Overview of ventilator-induced lung injury mechanisms

PURPOSE OF REVIEW: Mechanical ventilation is the main supportive therapy for patients with acute respiratory distress syndrome. As with any therapy, mechanical ventilation has side effects and may induce lung injury. This review will focus on stretch-dependent activation of alveolar epithelial and endothelial cells and polymorphonuclear leukocytes, and apoptosis/necrosis balance. RECENT FINDINGS: The past year has seen important research in the area of mechanotransduction and lung native immunity, suggesting further mechanisms of lung inflammation and injury in ventilator-induced lung injury. Research in the past year has also stressed the importance of inflammatory response by alveolar cells and role of polymorphonuclear leukocytes in stretch-induced lung injury and has suggested a role for apoptosis in the maintenance of the alveolar epithelium. SUMMARY: The proportion of patients receiving protective ventilatory strategies remains modest. If efforts to minimize the iatrogenic consequences of mechanical ventilation are to succeed, there must be a greater understanding of the signal transduction mechanisms and the development of potential pharmacologic targets to modulate the molecular and cellular effects of lung stretch.     

Bench-to-bedside review: microvascular and airspace linkage in ventilator-induced lung injury

Experimental and clinical evidence point strongly toward the potential for microvascular stresses to influence the severity and expression of ventilator associated lung injury. Intense microvascular stresses not only influence edema but predispose to structural failure of the gas–blood barrier, possibly with adverse consequences for the lung and for extrapulmonary organs. Taking measures to lower vascular stress may offer a logical, but as yet unproven, extension of a lung-protective strategy for life support in ARDS.     

Bench-to-bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury

Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non-infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill.     

Metformin attenuates ventilator-induced lung injury

ABSTRACT: INTRODUCTION: Diabetic 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. METHODS: Twenty-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 cmH2O, tidal volume ≈17 mL/Kg) or protective (peak airway pressure 11 cmH2O, 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. RESULTS: High-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. CONCLUSIONS: Pretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model.     

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.     

Science review: Apoptosis in acute lung injury

Apoptosis is a process of controlled cellular death whereby the activation of specific death-signaling pathways leads to deletion of cells from tissue. The importance of apoptosis resides in the fact that several steps involved in the modulation of apoptosis are susceptible to therapeutic intervention. In the present review we examine two important hypotheses that link apoptosis with the pathogenesis of acute lung injury in humans. The first of these, namely the 'neutrophilic hypothesis', suggests that during acute inflammation the cytokines granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor prolong the survival of neutrophils, and thus enhance neutrophilic inflammation. The second hypothesis, the 'epithelial hypothesis', suggests that epithelial injury in acute lung injury is associated with apoptotic death of alveolar epithelial cells triggered by soluble mediators such as soluble Fas ligand. We also review recent studies that suggest that the rate of clearance of apoptotic neutrophils may be associated with resolution of neutrophilic inflammation in the lungs, and data showing that phagocytosis of apoptotic neutrophils can induce an anti-inflammatory phenotype in activated alveolar macrophages.     

Hypercapnic acidosis in ventilator-induced lung injury

Rationale  

Permissive hypercapnia is established in lung injury management. Therapeutic hypercapnia causes benefit or harm, depending on the context. Ventilator-associated lung injury has a wide spectrum of candidate mechanisms, affording multiple opportunities for intervention such as hypercapnia to exert benefit or harm.     

Hydrogen inhalation ameliorates ventilator-induced lung injury

Introduction  

Mechanical ventilation (MV) can provoke oxidative stress and an inflammatory response, and subsequently cause ventilator-induced lung injury (VILI), a major cause of mortality and morbidity of patients in the intensive care unit. Inhaled hydrogen can act as an antioxidant and may be useful as a novel therapeutic gas. We hypothesized that, owing to its antioxidant and anti-inflammatory properties, inhaled hydrogen therapy could ameliorate VILI.     

Animal model of unilateral ventilator-induced lung injury

Objective To design, implement, and test a selective lung ventilator for setting a rat model of unilateral ventilator-induced lung injury (VILI).Design and setting Interventional animal study in a university laboratory for animal research.Subjects Anesthetized and paralyzed male Wistar rats.Interventions A selective ventilator designed to apply varying tidal volume, PEEP, and breathing gas to each lung of the rat was implemented and evaluated. Five control animals were ventilated at 7 ml/kg (3.5 ml/kg each lung). Unilateral VILI was induced in six animals subjected to selective ventilation (3.5 ml/kg in one lung and 15 ml/kg in the other lung). After 3 h of ventilation the animals were killed and the lungs excised.Measurements and results Lung edema was assessed by means of the ratio between wet and dry lung weights. No significant differences were found in lungs of control animals (5.16±0.22 and 4.96±0.25), but the W/D ratio in the over ventilated lung (8.98±3.80) was significantly greater than that in the normally ventilated lung (4.76±0.15), indicating selective induction of lung edema by over stretch.Conclusions This selective ventilator can be implemented into a rat model of unilateral VILI to gain further insight into the mechanisms of pulmonary injury induced by different ventilatory strategiesThis work was supported in part by grants from Ministerio de Ciencia y Tecnologia (SAF 2002-03616 and SAF 2003-01334) and Ministerio de Sanidad y Consumo (Red GIRA-G03/063 and Red RESPIRA-C03/11).     

