Mechanisms Of Ventilator-induced Lung Injury Research Articles

Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury

Lung inflammatory responses in the absence of infection are considered to be one of primary mechanisms of ventilator-induced lung injury. Here, we determined the role of calpain in the pathogenesis of lung inflammation attributable to mechanical ventilation. Male C57BL/6J mice were subjected to high (28 ml/kg) tidal volume ventilation for 2 h in the absence and presence of calpain inhibitor I (10 mg/kg). To address the isoform-specific functions of calpain 1 and calpain 2 during mechanical ventilation, we utilized a liposome-based delivery system to introduce small interfering RNAs targeting each isoform in pulmonary vasculature in vivo. Mechanical ventilation with high tidal volume induced rapid (within minutes) and persistent calpain activation and lung inflammation as evidenced by neutrophil recruitment, production of TNF-α and IL-6, pulmonary vascular hyperpermeability, and lung edema formation. Pharmaceutical calpain inhibition significantly attenuated these inflammatory responses caused by lung hyperinflation. Depletion of calpain 1 or calpain 2 had a protective effect against ventilator-induced lung inflammatory responses. Inhibition of calpain activity by means of siRNA silencing or pharmacological inhibition also reduced endothelial nitric oxide (NO) synthase (NOS-3)-mediated NO production and subsequent ICAM-1 phosphorylation following high tidal volume ventilation. These results suggest that calpain activation mediates early lung inflammation during ventilator-induced lung injury via NOS-3/NO-dependent ICAM-1 phosphorylation and neutrophil recruitment. Inhibition of calpain activation may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.

New images, new insights for VILI

prioritization of high-volume vs. low-volume mechanisms of ventilator-induced lung injury (VILI) is an issue that is often discussed and debated in clinical ventilator management. Abundant laboratory studies ([7][1]), as well as several prominent clinical studies ([1][2], [3][3], [14][4], [19][5]),

Linking lung function and inflammatory responses in ventilator-induced lung injury

Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1β, and TNF-α) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field.

Toll-like Receptor 4-Myeloid Differentiation Factor 88 Signaling Contributes to Ventilator-induced Lung Injury in Mice

The mechanisms of ventilator-induced lung injury, an iatrogenic inflammatory condition induced by mechanical ventilation, are not completely understood. Toll-like receptor 4 (TLR4) signaling via the adaptor protein myeloid differentiation factor 88 (MyD88) is proinflammatory and plays a critical role in host immune response to invading pathogen and noninfectious tissue injury. The role of TLR4-MyD88 signaling in ventilator-induced lung injury remains incompletely understood. Mice were ventilated with low or high tidal volume (HTV), 7 or 20 ml/kg, after tracheotomy for 4 h. Control mice were tracheotomized without ventilation. Lung injury was assessed by: alveolar capillary permeability to Evans blue albumin, wet/dry ratio, bronchoalveolar lavage analysis for cell counts, total proteins and cytokines, results of histopathological examination of the lung, and plasma cytokine levels. Wild-type mice subjected to HTV had increased pulmonary permeability, inflammatory cell infiltration/lung edema, and interleukin-6/macrophage-inflammatory protein-2 in the lavage compared with control mice. In HTV, levels of inhibitor of kappaB alpha decreased, whereas phosphorylated extracellular signal-regulated kinases increased. TLR4 mutant and MyD88 mice showed markedly attenuated response to HTV, including less lung inflammation, pulmonary edema, cell number, protein content, and the cytokines in the lavage. Furthermore, compared with wild-type mice, both TLR4 mutant and MyD88 mice had significantly higher levels of inhibitor of kappaB alpha and reduced extracellular signal-regulated kinase phosphorylation after HTV. TLR4-MyD88 signaling plays an important role in the development of ventilator-induced lung injury in mice, possibly through mechanisms involving nuclear factor-kappaB and mitogen-activated protein kinase pathways.

Year in review 2008: Critical Care - respirology

Original research contributions published in Critical Care in 2008 in the fields of respirology and critical care medicine are summarized. Eighteen articles were grouped into the following categories: acute lung injury and acute respiratory distress syndrome, mechanical ventilation, mechanisms of ventilator-induced lung injury, and tracheotomy decannulation and non-invasive ventilation.

Marcos F. Vidal Melo, M.D., Ph.D., Recipient of the 2007 Presidential Scholar Award

Marcos F. Vidal Melo, M.D., Ph.D., Recipient of the 2007 Presidential Scholar Award

Ventilator-induced lung injury and mechanotransduction: why we shall care?

Mechanotransduction holds the underlying mechanisms of ventilator-induced lung injury. Research on this subject, however, could be difficult for clinicians, especially when results are controversial. A recent study by Li and co-workers is used as an example, to explain how to critically read literatures related to basic science and how to understand the limitation of experimental studies.

