Microarray-based analysis of ventilator-induced lung injury

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are a frequent cause of intensive care unit admission, affecting over 200,000 patients in the United States each year. Mechanical ventilation is a life-saving intervention in the setting of ARDS and ALI, but clinical trials have demonstrated that mechanical ventilation with excessive tidal volumes plays a role in promoting and perpetuating lung injury and leads to excess mortality. This process has been labeled ventilator-induced lung injury (VILI), but the molecular mechanisms driving this process and its interactions with predisposing risk factors such as sepsis and chemical injury remain incompletely understood. Genome-wide measurements of gene expression using microarray technology represent a powerful tool to examine the pathophysiology of VILI. Several recent studies have used this approach to study VILI in isolation and associated with endotoxin instillation or saline lavage. These studies and others examining gene expression profiles in epithelial cells subjected to cyclic stretch have provided novel insights on the molecular mechanisms underlying VILI. This review will summarize these findings and discuss implications for future studies.     

Is permissive hypercapnia a beneficial strategy for pediatric acute lung injury?

It is clear that mechanical ventilation strategies influence the course of lung disease, and the choice of a ventilation strategy that avoids volutrauma and atelectrauma is firmly based on experimental literature and clinical experience. The application of a lung-protective strategy with reduced tidal volumes, effective lung recruitment, adequate PEEP to minimize alveolar collapse during expiration, and permissive hypercapnia has been shown to be advantageous in adult patients who have ARDS, although it has not been systematically studied in children. A significant body of literature confirms the beneficial effects of hypercapnic acidemia in the setting of acute lung injury. As a corollary, experimental evidence indicates that buffering hypercapnic acidosis abrogates its protective effects. The use of permissive hypercapnia as part of a lung-protective strategy in children should be accepted and perhaps even desired, provided it does not result in significant hemodynamic instability. This acceptance should be tempered with the recognition that a low-stretch, reduced-tidal volume strategy without hypercapnia has also been shown to improve outcomes in adults who have ARDS and that HFOV can generally provide lung-protective ventilation without necessarily inducing hypercapnia. Thus, a synthesis of the available clinical and research data strongly supports a graded approach to managing patients who have acute lung injury requiring intubation. The highest priority should be a mechanical ventilation strategy that limits the tidal volume, with the allowance of hypercapnia to a degree that does not compromise hemodynamic status.     

Absence of alveolar tears in rat lungs with significant alveolar instability

BACKGROUND: Lung injury associated with the acute respiratory distress syndrome can be exacerbated by improper mechanical ventilation creating a secondary injury known as ventilator-induced lung injury (VILI). We hypothesized that VILI could be caused in part by alveolar recruitment/derecruitment resulting in gross tearing of the alveolus. OBJECTIVES: The exact mechanism of VILI has yet to be elucidated though multiple hypotheses have been proposed. In this study we tested the hypothesis that gross alveolar tearing plays a key role in the pathogenesis of VILI. METHODS: Anesthetized rats were ventilated and instrumented for hemodynamic and blood gas measurements. Following baseline readings, rats were exposed to 90 min of either normal ventilation (control group: respiratory rate 35 min(-1), positive end-expiratory pressure 3 cm H(2)O, peak inflation pressure 14 cm H(2)O) or injurious ventilation (VILI group: respiratory rate 20 min(-1), positive end-expiratory pressure 0 cm H(2)O, peak inflation pressure 45 cm H(2)O). Parameters studied included hemodynamics, pulmonary variables, in vivo video microscopy of alveolar mechanics (i.e. dynamic alveolar recruitment/derecruitment) and scanning electron microscopy to detect gross tears on the alveolar surface. RESULTS: Injurious ventilation significantly increased alveolar instability after 45 min and alveoli remained unstable until the end of the study (electron microscopy after 90 min revealed that injurious ventilation did not cause gross tears in the alveolar surface). CONCLUSIONS: We demonstrated that alveolar instability induced by injurous ventilation does not cause gross alveolar tears, suggesting that the tissue injury in this animal VILI model is due to a mechanism other than gross rupture of the alveolus.     

