Study On Anti-CD11c Antibody, Efalizumab Attenuate Ventilator-induced Lung Injury

Acute lung injury (ALI) and acute respiratory distress syndrome(ARDS) are characterized by a disturbance of the alveolar-capillary barrier associated with several clinical disorders. In addition, mechanical ventilation has been part of basic life support for several decades. Several potential drawbacks and complications have been identified early in the use of mechanical ventilation. During mechanical ventilation, high endinspiratory lung volume (whether it be because of large tidal volume (VT) and/or high levels of positive end-expiratory pressure) results in a permeability type pulmonary oedema, called ventilator-induced lung injury (VILI). Of these, ventilator-induced lung injury has recently received much attention in both the experimental and the clinical field.VILI is becoming more and more attention. In recent years, there are a lot of research study on the pathogenesis of VILI. Current evidence suggested that injurious mechanical ventilation with high tidal volume or high pressure could cause excessive lung tissue expansion and induce mechanical lung injury. In addition, on the basis of mechanical damage,pulmonary inflammatory cells infiltrating in lung and releasing a lot of inflammatory mediators can further exacerbate the lung injury.Depending onthe type of damage,VILI is roughly divided into the following four types:barotrauma, volutrauma, pulmonary atelectasis injury,and biotrauxna. Generally,the former two types appeared in the early of VILI,then biotrauma appeared in the later period,which characterized by infiltration of inflammatory cells and overproduction of pro-inflammatory mediators. The mechanism of biotrauma is very complex,have become the focus in the VILI.A large number of studies have shown that the stretch stress produced by ventilation in lung could lead to to release amount of inflammatory factors such as TNF-α、IL-1β、IL-6 which cause leukocyte infiltration in lung tissues. Interaction between these inflammatory cells and cytokines, constitute a large and complex network system, not only can directly lead to lung tissue damage, can be also released into all tissues and organs through the blood circulation, cause systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction (MODS) or even have life-threatening.The neutrophils participating in acute lung injury have the ability to migrate to the site of lung injury by crossing endothelial barriers between blood and lung.The process of leukocytes recruitment comprises a tightly regulated cascade of adhesive interaction between leukocytes and endothelial cells. Two adhesion molecules are believed to play critical roles in this migration process:lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1(ICAM-1). LFA-1 is expressed on memory T cell and ICAM-1 is expressed on vascular endothelial cells at sites of inflammation as well as on keratinocytes in a variety of T cell-mediated disorders.Efalizumab (Raptiva, anti-CD11a) is a humanized form of a murine antibody directed against CD11a, the subunit of LFA-1. Previous studies suggested that efalizumab inhibits multiple key inflammatory step by binding to CDlla, such as T cell activation, T cell trafficking and T cell adhesion. These data suggested that efalizumab might have a therapeutic effect on ventilator-induced lung injury via inhibiting the inflammatory response and the infiltration of inflammatory cells.In this study, we hypothesised that efalizumab could protect the rat from ventilator-induced lung injury through the suppression of inflammatory response and neutrophils infiltration. So we treated ventilator-induced lung injury rats with efalizumab or human IgG protein via tail vein injection. Our results indicated that the treatment of efalizumab attenuated the lung injury induced by ventilator. Meanwhile, compared with the human IgG-treated group, the administration of efalizumab reduced the infiltration of neutrophils and decreased the MPO activity. In addition, we also found that efalizumab treatment suppressed the expression of pro-inflammatory cytokines in BALF, such as TNF-α, IL-6, IL-lb and MIP-2. In summary, our data suggested that efalizumab has a therapeutic effect of ventilator-induced lung injuryMethodsExperimental protocols1. Preparation of the ventilator-induced lung injury animal model in rats1.1 Rat model of VILI:Forty pathogen-free male Sprague-Dawley rats, weighing 240-290g, were anesthetized with thiopental (37 mg/kg), underwent tracheotomy and ventilated for 2 h in room air to maintain anesthesia, using either high or normal tidal volume. For high tidal volume ventilation, the rat was ventilated with a rodent volume ventilator (Harvard Apparatus, Ealing, Les Ulis, France), with a tidal volume of 42ml/kg, a respiratory rate of 40 breaths/min. and Ocm H2O end-expiratory pressure. For normal volume ventilation, the rat received 7 ml/kg of tidal volume, a respiratory rate of 40 breaths/min and 3cm H2O end expiratory pressure. In order to maintain PaCO2 between 35 and 45 cmH2O (4.7-6.0 kPa),5 ml of dead space was added to the ventilator circuit. Body temperature was maintained between 37℃ and 38℃. using a heating lamp. After 2h of mechanical ventilation, various measurements were obtained.1.2 inflammatory response of rats:The samples of pulmonary tissue and lung lavage fluid were collected after experiments. Then we detected the lung tissue wet/dry ratio, and the activity of myeloperoxidase (MPO) was determined. The concentration of protein, TNF-α, IL-6,IL-1 b and MIP-2 in the BALF were detected by ELISA.2. Effects of LFA-1/ICAM-1 mediated neurogenic inflammatory reaction in process of VILI.ResultsCompared with the human IgG control treated group, the treatment of Efalizumab attenuate the ventilator-induced lung injury, including the wet/dry ratio and the activity of myeloperoxidase (MPO), meanwhile, the level of pro-inflammatory cytokines, such as TNF-α, IL-6, IL-1 b and MIP-2 were decreased in the BALF of Efalizumab treated group rats compared with the human IgGtreated control group. In addition, the histopathological index of ventilator-induced lung injury was improved after efalizumab treatment, that also reduced the recruitment of inflammatory cells into the lung, such as neutrophils.ConclusionsOur data suggested that Efalizumab could protect rat from ventilator-induced lung injury and improve the survival time through the inhibition of intrapulmonary inflammatory response. As a T cell targeted monoclonal antibody, efalizumab treatment significantly alleviated the ventilator-induced lung injury and prolonged the survival time of injurious ventilation treated rats. Efalizumab might used as a drug for the treatment of ventilator-induced lung injury by inhibiting the infiltration of neutrophils into lung tissue and the inflammatory responses in the target lung tissue.