Pathogenetic Significance of Biological Markers of Ventilator-Associated Lung Injury in Experimental and Clinical Studies

For patients with acute lung injury, positive pressure mechanical ventilation is life saving. However, considerable experimental and clinical data have demonstrated that how clinicians set the tidal volume, positive end-expiratory pressure, and plateau airway pressure influences lung injury severity and patient outcomes including mortality. In order to better identify ventilator-associated lung injury (VALI), clinical investigators have sought to measure blood-borne and airspace biological markers of VALI. At the same time, several laboratory-based studies have focused on biological markers of inflammation and organ injury in experimental models in order to clarify the mechanisms of ventilator-induced lung injury (VILI) and VALI. This review summarizes data on biological markers of VALI and VILI from both clinical and experimental studies with an emphasis on markers identified in patients and in the experimental setting. This analysis suggests that measurement of some of these biological markers may be of value in diagnosing VALI and in understanding its pathogenesis.

Differential Regulation of Pulmonary Endothelial Monolayer Integrity by Varying Degrees of Cyclic Stretch

Ventilator-induced lung injury is a life-threatening complication of mechanical ventilation at high-tidal volumes. Besides activation of proinflammatory cytokine production, excessive lung distension directly affects blood-gas barrier and lung vascular permeability. To investigate whether restoration of pulmonary endothelial cell (EC) monolayer integrity after agonist challenge is dependent on the magnitude of applied cyclic stretch (CS) and how these effects are linked to differential activation of small GTPases Rac and Rho, pulmonary ECs were subjected to physiologically (5% elongation) or pathologically (18% elongation) relevant levels of CS. Pathological CS enhanced thrombin-induced gap formation and delayed monolayer recovery, whereas physiological CS induced nearly complete EC recovery accompanied by peripheral redistribution of focal adhesions and cortactin after 50 minutes of thrombin. Consistent with differential effects on monolayer integrity, 18% CS enhanced thrombin-induced Rho activation, whereas 5% CS promoted Rac activation during the EC recovery phase. Rac inhibition dramatically attenuated restoration of monolayer integrity after thrombin challenge. Physiological CS preconditioning (5% CS, 24 hours) enhanced EC paracellular gap resolution after step-wise increase to 18% CS (30 minutes) and thrombin challenge. These results suggest a critical role for the CS amplitude and the balance between Rac and Rho in mechanochemical regulation of lung EC barrier.

How to ventilate patients with acute lung injury and acute respiratory distress syndrome

The purpose of this paper is to review the mechanisms of ventilator-induced lung injury as a basis for providing the less damaging mechanical ventilation in patients with acute respiratory failure. In normal lungs, high tidal volume causes an immediate gene upregulation and downregulation. Although the importance of alveolar inflammatory reaction is well known, recent findings suggest the potential role of airway distension in causing ventilator-induced lung injury. The initial activation has been shown to occur in the airways, accounting for the damages induced by high peak flow. The healthier lung regions are more exposed to the injury, since they may be subjected to strain. Challenge with endotoxin enhances in a synergistic manner the pulmonary inflammation induced by mechanical ventilation. However, mechanical strain and endotoxin seem to trigger lung inflammation through two different pathways. Despite convincing experimental and clinical evidences of lung injury, the clinical implementation of low tidal volume ventilation is still limited and has not yet become part of standard clinical practice. Setting positive end-expiratory pressure remains an open problem because the ALVEOLI study did not provide any exhaustive answers, likely because of methodologic problems and, unphysiologic design. Gentle lung ventilation must be standard practice. Because stress and strain are the triggers of ventilator-induced lung injury, their clinical equivalents should be measured (transpulmonary pressure and the ratio between tidal volume and end-expiratory lung volume). For a rational application of positive end-expiratory pressure, the potential for recruitment in any single patient should be estimated.

Ventilator-induced Lung Injury: Role of Protein-Protein Interaction in Mechanosensation

For critically ill patients, mechanical ventilation is a commonly used life-supporting modality, but ventilation per se could also induce lung injury. Mechanical forces-induced cell damage and inflammatory responses have been considered as one of major mechanisms of ventilator-induced lung injury (VILI). Mechanotransduction related to VILI has been the subject of several recent reviews, which focused on the mechanical force-induced signal cascades. In this article, we will discuss the initial processes, mechanosensation, by which physical forces can be sensed by the cells and converted into biochemical reactions for intracellular signaling. In addition to suggested mechanosensors, such as stretch-activated ion channels, extracellular matrix-integrin-cytoskeleton complex, and growth factor receptors, we would like to introduce a new concept of intracellular mechanosensation through specific protein-protein interactions. Proteins associated with the cytoskeleton could transmit physical forces, and bind with signaling-related enzymes through specific functional domains and motifs. These interactions could lead to activation or inactivation of the enzymes, and subsequently alter the signal transduction processes in the cells. Understanding these mechanisms will help us to develop new strategies for the management of VILI.

Mechanisms of ventilator-induced lung injury: the clinician's perspective.

In the present issue of Critical Care, Frank and Matthay review the physiologic mechanisms that lead to ventilator-induced lung injury. Our greater understanding of basic physiologic principles has already had a major impact on the treatment of critically ill patients. Novel strategies to limit ventilator-induced lung injury have now been shown to improve survival. However, there has been debate in the literature regarding the safety and efficacy of the Acute Respiratory Distress Syndrome (ARDS) Network study protocol in reducing ventilator-induced lung injury. The issues surrounding the ARDS Network protocol and a recent meta-analysis criticizing its use are presented. As clinicians, we now have the responsibility to ensure that our patients benefit from these recent developments.

Mechanisms of ventilator-induced lung injury in premature infants

Mechanical ventilation in premature infants may injure the lungs or exacerbate the pre-existing condition that led to the need for mechanical ventilation. Ventilator-induced lung injury (VILI) may be associated with alveolar structural damage, pulmonary oedema, inflammation, and fibrosis. This injury is not uniform and is associated with surfactant dysfunction. Recovery from VILI includes clearance of pulmonary oedema and alveolar structural repair. Mechanisms of VILI include high airway pressure (barotrauma), large gas volumes (volutrauma), alveolar collapse and re-expansion (atelectotrauma), and increased inflammation (biotrauma). Injury to the lung may lead to other organ dysfunction. The premature lung is more susceptible to VILI, and lung injury may exacerbate the disturbance of lung development that occurs after birth. Therapies targeting specific processes in lung injury, and which complement the protective ventilator management strategies to avoid atelectotrauma and lung overdistension are an area of active research.

Lung Protective Ventilation Strategies

While traditional ventilation approaches are appropriate for the patient without significant lung disease and only requiring short-term mechanical ventilatory support, the strategy should be altered for the patient with severe lung disease. Research on the mechanisms of ventilator-induced lung injury has led to the development of mechanical ventilation strategies that imrove patient outcomes. The trend toward using lower tidal volmes, limited airway pressures, and PEEP have produced imroved outcome results. Predictive indices of outcome using laboratory values, biologic markers, and mediators of lung inury are being evaluated for early identification of patients at risk for lung injury. Nonconventional ventilatory approaches, such as noninvasive positive pressure ventilation and high freuency ventilation, as well as adjunctive therapies (inhaled niric oxide and extracorporeal circulation) are being explored as alternatives in ARDS and ALI. While more clinical studies outine outcomes in specific subgroups of patients, the ventilatoy strategy should continually be revised at the bedside.

Invited review: mechanisms of ventilator-induced lung injury: a perspective.

Despite advances in critical care, the mortality rate in patients with acute lung injury remains high. Furthermore, most patients who die do so from multisystem organ failure. It has been postulated that ventilator-induced lung injury plays a key role in determining the negative clinical outcome of patients exposed to mechanical ventilation. How mechanical ventilation exerts its detrimental effect is as of yet unknown, but it appears that overdistension of lung units or shear forces generated during repetitive opening and closing of atelectatic lung units exacerbates, or even initiates, significant lung injury and inflammation. The term "biotrauma" has recently been elaborated to describe the process by which stress produced by mechanical ventilation leads to the upregulation of an inflammatory response. For mechanical ventilation to exert its deleterious effect, cells are required to sense mechanical forces and activate intracellular signaling pathways able to communicate the information to its interior. This information must then be integrated in the nucleus, and an appropriate response must be generated to implement and/or modulate its response and that of neighboring cells. In this review, we present a perspective on ventilator-induced lung injury with a focus on mechanisms and clinical implications. We highlight some of the most recent findings, which we believe contribute to the generation and propagation of ventilator-induced lung injury, placing a special emphasis on their implication for future research and clinical therapies.

Mechanisms of ventilator-induced lung injury

To describe the physiologic mechanisms of ventilator-induced lung injury and to define the major ventilator and host-dependent risk factors that contribute to such injury. Basic science and clinical studies related to ventilator-induced barotrauma and lung pathophysiology. Emphasis on controlled, experimental studies and clinical studies related to specific mechanisms. Preference given to studies with quantitative end-points to assess damage and causal relationships. Related studies are integrated to obtain basic mechanisms of damage where possible. Ventilation with high tidal volumes can increase vascular filtration pressures; produce stress fractures of capillary endothelium, epithelium, and basement membrane; and cause lung rupture. Mechanical damage leads to leakage of fluid, protein, and blood into tissue and air spaces or leakage of air into tissue spaces. This process is followed by an inflammatory response and possibly a reduced defense against infection. Predisposing factors for lung injury are high peak inspiratory volumes and pressures, a high mean airway pressure, structural immaturity of lung and chest wall, surfactant insufficiency or inactivation, and preexisting lung disease. Damage can be minimized by preventing overdistention of functional lung units during therapeutic ventilation.