Hipercapnia permisiva o no permisiva: mecanismos de acción y consecuencias de altos niveles de dióxido de carbono

Acute lung injury is a disease with high incidence of mortality and its treatment is still controversial. Increasing the levels of CO₂ beyond the physiological range has been proposed as a potential protective strategy for patients on mechanical ventilation, as it could moderate the inflammatory response. In this article we review the published evidence on the role of CO₂ during acute lung injury. We conclude that although there are reports suggesting benefits from hypercapnia, more recent evidence suggests that hypercapnia could be deleterious, contributing to worsening of the lung injury     

Conventional mechanical ventilation in acute lung injury and acute respiratory distress syndrome

Acute lung injury and acute respiratory distress syndrome are inflammatory conditions involving a broad spectrum of lung injury from mild respiratory abnormality to severe respiratory derangement. Regardless of cause (direct or indirect lung injury), pulmonary physiology and mechanics are altered, leading to hypoxemic respiratory failure. the use of positive pressure ventilation itself may cause lung injury (ventilator-induced lung injury, or VILI). VILI may amplify preexisting injury, delay lung recovery, and result in adverse outcomes. This article examines the evidence supporting lung-protective ventilation strategies and addresses the methods, outcomes, and potential obstacles to implementation of such approaches.     

Prevention and Amelioration of Rodent Ventilation-Induced Lung Injury with Either Prophylactic or Therapeutic feG Administration

Purpose

Mechanical ventilation is a well-established therapy for patients with acute respiratory failure. However, up to 35% of mortality in acute respiratory distress syndrome may be attributed to ventilation-induced lung injury (VILI). We previously demonstrated the efficacy of the synthetic tripeptide feG for preventing and ameliorating acute pancreatitis-associated lung injury. However, as the mechanisms of induction of injury during mechanical ventilation may differ, we aimed to investigate the effect of feG in a rodent model of VILI, with or without secondary challenge, as a preventative treatment when administered before injury (prophylactic), or as a therapeutic treatment administered following initiation of injury (therapeutic).

Methods

Lung injury was assessed following prophylactic or therapeutic intratracheal feG administration in a rodent model of ventilation-induced lung injury, with or without secondary intratracheal lipopolysaccharide challenge.

Results

Prophylactic feG administration resulted in significant improvements in arterial blood oxygenation and respiratory mechanics, and decreased lung oedema, bronchoalveolar lavage protein concentration, histological tissue injury scores, blood vessel activation, bronchoalveolar lavage cell infiltration and lung myeloperoxidase activity in VILI, both with and without lipopolysaccharide. Therapeutic feG administration similarly ameliorated the severity of tissue damage and encouraged the resolution of injury. feG associated decreases in endothelial adhesion molecules may indicate a mechanism for these effects.

Conclusions

This study supports the potential for feG as a pharmacological agent in the prevention or treatment of lung injury associated with mechanical ventilation.

     

Ventilator-induced lung injury and recommendations for mechanical ventilation of patients with ARDS

Mechanical ventilation is life sustaining and is the standard therapy for acute respiratory failure. The 16th century anatomist Vesalius is often credited for the earliest account of positive-pressure ventilation. In his work De humani corporis fabrica (On the Fabric of the Human Body), he described how an animal could be resuscitated by blowing into a reed inserted into a hole in its trachea. Although positive pressure ventilation using bellows was first used for drowning victims in the 1700s, there were soon concerns that such therapy could in fact be harmful to the lungs. In 1827, Leroy d'Etoille condemned bellows ventilation after discovering that it could lead to emphysema and tension pneumothoraces. Subsequently, positive pressure ventilation would be virtually abandoned for over 100 years. Despite this early concern about the potential for harm from mechanical ventilation, it is only in the last one to two decades that research into so-called ventilator-induced lung injury (VILI) has blossomed. Indeed, although initial studies have focused on which ventilatory parameters are associated with the most (or least) harm, there has been an explosion of research in the last 5 years attempting to delineate the basic cellular mechanisms by which mechanical ventilation injures the lung. Recently, there has been exciting evidence to suggest that lung injury induced by mechanical ventilation may have important systemic consequences, including multi-organ dysfunction. Lastly and most importantly, there is accumulating data from clinical trials in humans that ventilatory strategies designed to avoid VILI can in fact save lives.     