Heat shock proteins and ventilator-induced lung injury

In this review, we discuss the heat shock response, a specific example of gene expression that has been studied over the past 25 years, and its relevance to acute lung injury and other critical conditions. The heat shock response has been observed in virtually all organisms and involves the rapid induction of a set of highly conserved genes that encode heat shock proteins (HSPs). The HSP70 family represents the most prominent eukaryotic group of HSPs. It has been suggested that members of the HSP70 family act in the protection of cellular damage by binding to denatured or abnormal proteins after heat shock, thereby preventing protein aggregation. The capacity of HSPs to subserve cytoprotection has produced considerable interest from the perspective of elucidating the pathophysiology of organ damage and dysfunction. Several studies support the hypothesis that HSPs are cytoprotective In addition, recent investigations have demonstrated that HSP70 is released into the systemic circulation and is involved in the activation of innate immunity.     

Simvastatin attenuates ventilator-induced lung injury in mice

Introduction

Different isoforms of nitric oxide synthases (NOS) and determinants of oxidative/nitrosative stress play important roles in the pathophysiology of pulmonary dysfunction induced by acute lung injury (ALI) and sepsis. However, the time changes of these pathogenic factors are largely undetermined.

Methods

Twenty-four chronically instrumented sheep were subjected to inhalation of 48 breaths of cotton smoke and instillation of live Pseudomonas aeruginosa into both lungs and were euthanized at 4, 8, 12, 18, and 24 hours post-injury. Additional sheep received sham injury and were euthanized after 24 hrs (control). All animals were mechanically ventilated and fluid resuscitated. Lung tissue was obtained at the respective time points for the measurement of neuronal, endothelial, and inducible NOS (nNOS, eNOS, iNOS) mRNA and their protein expression, calcium-dependent and -independent NOS activity, 3-nitrotyrosine (3-NT), and poly(ADP-ribose) (PAR) protein expression.

Results

The injury induced severe pulmonary dysfunction as indicated by a progressive decline in oxygenation index and concomitant increase in pulmonary shunt fraction. These changes were associated with an early and transient increase in eNOS and an early and profound increase in iNOS expression, while expression of nNOS remained unchanged. Both 3-NT, a marker of protein nitration, and PAR, an indicator of DNA damage, increased early but only transiently.

Conclusions

Identification of the time course of the described pathogenetic factors provides important additional information on the pulmonary response to ALI and sepsis in the ovine model. This information may be crucial for future studies, especially when considering the timing of novel treatment strategies including selective inhibition of NOS isoforms, modulation of peroxynitrite, and PARP.     

Effects of body temperature on ventilator-induced lung injury

PURPOSE: To evaluate the effects of body temperature on ventilator-induced lung injury. MATERIAL AND METHODS: Thirty-four male Sprague-Dawley rats were randomized into 6 groups based on their body temperature (normothermia, 37 +/- 1 degrees C; hypothermia, 31 +/- 1 degrees C; hyperthermia, 41 +/- 1 degrees C). Ventilator-induced lung injury was achieved by ventilating for 1 hour with pressure-controlled ventilation mode set at peak inspiratory pressure (PIP) of 30 cmH2O (high pressure, or HP) and positive end-expiratory pressure (PEEP) of 0 cmH2O. In control subjects, PIP was set at 14 cmH2O (low pressure, or LP) and PEEP set at 0 cmH2O. Systemic chemokine and cytokine (tumor necrosis factor alpha , interleukin 1 beta , interleukin 6, and monocyte chemoattractant protein 1) levels were measured. The lungs were assessed for histological changes. RESULTS: Serum chemokines and cytokines were significantly elevated in the hyperthermia HP group compared with all 3 groups, LP (control), normothermia HP, and hypothermia HP. Oxygenation was better but not statistically significant in hypothermia HP compared with other HP groups. Cumulative mean histology scores were higher in hyperthermia HP and normothermia HP groups compared with control and normothermia HP groups. CONCLUSIONS: Concomitant hyperthermia increased systemic inflammatory response during HP ventilation. Although hypothermia decreased local inflammation in the lung, it did not completely attenuate systemic inflammatory response associated with HP ventilation.     

Glucocorticoid suppresses neutrophil activation in ventilator-induced lung injury

OBJECTIVE: To investigate, in a rat model, the role of the Mac-1/ICAM-1 pathway and the anti-inflammatory activity of steroid in ventilator-induced lung injury. DESIGN: Prospective, randomized controlled study. SETTING: Animal investigation using Wistar rats. INTERVENTION: Rats in three randomly assigned groups of 18, a total of 54 animals, were subject to the following: Two groups received high peak inspiratory pressure (35 cm H2O) ventilation after pretreatment with methylprednisolone (high-methylprednisolone group) or pretreatment with methylprednisolone vehicle (high-vehicle group). The third group of animals received low peak inspiratory pressure (7 cm H2O) ventilation after pretreatment with methylprednisolone vehicle (low-vehicle group). Except for animals previously killed to establish baseline values, after 40 mins of mechanical ventilation, the animals in each group were killed. Some animals provided histological samples, and the rest received total lung lavage. MEASUREMENT: We measured flow cytometry of lavage fluid, cell counts of tissue samples, and pressure-volume curves before and after mechanical ventilation. RESULTS: In the groups that received high peak inspiratory pressure ventilation, both the number of neutrophils that infiltrated the lungs and the expression of Mac-1 and ICAM-1 on neutrophils and macrophages increased significantly more than in the low-vehicle group. Static lung compliance was reduced in the high peak inspiratory pressure groups. In the high peak inspiratory pressure groups, there were significantly fewer neutrophils in samples from the high-methylprednisolone group (0.412 +/- 0.1 x 10(5)) than from the high-vehicle group (1.10 +/- 0.1 x 10(5); p < .05). The high-vehicle group showed greater expression of CD11b on neutrophils, but this was significantly decreased by methylprednisolone (mean fluorescence intensity: high-vehicle, 118.4 +/- 34.3; high-methylprednisolone, 25.8 +/- 4.2; p < .05). The lung mechanics measured by pressure-volume curve analysis were deteriorated less in the high-methylprednisolone group. CONCLUSION: Our study suggests that a neutrophil-endothelium interaction via the Mac-1/ICAM-1 pathway is involved in the activation and recruitment of neutrophils in ventilator-induced lung injury. Activation and recruitment of neutrophils were lessened by pretreatment with methylprednisolone, which might have contributed to the improvement of lung dysfunction after mechanical ventilation.     

Neonatal lung remodeling: structural, inflammatory, and ventilator-induced injury

The developing lung is subject to events, both prenatal and postnatal, that alter the normal developmental process. The degree of insult or injury affects how the lung functions at birth and then responds to the insult throughout childhood. In this article, only 3 of the influences are examined: structural, inflammatory, and mechanical. It is recognized that there is a plethora of other factors that influence lung remodeling.     

Lack of phosphoinositide 3-kinase-gamma attenuates ventilator-induced lung injury

OBJECTIVE: G protein-coupled receptors may up-regulate the inflammatory response elicited by ventilator-induced lung injury but also regulate cell survival via protein kinase B (Akt) and extracellular signal regulated kinases 1/2 (ERK1/2). The G protein-sensitive phosphoinositide-3-kinase gamma (PI3Kgamma) regulates several cellular functions including inflammation and cell survival. We explored the role of PI3Kgamma on ventilator-induced lung injury. DESIGN: Prospective, randomized, experimental study. SETTING: University animal research laboratory. SUBJECTS: Wild-type (PI3Kgamma), knock-out (PI3Kgamma ), and kinase-dead (PI3Kgamma) mice. INTERVENTIONS: Three ventilatory strategies (no stretch, low stretch, high stretch) were studied in an isolated, nonperfused model of acute lung injury (lung lavage) in PI3Kgamma, PI3Kgamma, and PI3Kgamma mice. MEASUREMENTS AND MAIN RESULTS: Reduction in lung compliance, hyaline membrane formation, and epithelial detachment with high stretch were more pronounced in PI3Kgamma than in PI3Kgamma and PI3Kgamma (p < .01). Inflammatory cytokines and IkBalpha phosphorylation with high stretch did not differ among PI3Kgamma, PI3Kgamma, and PI3Kgamma. Apoptotic index (terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling) and caspase-3 (immunohistochemistry) with high stretch were larger (p < .01) in PI3Kgamma and PI3Kgamma than in PI3Kgamma. Electron microscopy showed that high stretch caused apoptotic changes in alveolar cells of PI3Kgamma mice whereas PI3Kgamma mice showed necrosis. Phosphorylation of Akt and ERK1/2 with high stretch was more pronounced in PI3Kgamma than in PI3Kgamma and PI3Kgamma (p < .01). CONCLUSIONS: Silencing PI3Kgamma seems to attenuate functional and morphological consequences of ventilator-induced lung injury independently of inhibitory effects on cytokines release but through the enhancement of pulmonary apoptosis.