Showing papers by "Michael A. Matthay published in 2005"

Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury.

Abstract: Objectives:To evaluate the association between interleukin-6, interleukin-8, and interleukin-10 and clinical outcomes including mortality in patients with acute lung injury and to determine whether lower tidal volume ventilation was associated with a decrease in plasma cytokines in patients with acu

Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management.

Abstract: In 2005, the American Thoracic Society marks its 100th year of existence. For over a third of this span, since 1967, clinicians and investigators have struggled with a common, often lethal condition originally termed the adult respiratory distress syndrome (ARDS) (1).* While the syndrome almost certainly occurred in earlier times well before the advent of intensive care units, this date establishes its modern era. Subsequently, ARDS has more correctly come to indicate the acute respiratory distress syndrome because it occurs in children as well as in adults (2). ARDS causes severe acute respiratory failure with dynamic impairment in oxygen and carbon dioxide transfer, with the need for high levels of supplementary oxygen and a high minute ventilation (3, 4). Efforts to understand the pathophysiologic events underlying ARDS, a constellation that is now generally termed acute lung injury (ALI), have been substantial and remain a priority of the National Institutes of Health (5). The expectation has been that basic, translational, and clinical studies will result in new strategies for management of ALI/ARDS based on clear definition of the cellular and molecular events requisite in lung injury and repair. While important discoveries have been made, the goal of fundamental characterization of ALI/ARDS in a way that results in highly effective prevention and treatment remains incomplete and elusive. One major advance in supportive care, a strategy of lung protective mechanical ventilation, has substantially reduced mortality in ALI/ARDS (6, 7). This therapeutic intervention resulted from both experimental and clinical studies that evaluated the effect of different ventilation strategies on the course of ALI, and continues a theme initiated in the original description of ALI/ARDS in which positive end-expiratory pressure was introduced as a management modality (1). In spite of the advances in supportive care of patients with ALI/ARDS, unacceptable morbidity and mortality persist and formidable challenges remain. Our objective here is to review briefly what we knew in 1967 regarding pathogenesis and what we know in 2005, and to provide a perspective on how insights have evolved over the last four decades.

Clinical practice. Acute pulmonary edema.

Abstract: A 62-year-old man presents with a three-day history of progressive dyspnea, nonproductive cough, and low-grade fever. His blood pressure is 100/60 mm Hg, his heart rate 110 beats per minute, his temperature 37.9°C, and his oxygen saturation while breathing room air 86 percent. Chest auscultation reveals rales and rhonchi bilaterally. A chest radiograph shows bilateral pulmonary infiltrates consistent with pulmonary edema and borderline enlargement of the cardiac silhouette. How should this patient be evaluated to establish the cause of the acute pulmonary edema and to determine appropriate therapy?

Pediatric acute lung injury: prospective evaluation of risk factors associated with mortality.

Abstract: Rationale: The 1994 American European Consensus Committee definitions of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) have not been applied systematically in the pediatric population. Objectives: The purpose of this study was to evaluate prospectively the epidemiology and clinical risk factors associated with death and prolonged mechanical ventilation in all pediatric patients admitted to two large, pediatric intensive care units with ALI/ARDS using Consensus criteria. Methods: All pediatric patients meeting Consensus Committee definitions for ALI were prospectively identified and included in a relational database. Measurements and Main Results: There were 328 admissions for ALI/ARDS with a mortality of 22%. Multivariate logistic regression analyses revealed (1) the initial severity of oxygenation defect, as measured by the PaO2/FIO2 ratio; (2) the presence of nonpulmonary and non–central nervous system (CNS) organ dysfunction; and (3) the presence of CNS dysfunction were ind...

Effect of Prone Positioning on Clinical Outcomes in Children with Acute Lung Injury: A Randomized Controlled Trial