The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury

Mortality rates from acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) range from 30 to 65%. Although mechanical ventilation (MV) may delay mortality in critically ill patients with ALI/ARDS, it may also cause a lung injury that further promotes and perpetuates ALI/ARDS and multiorgan dysfunction syndrome (MODS). Recent studies have demonstrated that lung protective strategies of MV, as compared with the injurious strategy of conventional MV (CMV) can reduce absolute mortality rates during ALI/ARDS. The protective strategies limit tidal volumes and peak/plateau pressures while maximizing positive end-expiratory pressure. The injury to the lung by CMV is characterized histologically by edema, leukocyte extravasation, and endothelial and epithelial damage. Both human and animal studies suggest that alveolar cell deformation from CMV leads to the release of cytokines/chemokines which orchestrate the extravasation, activation, and recruitment of leukocytes, causing ventilator-associated lung injury (VALI) and ventilator-induced lung injury (VILI). Moreover, VALI/VILI can perpetuate the chronic inflammatory response during ALI/ARDS and MODS. This article explores the role of cytokines/chemokines during the pathogenesis of VALI/VILI.     

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.     

Nichtinvasive Beatmung – gestern, heute und morgen

Noninvasive mechanical ventilation (NIV) is used to treat chronic ventilatory insufficiency (CVI) and acute respiratory failure (ARF). Various diseases cause CVI and here home mechanical ventilation (HMV) has become an important treatment option. Clinical improvements due to HMV have been shown for CVI due to restrictive disorders of the rib cage like kyphoscoliosis or posttuberculosis sequelae, with an increase of quality of life, walking distance and a decrease in pulmonary hypertension. Conversely, HMV in patients with COPD is controversial and should be limited to patients with severe hypercapnia, using effective inspiratory pressures which significantly reduce work of breathing. NIV is an important treatment of ARF. Based on the evidence, NIV should be used to prevent intubation in patients with hypercapnic ARF due to COPD exacerbations or acute cardiogenic pulmonary edema, and in immunocompromised patients, as well as to facilitate extubation in patients with COPD who require initial intubation. Weaker evidence supports consideration of NIV in hypoxemic ARF due to severe pneumonia, acute lung injury, or acute respiratory distress syndrome.     

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-1β, 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.     

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.     

巨噬细胞炎症蛋白与呼吸机所致肺损伤

呼吸机所致肺损伤（ventilator induced lung injury,VILI）是机械通气过程中的严重的并发症,也是促使患者病情加重和死亡的重要因素。巨噬细胞炎症蛋白（macrophage inflammatory protein,MIP）是近年来发现的一种参与机体炎症反应和免疫反应的趋化性细胞因子,其在VILI中的作用日益受到人们的关注,文献报道越来越多。本文就其分子结构、细胞来源、生物学活性、自身表达调节以及与VILI的关系作一综述。     

Adenosine triphosphate-dependent calcium signaling during ventilator-induced lung injury is amplified by hypercapnia

Adenosine triphosphate (ATP) is released by alveolar epithelial cells during ventilator-induced lung injury (VILI) and regulates fluid transport across epithelia. High CO(2) levels are observed in patients with "permissive hypercapnia," which inhibits alveolar fluid reabsorption (AFR) in alveolar epithelial cells. The authors set out to determine whether VILI affects AFR and whether the purinergic pathway is modulated in cells exposed to hypercapnia. Control group was compared against VILI (tidal volume [Vt] = 35 mL/kg, zero positive end-expiratory pressure [PEEP]) and protective ventilation (Vt = 6 mL/kg, PEEP = 10 cm H(2)O) groups. Lung mechanics, histology, and AFR were evaluated. Alveolar epithelial cells (AECs) were loaded with Fura 2-AM to measure intracellular calcium in the presence ATP (10 μM) at 5% or 10% CO(2) as compared with baseline. High tidal volume ventilation impairs lung mechanics and AFR. Hypercapnia (HC) increases intracellular calcium levels in response to ATP stimulation. HC + ATP is the most detrimental combination decreasing AFR. Purinergic signaling in AECs is modulated by high CO(2) levels via increased cytosolic calcium. The authors reason that this modulation may play a role in the impairment of alveolar epithelial functions induced by hypercapnia.     

Clinical outcome of respiratory failure in patients requiring prolonged (greater than 24 hours) mechanical ventilation

Patients requiring prolonged (greater than 24 hours) mechanical ventilation have various conditions that result in respiratory failure. All patients requiring prolonged mechanical ventilation were subdivided into the following six groups: uncomplicated acute lung injury; respiratory failure complicated by multisystem failure; previous lung disease; trauma; other medical causes; and routine postoperative ventilation. During a one-year period, 327 patients required prolonged mechanical ventilation; acute lung injury and chronic obstructive pulmonary disease were the predominant conditions. Sepsis was both the major predisposing factor for and complication of acute lung injury. Mortality for patients with acute lung injury was 40 percent in the uncomplicated group and 81 percent in patients with acute lung injury complicated by multisystem failure. Acute respiratory failure in association with acute renal failure had a mortality of 89 percent. Number of organ systems involved also correlated with mortality. In patients with chronic obstructive pulmonary disease and pneumonitis or retained secretions, mortality was lower (30 percent), but a significant percentage of these patients (43 percent) became ventilator-dependent. Ventilator dependence did not significantly increase mortality during the course of respiratory failure.     

Synthetic RGDS peptide attenuates mechanical ventilation-induced lung injury in rats

Pulmonary inflammation is the key pathological presentation of mechanical ventilation-induced lung injury (VILI), and synthetic RGDS peptide has been suggested to attenuate pulmonary inflammation. The present study aimed to determine whether RGDS peptide has protective effects on VILI. Rats received 4 hours of high tidal volume mechanical ventilation with or without pretreatment with RGDS. Rats that were kept on spontaneous respiration served as controls. At the end of 4 hours, rats that received 4 hours of mechanical ventilation exhibited serious pulmonary pathological changes, more polymorphonulear and mononuclear leukocyte recruitment, more tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) production, higher total protein contents in the bronchoalveolar lavage fluids (BALFs) and more lung phosphorylation of integrin β3 and nuclear factor-κB inhibitor (I-κB), and increased NF-κB p65 binding activity than did the control group. Administration of RGDS peptide tended to significantly inhibit all these changes induced by mechanical ventilation. These results suggested that RGDS pretreatment might improve VILI in rats by attenuating inflammatory cascade related to integrin αVβ3 and NF-κB.     

Systemic microvascular leak in an in vivo rat model of ventilator-induced lung injury

Positive pressure mechanical ventilation has significant systemic effects, but the systemic effects associated with ventilator-induced lung injury (VILI) are unexplored. We hypothesized that VILI would cause systemic microvascular leak that is dependent on nitric oxide synthase (NOS) expression. Rats were ventilated with room air at 85 breaths/minute for 2 hours with either VT 7 or 20 ml/kg. Kidney microvascular leak, which was assessed by measuring 24-hour urine protein and Evans blue dye, was used as a marker of systemic microvascular leak. A significant microvascular leak occurred in both lung and kidney with large VT (20 ml/kg) ventilation. Injection of 0.9% NaCl corrected the hypotension and the decreased cardiac output related to large VT, but it did not attenuate microvascular leak of lung and kidney. Serum vascular endothelial growth factor was significantly elevated in large VT groups. Endothelial NOS expression significantly increased in the lung and kidney tissue with large VT ventilation but not inducible NOS. The NOS inhibitor, N-nitro-L-arginine methyl ester, attenuated the microvascular leak of lung and kidney and the proteinuria with large VT ventilation. Endothelial NOS may mediate the systemic microvascular leak of the present model of VILI.     

Noninvasive face mask ventilation in patients with acute respiratory failure

Noninvasive face mask ventilation has been used successfully in patients with paralytic respiratory failure. This study evaluated whether noninvasive face mask ventilation can be used for patients with acute respiratory failure due to intrinsic lung disease. Six patients with hypercapnia and four with hypoxemic acute respiratory failure met clinical and objective criteria for mechanical ventilation, which was delivered with pressure control and pressure support via a tightly strapped, clear face mask. No patient terminated the study because of inability to deliver adequate ventilation or to improve oxygen exchange; three eventually required endotracheal intubation. The mask was generally well tolerated. All patients had a nasogastric tube placed on suction, and none vomited or aspirated. The mean duration of treatment was 33 h (range, 3 to 88). The physiologic response was considered similar to that which would have been achieved with conventionally delivered ventilation. Noninvasive face mask ventilation may have a role in managing respiratory failure.     

慢性阻塞性肺疾病合并呼吸衰竭小潮气量机械通气治疗

目的 研究慢性阻塞性肺疾病(COPD)合并呼吸衰竭患者进行小潮气量机械通气的肺保护效果。方法 30例COPD合并呼吸衰竭患者分为小潮气量组15例和常规潮气量通气组15例，观察两组思者机械通气期间发生气压伤的情况，机械通气时间，平均住院时间及最终预后情况。结果 两组患者在存活率方面无显著差异，小潮气量组气压伤发生率、机械通气时间、住院时间明显少于常规通气组。结论 对于COPD合并呼吸衰竭患者，选用小潮气量进行机械通气，可以减轻机械通气相关性肺损伤，缩短机械通气时间和住院时间。     

Clinical features and outcome in patients with acute asthma presenting with hypercapnia

To determine the clinical features and outcome of patients with hypercapnia from acute asthma, we examined 229 (62 men, 167 women) consecutive episodes of acute asthma over a 6-yr period. Sixty-one episodes were associated with hypercapnia at presentation (PaCO2 greater than 38 mm Hg). Men more commonly presented with hypercapnia: 31 of 62 (50%) men with acute asthma had hypercapnia compared with only 30 of 167 (18%) women (p less than 0.001). Patients with hypercapnia had a longer duration of chronic asthma and were more likely to be steroid-dependent. Hypercapnic patients had greater airway obstruction, respiratory rate, and pulsus paradoxus than did nonhypercapnic patients. Findings of a quiet chest on auscultation, inability to talk, and cyanosis also suggested the presence of hypercapnia. Five hypercapnic patients required mechanical ventilation, but hypercapnia did not prolong hospitalization. In nonventilated patients, hypercapnia resolved in a mean time of 5.9 h; 50% of hypercapnic episodes resolved by 4 h, and all resolved by 16 h. No patient presenting with normocapnia progressed to hypercapnia with therapy, and there were no deaths in either the hypercapnic group or the nonhypercapnic group. In patients with more than one admission, the PaCO2 of one episode correlated with the PaCO2 on a subsequent admission, suggesting a role for individual variation in ventilatory control. With appropriate medical therapy, most patients with hypercapnia from acute asthma have rapid reversibility, and mechanical ventilation usually can be avoided. However, these patients require close inhospital observation until it is certain that the acute asthmatic episode has resolved.