups received mechanical ventilation: seven rats without SCI, seven rats with cervical injury (C4-C5), and seven rats with thoracic injury (T10); whereas, two groups were non-ventilated: six rats without SCI; and six rats with thoracic injury (T10). Changes in inflammatory responses were determined in the spinal cord tissues collected at the local site of injury. Cytokines were measured using ELISA. Main results: SCI induced local pro-inflammatory cytokine IL-6 expression for all groups. Mechanical ventilation also had effects on pro-inflammatory cytokines and independently increased TNF-α and decreased IL-1β levels in the spinal cords of anesthetized rats. Conclusion: These data provide the first evidence that mechanical ventilation contributes to local inflammation after SCI and in the absence of direct tissue injury

Placement of the nebulizer before the humidifier during mechanical ventilation: Effect on aerosol delivery

Background: Therapeutic aerosols are commonly used in mechanically ventilated patients. The position of the nebulizer in the ventilator circuit and the humidification of inhaled gases can influence the efficiency of aerosol delivery. We evaluated the effect of nebulizer position on the pulmonary bioavailability of nebulized ipratropium in ventilated patients without known preexisting respiratory disease. Methods: The study included 38 mechanically ventilated and sedated patients after open heart surgery. Ipratropium (500 μg) was delivered by an ultrasonic nebulizer. Patients were randomized into 2 groups: the nebulizer positioned before the heat humidification system (group 1, n = 19) or at the end of the inspiratory limb before the Y-piece (group 2, n = 19). The amount of ipratropium in the urine collected during the 4 hours after drug administration was measured by mass spectrometry. Results: There were no statistically significant differences in tidal volume or respiratory rate between groups. There were no significant differences between the 2 groups in the amount of drug excreted (group 1 vs 2: 13,237 ± 2313 pg/mL vs 15,529 ± 3204 pg/mL) or in pulmonary bioavailability (.9% ± .1% vs 1.1% ± .2%). Conclusion: The position of the nebulizer in the ventilatory circuit had no effect on the pulmonary bioavailability of ipratropium. © 2009 Mosby, Inc. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe