Nivel de conocimientos del personal de enfermería sobre el manejo del paciente con ventilación mecánica invasiva / Level of knowledge of the nursing staff on the management of the patient with invasive mechanical ventilation

Introducción: En las unidades de cuidados intensivos, los pacientes son hospitalizados en una condición potencial mortal. Por ello requieren ventilación mecánica invasiva como método para ayudar a promover y mantener la permeabilidad de las vías respiratorias. Los cuidados de enfermería en dichas unidades son un pilar importante para el seguimiento y evolución de los pacientes ventilados. Objetivo: Identificar el nivel de conocimientos del personal de enfermería sobre el manejo del paciente con ventilación mecánica invasiva. Métodos: Se realizó un estudio descriptivo y de corte transversal en la Unidad de Cuidados Intensivos del Hospital Universitario Clínico Quirúrgico Comandante Faustino Pérez Hernández, de Matanzas, entre enero de 2022 y julio de 2023. El universo estuvo conformado por 62 enfermeros. Se tuvieron en cuenta como criterios de inclusión la voluntad de participar en el estudio y estar activo en el servicio, y como criterio de exclusión, aquellos enfermeros de estancia transitoria. Se diseñó un cuestionario. Resultados: El mayor por ciento de los enfermeros estudiados fue a pie de cama. El nivel de conocimientos que prevaleció en el cuestionario fue el regular. Conclusiones: El diagnóstico permitió identificar problemas y potencialidades del objeto estudiado. La dimensión cognoscitiva presentó las mayores dificultades. Se reafirmó la necesidad de desarrollar un sistema de superación que contribuya a fortalecer los conocimientos de los enfermeros sobre el cuidado del paciente con ventilación mecánica invasiva(AU)

Introduction: In intensive care units, patients are hospitalized in a potential mortal condition. Therefore, they require invasive mechanical ventilation as a method to help promote and to maintain airway permeability. Nursing care in these units is an important pillar for the monitoring and evolution of ventilated patients. Objective: To identify the level of knowledge of the nursing staff on the management of the patient with invasive mechanical ventilation Methods: A descriptive and cross sectional study was carried out in the Intensive Care Unit of the Clinical Surgical University Hospital Comandante Faustino Pérez Hernández, in Matanzas, between January 2022 and July 2023. The universe was made up of 62 nurses. As inclusion criteria were taken into consideration the willingness to participate in the study and be active in the service, and as exclusion criteria those nurses of temporary stay. A questionnaire was designed. Results: The largest percent of the nurses studied were at the bedside. The level of knowledge that prevailed in the questionnaire was regular. Conclusions: The diagnosis allowed us to identify problems and potentialities of the object studied. The cognitive dimension presented the greatest difficulties. The need to develop an improvement system that contributes to strengthening nurses' knowledge about the care of patients with invasive mechanical ventilation was reaffirmed(AU)

Electric Cell-Substrate Impedance Sensing (ECIS) as a Platform for Evaluating Barrier-Function Susceptibility and Damage from Pulmonary Atelectrauma.

Biophysical insults that either reduce barrier function (COVID-19, smoke inhalation, aspiration, and inflammation) or increase mechanical stress (surfactant dysfunction) make the lung more susceptible to atelectrauma. We investigate the susceptibility and time-dependent disruption of barrier function associated with pulmonary atelectrauma of epithelial cells that occurs in acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). This in vitro study was performed using Electric Cell-substrate Impedance Sensing (ECIS) as a noninvasive evaluating technique for repetitive stress stimulus/response on monolayers of the human lung epithelial cell line NCI-H441. Atelectrauma was mimicked through recruitment/derecruitment (RD) of a semi-infinite air bubble to the fluid-occluded micro-channel. We show that a confluent monolayer with a high level of barrier function is nearly impervious to atelectrauma for hundreds of RD events. Nevertheless, barrier function is eventually diminished, and after a critical number of RD insults, the monolayer disintegrates exponentially. Confluent layers with lower initial barrier function are less resilient. These results indicate that the first line of defense from atelectrauma resides with intercellular binding. After disruption, the epithelial layer community protection is diminished and atelectrauma ensues. ECIS may provide a platform for identifying damaging stimuli, ventilation scenarios, or pharmaceuticals that can reduce susceptibility or enhance barrier-function recovery.

Innovative in vitro method to study ventilator induced lung injury.

Mechanical ventilation (MV) is a life-saving therapy for critically ill patients, alleviating the work of breathing and supporting adequate gas exchange. However, MV can cause ventilator induced lung injury (VILI) by baro/volu- and atelectrauma, even lead to acute respiratory distress syndrome (ARDS), and substantially augment mortality. There is a need for specific biomarkers and novel research platforms for VILI/ARDS research to study these detrimental disorders and seek ways to avoid or prevent them. Previous in vitro studies on bronchial epithelium, cultured in air-liquid interface (ALI) conditions, have generally utilized static or constant pressure.  We have developed a Cyclical Pressure ALI Device (CPAD) that enables cyclical stress on ALI cultured human bronchial cells, with the aim of mimicking the effects of MV. Using CPAD we were able to analyze differentially expressed VILI/ARDS and innate immunity associated genes along with increased expression of associated proteins. CPAD provides an easy and accessible way to analyze functional and phenotypic changes that occur during VILI and may provide a platform for future drug testing.

Ventilator-induced lung injury is aggravated by antibiotic mediated microbiota depletion in mice.

BACKGROUND: Antibiotic exposure alters the microbiota, which can impact the inflammatory immune responses. Critically ill patients frequently receive antibiotic treatment and are often subjected to mechanical ventilation, which may induce local and systemic inflammatory responses and development of ventilator-induced lung injury (VILI). The aim of this study was to investigate whether disruption of the microbiota by antibiotic therapy prior to mechanical ventilation affects pulmonary inflammatory responses and thereby the development of VILI. METHODS: Mice underwent 6-8 weeks of enteral antibiotic combination treatment until absence of cultivable bacteria in fecal samples was confirmed. Control mice were housed equally throughout this period. VILI was induced 3 days after completing the antibiotic treatment protocol, by high tidal volume (HTV) ventilation (34 ml/kg; positive end-expiratory pressure = 2 cmH2O) for 4 h. Differences in lung function, oxygenation index, pulmonary vascular leakage, macroscopic assessment of lung injury, and leukocyte and lymphocyte differentiation were assessed. Control groups of mice ventilated with low tidal volume and non-ventilated mice were analyzed accordingly. RESULTS: Antibiotic-induced microbiota depletion prior to HTV ventilation led to aggravation of VILI, as shown by increased pulmonary permeability, increased oxygenation index, decreased pulmonary compliance, enhanced macroscopic lung injury, and increased cytokine/chemokine levels in lung homogenates. CONCLUSIONS: Depletion of the microbiota by broad-spectrum antibiotics prior to HTV ventilation renders mice more susceptible to developing VILI, which could be clinically relevant for critically ill patients frequently receiving broad-spectrum antibiotics.

Deferoxamine preconditioning ameliorates mechanical ventilation-induced lung injury in rat model via ROS in alveolar macrophages: a randomized controlled study.

BACKGROUND: Mechanical ventilation (MV) can provide effective breathing support; however, ventilatior-induced lung injury (VILI) has also been widely recognized in clinical practice, including in the healthy lung. Unfortunately, the morbidity and mortality of VILI remain unacceptably high, and no satisfactory therapeutic effect can be achieved. The current study aimed to examine the effects of iron chelator preconditioning on the mitochondrial reactive oxygen species (ROS) in alveolar macrophages and pathological lung injury in VILI. METHODS: Twenty four healthy male Sprague-Dawley (SD) rats (250-300 g in weight) were randomly divided into 3 groups, including the control group (NC group, n = 8), the high-volume mechanical ventilation group (HV group, n = 8), and the deferoxamine treatment group (HV + DFO group, n = 8). Rats in the HV and HV + DFO groups were subjected to high-volume MV at a dose of 40 ml/kg. DFO was administered at a dose of 200 mg/kg 15 min prior to over-ventilation. Spontaneously breathing anesthetized rats were used as the controls. The animals were sacrificed after 4 h of high-volume ventilation or under control conditions, the animals were sacrificed. Purified alveolar macrophages from bronchoalveolar lavage fluid (BALF) and lung tissue were collected for further analysis through light microscopy and flow cytometry. RESULTS: Compared with the controls, the high-volume-ventilated rats had exhibited typical lung edema and histological lung injury, and ROS were markedly increased in alveolar macrophages and mitochondria. Moreover, all indices of VILI were remarkably different in rats treated with DFO preconditioning. DFO could ameliorate lung injury in the mechanically ventilated SD rat model. CONCLUSIONS: DFO preconditioning contributes to mitigating the histological lung damage while reducing ROS levels in alveolar macrophages and mitochondria, suggesting that iron metabolism in alveolar macrophages may participate in VILI.

Curcumin ameliorated ventilator-induced lung injury in rats.

BACKGROUND: Curcumin (CUR) is a Chinese medicine monomer with antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects and mechanisms of CUR treatment on ventilator-induced lung injury (VILI) in rats. METHODS: Total 50 SD rats were divided into five groups: sham, VILI, VILI+CUR-50 (CUR 50?mg/kg pretreated intraperitoneal), VILI+CUR-200 (CUR 200?mg/kg pretreated intraperitoneal) and VILI?+?DXM (5?mg/kg pretreated intraperitoneal). The morphology and ultrastructure were observed by microscope and transmission electron microscope. The wet to dry ratio, protein concentration in bronchoalveolar lavage fluid (BALF), evans blue dye (EBD) content, nuclear factor kappa B (NF-?B) activity, myeloperoxidase (MPO), malondialdehyde (MDA), xanthine oxidase (XO) and total antioxidative capacity (TAOC) levels were measured. RESULTS: Histological studies revealed that inflammatory cells infiltration and alveolar edema were significantly severe in VILI as compared to other groups. CUR-200 and DXM treatment reversed lung injury significantly. The wet to dry ratio, protein concentration in BALF, EBD content, MPO activity, tumor necrosis factor (TNF)-? level and NF-?B activity were significantly increased in VILI group as compared to other groups. CUR-200 and DXM treatment significantly suppressed permeability and inflammation induced by ventilation. Furthermore, the significantly higher MDA content in VILI could be markedly decreased by CUR-200 and DXM treatment while the levels of XO and TAOC were markedly recovered only by CUR (200?mg/kg) treatment after VILI. CONCLUSION: CUR could inhibit the inflammatory response and oxidative stress during VILI, which is partly through NF-?B pathway.

Knockout Mice Reveal a Major Role for Alveolar Epithelial Type I Cells in Alveolar Fluid Clearance.

Active ion transport by basolateral Na-K-ATPase (Na pump) creates an Na(+) gradient that drives fluid absorption across lung alveolar epithelium. The α1 and ß1 subunits are the most highly expressed Na pump subunits in alveolar epithelial cells (AEC). The specific contribution of the ß1 subunit and the relative contributions of alveolar epithelial type II (AT2) versus type I (AT1) cells to alveolar fluid clearance (AFC) were investigated using two cell type-specific mouse knockout lines in which the ß1 subunit was knocked out in either AT1 cells or both AT1 and AT2 cells. AFC was markedly decreased in both knockout lines, revealing, we believe for the first time, that AT1 cells play a major role in AFC and providing insights into AEC-specific roles in alveolar homeostasis. AEC monolayers derived from knockout mice demonstrated decreased short-circuit current and active Na(+) absorption, consistent with in vivo observations. Neither hyperoxia nor ventilator-induced lung injury increased wet-to-dry lung weight ratios in knockout lungs relative to control lungs. Knockout mice showed increases in Na pump ß3 subunit expression and ß2-adrenergic receptor expression. These results demonstrate a crucial role for the Na pump ß1 subunit in alveolar ion and fluid transport and indicate that both AT1 and AT2 cells make major contributions to these processes and to AFC. Furthermore, they support the feasibility of a general approach to altering alveolar epithelial function in a cell-specific manner that allows direct insights into AT1 versus AT2 cell-specific roles in the lung.

Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak.

Cytokines and clinical predictors in distinguishing pulmonary transfusion reactions.

BACKGROUND: Pulmonary transfusion reactions are important complications of blood transfusion, yet differentiating these clinical syndromes is diagnostically challenging. We hypothesized that biologic markers of inflammation could be used in conjunction with clinical predictors to distinguish transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and possible TRALI. STUDY DESIGN AND METHODS: In a nested case-control study performed at the University of California at San Francisco and Mayo Clinic, Rochester, we evaluated clinical data and blood samples drawn before and after transfusion in patients with TRALI (n = 70), possible TRALI (n = 48), TACO (n = 29), and controls (n = 147). Cytokines measured included granulocyte-macrophage-colony-stimulating factor, interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-α. Logistic regression and receiver operating characteristics curve analyses were used to determine the accuracy of clinical predictors and laboratory markers in differentiating TACO, TRALI, and possible TRALI. RESULTS: Before and after transfusion, IL-6 and IL-8 were elevated in patients with TRALI and possible TRALI relative to controls, and IL-10 was elevated in patients with TACO and possible TRALI relative to that of TRALI and controls. For all pulmonary transfusion reactions, the combination of clinical variables and cytokine measurements displayed optimal diagnostic performance, and the model comparing TACO and TRALI correctly classified 92% of cases relative to expert panel diagnoses. CONCLUSIONS: Before transfusion, there is evidence of systemic inflammation in patients who develop TRALI and possible TRALI but not TACO. A predictive model incorporating readily available clinical and cytokine data effectively differentiated transfusion-related respiratory complications such as TRALI and TACO.

Glutamine attenuates acute lung injury caused by acid aspiration.

Inadequate ventilator settings may cause overwhelming inflammatory responses associated with ventilator-induced lung injury (VILI) in patients with acute respiratory distress syndrome (ARDS). Here, we examined potential benefits of glutamine (GLN) on a two-hit model for VILI after acid aspiration-induced lung injury in rats. Rats were intratracheally challenged with hydrochloric acid as a first hit to induce lung inflammation, then randomly received intravenous GLN or lactated Ringer's solution (vehicle control) thirty min before different ventilator strategies. Rats were then randomized to receive mechanical ventilation as a second hit with a high tidal volume (TV) of 15 mL/kg and zero positive end-expiratory pressure (PEEP) or a low TV of 6 mL/kg with PEEP of 5 cm H2O. We evaluated lung oxygenation, inflammation, mechanics, and histology. After ventilator use for 4 h, high TV resulted in greater lung injury physiologic and biologic indices. Compared with vehicle treated rats, GLN administration attenuated lung injury, with improved oxygenation and static compliance, and decreased respiratory elastance, lung edema, extended lung destruction (lung injury scores and lung histology), neutrophil recruitment in the lung, and cytokine production. Thus, GLN administration improved the physiologic and biologic profiles of this experimental model of VILI based on the two-hit theory.

Spillover of cytokines and reactive oxygen species in ventilator-induced lung injury associated with inflammation and apoptosis in distal organs.

BACKGROUND: The mechanism between ventilator-induced lung injury (VILI) and multiple organ injury is unclear. The aim of our study was to investigate the mechanisms of VILI-induced distal organ injury. METHODS: VILI was induced in rat lungs with high tidal volume (V(T)) ventilation of 40 mL/kg for 6 h. Rats with low V(T) ventilation of 6 mL/kg served as controls. Inflammatory and apoptotic indices in lung and distal organs were assessed. RESULTS: VILI increased lung weight, airway pressure, inflammation, and apoptotic pathologic changes without hemodynamic changes. The white blood cell count and the levels of H2O2, interleukin-1ß (IL-1ß), tumor necrosis factor alpha, and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid were higher in the VILI group compared with the control group. H2O2, IL-1ß, and tumor necrosis factor alpha in blood from the left ventricle were up-regulated. H2O2, IL-1ß, tumor necrosis factor alpha, macrophage inflammatory protein-2, c-Jun N-terminal kinase, p38, nuclear factor kappa B, and caspase-3 in lung, heart, liver, and kidney tissues in the VILI group were up-regulated. Furthermore, the apoptotic score for the kidneys was higher than those for other distal organs in the VILI group. CONCLUSIONS: High V(T) ventilation induces VILI and is associated with inflammation and apoptosis in distal organs. Up-regulation of reactive oxygen species and cytokines in VILI is associated with systemic inflammatory responses. Kidney tissue appears to be more vulnerable than heart and liver tissues following VILI.

Initiation of ECMO for ventilator-dependent respiratory failure in an infant with Pompe's.

We present a 7-month-old male with Pompe's disease with respiratory failure requiring extracorporeal membrane oxygenation that received enzyme replacement therapy. There are no published cases of the use of extracorporeal membrane oxygenation in a patient with Pompe's disease, or the use of enzyme replacement therapy in the setting of acute respiratory failure.

A study on circadian rhythm disorder of rat lung tissue caused by mechanical ventilation induced lung injury.

Ventilator-induced lung injury (VILI), the most serious complication of mechanical ventilation therapy, is an excessive inflammatory response in lung tissue characterized by infiltration of inflammatory cells and overproduction of inflammatory mediators. The pathogenesis of VILI is very complex. It is becoming increasingly evident that disruption of circadian rhythm affects the immune response. Whether the pathogenesis of VILI is associated with circadian rhythm disruption has not been reported. In this study, we establish VILI model in SD rat by performing an endotracheal intubation and placing the rat on a mechanical ventilator (tidal volume of 40 ml/kg or 10 ml/kg without positive end-expiratory pressure). To examine the effect of VILI on clock gene expression, real-time quantitative PCR was performed to measure bmal1, clock, per2 and Rev-erbα mRNA expression. We found that Rev-erbα mRNA was significantly decreased in high tide volume mechanical ventilation group compared with spontaneous group, the same as REV-ERBα protein product which was tested by Western blot approach. Stimulation of REV-ERBα activity by SR9009 greatly diminished VILI-induced lung edema, inflammatory cell infiltration and the production of the pro-inflammatory cytokine TNF-α. Collectively, our findings are the first to show that REV-ERBα plays an important role in VILI and inflammation, and circadian rhythm disorder in inflammation response may be a novel pathogenesis of VILI.

Acute respiratory distress syndrome after spontaneous intracerebral hemorrhage*.

OBJECTIVES: Acute respiratory distress syndrome develops commonly in critically ill patients in response to an injurious stimulus. The prevalence and risk factors for development of acute respiratory distress syndrome after spontaneous intracerebral hemorrhage have not been reported. We sought to determine the prevalence of acute respiratory distress syndrome after intracerebral hemorrhage, characterize risk factors for its development, and assess its impact on patient outcomes. DESIGN: Retrospective cohort study at two academic centers. PATIENTS: We included consecutive patients presenting from June 1, 2000, to November 1, 2010, with intracerebral hemorrhage requiring mechanical ventilation. We excluded patients with age less than 18 years, intracerebral hemorrhage secondary to trauma, tumor, ischemic stroke, or structural lesion; if they required intubation only during surgery; if they were admitted for comfort measures; or for a history of immunodeficiency. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were collected both prospectively as part of an ongoing cohort study and by retrospective chart review. Of 1,665 patients identified by database query, 697 met inclusion criteria. The prevalence of acute respiratory distress syndrome was 27%. In unadjusted analysis, high tidal volume ventilation was associated with an increased risk of acute respiratory distress syndrome (hazard ratio, 1.79 [95% CI, 1.13-2.83]), as were male sex, RBC and plasma transfusion, higher fluid balance, obesity, hypoxemia, acidosis, tobacco use, emergent hematoma evacuation, and vasopressor dependence. In multivariable modeling, high tidal volume ventilation was the strongest risk factor for acute respiratory distress syndrome development (hazard ratio, 1.74 [95% CI, 1.08-2.81]) and for inhospital mortality (hazard ratio, 2.52 [95% CI, 1.46-4.34]). CONCLUSIONS: Development of acute respiratory distress syndrome is common after intubation for intracerebral hemorrhage. Modifiable risk factors, including high tidal volume ventilation, are associated with its development and in-patient mortality.

Incidencia y consecuencias de la traqueobronquitis asociada a ventilación mecánica en unidades de cuidados intensivos / Incidence and consequences of tracheobronchitis associated with ventilator in ICUs

Introducción: las infecciones respiratorias bajas ocupan el primer lugar entre las infecciones relacionadas con el cuidado sanitario en unidades de cuidados intensivos. Objetivos: describir la incidencia y las consecuencias, sobre estadía y mortalidad, de la traqueobronquitis asociada a ventilación mecánica (TAVM) en UCI. Métodos: estudio multricéntrico, descriptivo, prospectivo y transversal, en 6 UCI de adultos. Se estudiaron 454 pacientes. Las variables de estudio fueron recogidas en 2 bases de datos. Resultados: tasa de incidencia de TAVM: 1,76 por ciento.Con respecto al número total de pacientes con factor de riesgo: 6,06 por ciento, Densidad de incidencia: 7,61 por ciento por 1 000 d con factor de riesgo. Estadía media, TAVM: 13,13 d, pacientes sin IRCS: 5,49 d (p=0,006). Mortalidad, TAVM: 25 por ciento, NAVM: 55,2 por ciento, pacientes sin IRCS: 14,9 por ciento(p=0,000). Conclusiones: la TAVM no es infrecuente en UCI. Su diagnóstico implica aumento de estadía y mortalidad en pacientes ventilados. Se justifica la implementación de medidas de vigilancia y prevención

Introduction: lower respiratory infections rank first among related infections in health care intensive care units. Objectives: to describe the incidence and consequences of stay and mortality of ventilator-associated tracheobronchitis (TAVM) in ICU. Methods: a multicenter, descriptive, prospective and cross-sectional study was conducted in 6 adult ICU. 454 patients were studied. The study variables were collected in two databases. Results: TAVM incidence rate: 1.76 percent, relative to the total number of patients with risk factor: 6.06 percent. Incidence density: 7.61 percent by 1000 d with risk factor. Average stay, TAVM: 13.13 d, patients without IRCS: 5.49 d (p = 0.006). Mortality, TAVM: 25 percent, VAP: 55.2 percent , patients without IRCS: 14.9 percent (p = 0.000). Conclusions: TAVM is not uncommon in ICU. Its diagnosis involves increased stay and its mortality in ventilated patients. The implementation of surveillance and prevention measures is requiered

Pre-treatment with mesenchymal stem cells reduces ventilator-induced lung injury.

Bone marrow-derived mesenchymal stem cells (MSCs) reduce acute lung injury in animals challenged by bleomycin or bacterial lipopolysaccaride. It is not known, however, whether MSCs protect from ventilator-induced lung injury (VILI). This study investigated whether MSCs have a potential role in preventing or modulating VILI in healthy rats subjected to high-volume ventilation. 24 Sprague-Dawley rats (250-300 g) were subjected to high-volume mechanical ventilation (25 mL·kg(-1)). MSCs (5 × 10(6)) were intravenously or intratracheally administered (n=8 each) 30 min before starting over-ventilation and eight rats were MSC-untreated. Spontaneously breathing anesthetised rats (n=8) served as controls. After 3 h of over-ventilation or control the animals were sacrificed and lung tissue and bronchoalveolar lavage fluid (BALF) were sampled for further analysis. When compared with controls, MSC-untreated over-ventilated rats exhibited typical VILI features. Lung oedema, histological lung injury index, concentrations of total protein, interleukin-1ß, macrophage inflammatory protein-2 and number of neutrophils in BALF and vascular cell adhesion protein-1 in lung tissue significantly increased in over-ventilated rats. All these indices of VILI moved significantly towards normalisation in the rats treated with MSCs, whether intravenously or intratracheally. Both local and systemic pre-treatment with MSCs reduced VILI in a rat model.

Selective inhibition of intra-alveolar p55 TNF receptor attenuates ventilator-induced lung injury.

BACKGROUND: Tumour necrosis factor (TNF) is upregulated in the alveolar space early in the course of ventilator-induced lung injury (VILI). Studies in genetically modified mice indicate that the two TNF receptors play opposing roles during injurious high-stretch mechanical ventilation, with p55 promoting but p75 preventing pulmonary oedema. AIM: To investigate the effects of selective inhibition of intra-alveolar p55 TNF receptor on pulmonary oedema and inflammation during ventilator-induced lung injury using a newly developed domain antibody. METHODS: Anaesthetised mice were ventilated with high tidal volume and given an intratracheal bolus of p55-specific domain antibody or anti-TNF monoclonal antibody ('pure' VILI model). As a model of enhanced inflammation, a subclinical dose of lipopolysaccharide (LPS) was included in the intratracheal antibody bolus (LPS+VILI model). Development of lung injury was assessed by respiratory mechanics and blood gases and protein levels in lavage fluid. Flow cytometry was used to determine leucocyte recruitment and alveolar macrophage activation, while lavage fluid cytokines were assessed by ELISA. RESULTS: The ventilation protocol produced deteriorations in respiratory mechanics and gas exchange with increased lavage fluid protein levels in the two models. The p55-specific domain antibody substantially attenuated all of these changes in the 'pure' VILI model, while anti-TNF antibody was ineffective. In the LPS+VILI model, p55 blockade prevented deteriorations in respiratory mechanics and oxygenation and significantly decreased neutrophil recruitment, expression of intercellular adhesion molecule 1 on alveolar macrophages, and interleukin 6 and monocyte chemotactic protein 1 levels in lavage fluid. CONCLUSIONS: Selective inhibition of intra-alveolar p55 TNF receptor signalling by domain antibodies may open new therapeutic approaches for ventilated patients with acute lung injury.

Inflammation and matrix remodeling during repair of ventilator-induced lung injury.

High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.

Neuroimmune regulation of ventilator-induced lung injury.

RATIONALE: Ventilator-induced lung injury (VILI) contributes to the mortality in patients with acute lung injury by increasing inflammation. Recent evidence suggests that stimulation of the cholinergic antiinflammatory pathway may be an attractive way to attenuate inflammatory injury. OBJECTIVES: To determine the role of vagus nerve signaling in VILI and establish whether stimulation of the vagus reflex can mitigate VILI. METHODS: We performed bilateral vagotomy in a mouse model of high-tidal volume-induced lung injury. We performed pharmacological and electrical vagus nerve stimulation in a rat model of VILI following ischemia/reperfusion injury. To determine the contribution of the alpha 7 acetylcholine nicotinic receptor to pulmonary cell injury, we exposed human bronchial epithelial cells to cyclic stretch in the presence of specific agonist or antagonist of the alpha 7 receptor. MEASUREMENTS AND MAIN RESULTS: Vagotomy exacerbates lung injury from VILI in mice as demonstrated by increased wet-to-dry ratio, infiltration of neutrophils, and increased IL-6. Vagal stimulation attenuates lung injury in rats after ischemia/reperfusion injury ventilated with high-volume strategies. Treatment of both mice and rats with the vagus mimetic drug semapimod resulted in decreased lung injury. Vagotomy also increased pulmonary apoptosis, whereas vagus stimulation (electrical and pharmacological) attenuated VILI-induced apoptosis. In vitro studies suggest that vagus-dependent effects on inflammation and apoptosis are mediated via the α7 nicotinc acetylcholine receptor-dependent effects on cyclic stretch-dependent signaling pathways c-jun N-terminal kinase and tumor necrosis factor receptor superfamily, member 6. CONCLUSIONS: Stimulation of the cholinergic antiinflammatory reflex may represent a promising alternative for the treatment of VILI.