Sex susceptibility to ventilator-induced lung injury.
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ABSTRACT:
SUBMITTER: Lopez-Alonso I
PROVIDER: S-EPMC6329690 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
Publications
Sex susceptibility to ventilator-induced lung injury.
López-Alonso Inés I Amado-Rodriguez Laura L López-Martínez Cecilia C Huidobro Covadonga C Albaiceta Guillermo M GM
Intensive care medicine experimental 20190111 1
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Project description:Gender susceptibility to ventilator-induced lung injury
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Project description:BackgroundMechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-Jun-NH(2)-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation.Methodology and principle findingsC57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3(-/-)) or c-Jun-NH(2)-terminal kinase-1 (jnk1(-/-)) were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3(-/-) or jnk1(-/-) mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1(-/-) mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1(-/-) mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8) and GADD45alpha. Functional characterization of MMP8 revealed that mmp8(-/-) mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability.ConclusionsWe demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH(2)-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage.
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Project description:Isolated perfused and ventilated BALB/c mouse lung model 3 conditions c-10cmH2O pressure ventilation 3h, LPS-10cmH2O pressure ventilation 3h in the presence of E. coli LPS in the perfusion buffer (3mg/kg), ov-overventilation with 25cmH2O pressure 3h Keywords: parallel sample
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Project description:IntroductionDiabetic patients may develop acute lung injury less often than non-diabetics; a fact that could be partially ascribed to the usage of antidiabetic drugs, including metformin. Metformin exhibits pleiotropic properties which make it potentially beneficial against lung injury. We hypothesized that pretreatment with metformin preserves alveolar capillary permeability and, thus, prevents ventilator-induced lung injury.MethodsTwenty-four rabbits were randomly assigned to pretreatment with metformin (250 mg/Kg body weight/day per os) or no medication for two days. Explanted lungs were perfused at constant flow rate (300 mL/min) and ventilated with injurious (peak airway pressure 23 cmH?O, tidal volume ?17 mL/Kg) or protective (peak airway pressure 11 cmH?O, tidal volume ?7 mL/Kg) settings for 1 hour. Alveolar capillary permeability was assessed by ultrafiltration coefficient, total protein concentration in bronchoalveolar lavage fluid (BALF) and angiotensin-converting enzyme (ACE) activity in BALF.ResultsHigh-pressure ventilation of the ex-vivo lung preparation resulted in increased microvascular permeability, edema formation and microhemorrhage compared to protective ventilation. Compared to no medication, pretreatment with metformin was associated with a 2.9-fold reduction in ultrafiltration coefficient, a 2.5-fold reduction in pulmonary edema formation, lower protein concentration in BALF, lower ACE activity in BALF, and fewer histological lesions upon challenge of the lung preparation with injurious ventilation. In contrast, no differences regarding pulmonary artery pressure and BALF total cell number were noted. Administration of metformin did not impact on outcomes of lungs subjected to protective ventilation.ConclusionsPretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model.
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Project description:Mechanical ventilation (MV) is inextricably linked to the care of critically ill patients admitted to the paediatric intensive care unit (PICU). Even today, little evidence supports best MV practices for life-threatening acute respiratory failure in children. However, careful attention must be paid because this life-saving technique induces pulmonary inflammation that aggravates pre-existing lung injury, a concept that is known as ventilator-induced lung injury (VILI). The delivery of too large tidal volumes (Vt) (i.e., volutrauma) and repetitive opening and closure of alveoli (i.e., atelectrauma) are two key mechanisms underlying VILI. Despite the knowledge of these mechanisms, the clinical relevance of VILI in critically ill children is poorly understood as almost all of our knowledge has been obtained from studies in adults or experimental studies mimicking the adult critical care situation. This leaves the question if VILI is relevant in the paediatric context. In fact, limited paediatric experimental data showed that the use of large, supraphysiologic Vt resulted in less inflammation and injury in paediatric animal models compared to adult models. Furthermore, the association between large Vt and adverse outcome has not been confirmed and the issue of setting positive end-expiratory pressure (PEEP) to prevent atelectrauma has hardly been studied in paediatric clinical studies. Hence, even today, the question whether or not there VILI is relevant in pediatric critical remains to be answered. Consequently, how MV is used remains thus based on institutional preferences, personal beliefs and clinical data extrapolated from adults. This signifies the need for clinical and experimental studies in order to better understand the use and effects of MV in paediatric patients with or without lung injury.
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Project description:BACKGROUND:Although mechanical ventilation is often lifesaving, it can also cause injury to the lungs. The lung injury is caused by not only high pressure and mechanical forces but also by inflammatory processes that are not fully understood. Heparin-binding protein (HBP), released by activated granulocytes, has been indicated as a possible mediator of increased vascular permeability in the lung injury associated with trauma and sepsis. We investigated if HBP levels were increased in the bronchoalveolar lavage fluid (BALF) or plasma in a pig model of ventilator-induced lung injury (VILI). We also investigated if HBP was present in BALF from healthy volunteers and in intubated patients in the intensive care unit (ICU). METHODS:Anaesthetized pigs were randomized to receive ventilation with either tidal volumes of 8 ml/kg (controls, n?=?6) or 20 ml/kg (VILI group, n?=?6). Plasma and BALF samples were taken at 0, 1, 2, 4, and 6 h. In humans, HBP levels in BALF were sampled from 16 healthy volunteers and from 10 intubated patients being cared for in the ICU. RESULTS:Plasma levels of HBP did not differ between pigs in the control and VILI groups. The median HBP levels in BALF were higher in the VILI group after 6 h of ventilation compared to those in the controls (1144 ng/ml (IQR 359-1636 ng/ml) versus 89 ng/ml (IQR 33-191 ng/ml) ng/ml, respectively, p?=?0.02). The median HBP level in BALF from healthy volunteers was 0.90 ng/ml (IQR 0.79-1.01 ng/ml) as compared to 1959 ng/ml (IQR 612-3306 ng/ml) from intubated ICU patients (p?<?0.001). CONCLUSIONS:In a model of VILI in pigs, levels of HBP in BALF increased over time compared to controls, while plasma levels did not differ between the two groups. HBP in BALF was high in intubated ICU patients in spite of the seemingly non-harmful ventilation, suggesting that inflammation from other causes might increase HBP levels.
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Project description:Despite over 40 years of research, there is no specific lung-directed therapy for the acute respiratory distress syndrome (ARDS). Although much has evolved in our understanding of its pathogenesis and factors affecting patient outcome, supportive care with mechanical ventilation remains the cornerstone of treatment. Perhaps the most important advance in ARDS research has been the recognition that mechanical ventilation, although necessary to preserve life, can itself aggravate or cause lung damage through a variety of mechanisms collectively referred to as ventilator-induced lung injury (VILI). This improved understanding of ARDS and VILI has been important in designing lung-protective ventilatory strategies aimed at attenuating VILI and improving outcomes. Considerable effort has been made to enhance our mechanistic understanding of VILI and to develop new ventilatory strategies and therapeutic interventions to prevent and ameliorate VILI with the goal of improving outcomes in patients with ARDS. In this review, we will review the pathophysiology of VILI, discuss a number of novel physiological approaches for minimizing VILI, therapies to counteract biotrauma, and highlight a number of experimental studies to support these concepts.
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