Abstract: ContextIn uncontrolled clinical studies, prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury. However, the effect of prone positioning on clinical outcomes in children is not known.ObjectiveTo test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning.Design, Setting, and PatientsMulticenter, randomized, controlled clinical trial conducted from August 28, 2001, to April 23, 2004, of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning. Randomization was concealed and group assignment was not blinded.InterventionPatients were randomized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria, with those patients in the prone group being positioned within 4 hours of randomization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days, after which they were positioned supine. Both groups were treated using lung protective ventilator and sedation protocols, extubation readiness testing, and hemodynamic, nutrition, and skin care guidelines.Main Outcome MeasureVentilator-free days to day 28.ResultsThe trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule. There were no differences in the number of ventilator-free days between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, −0.2 days; 95% CI, −3.6 to 3.2; P = .91). After controlling for age, Pediatric Risk of Mortality III score, direct vs indirect acute lung injury, and mode of mechanical ventilation at enrollment, the adjusted difference in ventilator-free days was 0.3 days (95% CI, −3.0 to 3.5; P = .87). There were no differences in the secondary end points, including proportion alive and ventilator-free on day 28 (P = .45), mortality from all causes (P>.99), the time to recovery of lung injury (P = .78), organ-failure−free days (P = .88), and cognitive impairment (P = .16) or overall functional health (P = .12) at hospital discharge or on day 28.ConclusionProne positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury.

Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury

Abstract: Ventilator-induced lung injury (VILI) is an inflammatory process that can be attenuated by lung protective ventilation strategies. Our objectives to further investigate the pathogenesis of ALI and ...

Alveolar epithelium: role in lung fluid balance and acute lung injury.

Abstract: The resolution of alveolar edema is regulated by active sodium and chloride transport across the pulmonary epithelium, including alveolar epithelial type I and II cells as well as distal airway epithelia. Catecholamine-dependent mechanisms can markedly upregulate alveolar fluid clearance even under pathological conditions, an effect that is mediated by both epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR). Under pathological conditions, impaired alveolar fluid clearance is associated with worse survival in patients with acute lung injury. However, there is some experimental and clinical evidence that cAMP stimulation could accelerate the resolution of pulmonary edema in the presence of acute lung injury. Clinical trials are needed to test this potential therapeutic strategy in patients with acute lung injury.

TNFα-Induced Long Pentraxin PTX3 Expression in Human Lung Epithelial Cells via JNK

Abstract: Long pentraxin 3 (PTX3), an acute-phase protein, is a newly clarified mediator for innate immunity and inflammation. As a soluble pattern recognition receptor, it has a nonredundant role in antifungal infection. Overexpression of PTX3 worsens acute lung injury. The lung epithelium is a critical factor in defense against pulmonary pathogens; it is also involved in acute inflammatory responses related to tissue injury. However, very little is known about how PTX3 is regulated in the lung epithelium. In this study, we found that i.v. injection of LPS induced PTX3 expression in rat lung alveolar epithelium. Using human lung cell lines and primary epithelial cells, we found that PTX3 expression was significantly up-regulated by TNF-α in a time- and dose-dependent manner, but not by LPS. Pretreatment with either actinomycin D or cycloheximide abolished TNF-α-induced PTX3 expression, indicating the requirement for both transcriptional and translational regulation. The TNF-α-induced PTX3 expression was blocked by SP600125, a JNK-specific inhibitor, but not by the inhibitors against NF-κB, ERKs, or p38 MAPK. Knockdown of either JNK1 or JNK2 with small interfering RNA also significantly reduced the regulated PTX3 expression. Thus, lung epithelial cells appear to be a major local source for PTX3 production, which could be induced in vivo from these cells by LPS or other inflammatory stimuli, and may be an important mediator for host defense and tissue damage. The importance of the JNK pathway for the regulated PTX3 expression may be a potential target for its regulation in the lung.

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Abstract: Apoptosis of distal lung epithelial cells plays a pivotal role in the pathogenesis of acute lung injury. In this context, proteinases, either circulating or leukocyte-derived, may contribute to epithelial apoptosis and lung injury. We hypothesized that apoptosis of lung epithelial cells induced by leukocyte elastase is mediated via the proteinase activated receptor (PAR)-1. Leukocyte elastase, thrombin, and PAR-1-activating peptide, but not the control peptide, induced apoptosis in human airway and alveolar epithelial cells as assessed by increases in cytoplasmic histone-associated DNA fragments and TUNEL staining. These effects were largely prevented by a specific PAR-1 antagonist and by short interfering RNA directed against PAR-1. To ascertain the mechanism of epithelial apoptosis, we determined that PAR-1AP, thrombin, and leukocyte elastase dissipated mitochondrial membrane potential, induced translocation of cytochrome c to the cytosol, enhanced cleavage of caspase-9 and caspase-3, and led to JNK activation and Akt inhibition. In concert, these observations provide strong evidence that leukocyte elastase mediates apoptosis of human lung epithelial cells through PAR-1-dependent modulation of the intrinsic apoptotic pathway via alterations in mitochondrial permeability and by modulation of JNK and Akt.

Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms

Abstract: Protease-activated receptors (PARs) and tachykinin-immunoreactive fibers are located in the lung as sentries to respond to a variety of pathological stimuli. The effects of PAR activation on the lung have not been adequately studied. We report on the effects of instilling PAR-activating peptides (PAR-APs, including PAR1-, PAR2-, and PAR4-AP) into the lungs of ventilated or spontaneously breathing mice. PAR2-AP, but not PAR1-AP or PAR4-AP, caused a sharp increase in lung endothelial and epithelial permeability to protein, extravascular lung water, and airway tone. No responses to PAR2-AP were detected in PAR2 knockout mice. In bronchoalveolar lavage, PAR2 activation caused 8- and 5-fold increase in MIP-2 and substance P levels, respectively, and a 12-fold increase in the number of neutrophils. Ablation of sensory neurons (by capsaicin) markedly decreased the PAR2-mediated airway constriction, and virtually abolished PAR2-mediated pulmonary inflammation and edema, as did blockade of NK1 or NK2 receptors. Thus, PAR2 activation in the lung induces airway constriction, lung inflammation, and protein-rich pulmonary edema. These effects were either partly or completely neuropeptide dependent, suggesting that PAR2 can cause lung inflammation by a neurogenic mechanism.

Acute effects of tidal volume strategy on hemodynamics, fluid balance, and sedation in acute lung injury.

Abstract: Objective: To examine the effects of mechanical ventilation with a tidal volume of 6 mL/kg compared with 12 mL/kg predicted body weight on hemodynamics, vasopressor use, fluid balance, diuretics, sedation, and neuromuscular blockade within 48 hrs in patients with acute lung injury and acute respiratory distress syndrome. Design: Retrospective analysis of a previously conducted randomized, clinical trial. Setting: Two adult intensive care units at a tertiary university medical center and a large county hospital. Patients: One hundred eleven patients who were enrolled in the National Institutes of Health ARDS Network trial at the University of California, San Francisco. Interventions: None. Measurements and Main Results: Compared with 12 mL/kg predicted body weight, treatment with a tidal volume of 6 mL/kg predicted body weight had no adverse effects on hemodynamics. There were also no differences in the need for supportive therapies, including vasopressors, intravenous fluids, or diuretics. In addition, there were no differences in body weight, urine output, and fluid balance. Finally, there was no difference in the need for sedation or neuromuscular blockade between the two tidal volume protocols. Conclusions: When compared with ventilation with 12 mL/kg predicted body weight, patients treated with the lung-protective 6 mL/kg predicted body weight tidal volume protocol had no difference in their supportive care requirements. Therefore, concerns regarding potential adverse effects of this protocol should not preclude its use in patients with acute lung injury or the acute respiratory distress syndrome. (Crit Care Med 2005; 33:63‐70)

In vitro and in vivo regulation of transepithelial lung alveolar sodium transport by serine proteases.

Abstract: The amiloride-sensitive epithelial sodium channel (ENaC) constitutes a rate-limiting step for sodium (Na+) and water absorption across lung alveolar epithelium. Recent reports suggested that ENaC i...

Accuracy of Physiologic Dead Space Measurements in Patients With Acute Respiratory Distress Syndrome Using Volumetric Capnography: Comparison With the Metabolic Monitor Method

Abstract: BACKGROUND: Volumetric capnography is an alternative method of measuring expired carbon dioxide partial pressure (PeCO2) and physiologic dead-space-to-tidal-volume ratio (VD/VT) during mechanical ventilation. In this method, PeCO2 is measured at the Y-adapter of the ventilator circuit, thus eliminating the effects of compression volume contamination and the need to apply a correction factor. We investigated the accuracy of volumetric capnography in measuring VD/VT, compared to both uncorrected and corrected measurements, using a metabolic monitor in patients with acute respiratory distress syndrome (ARDS). METHODS: There were 90 measurements of VD/VT made in 23 patients with ARDS. The PeCO2 was measured during a 5-min expired-gas collection period with a Delta-trac metabolic monitor, and was corrected for compression volume contamination using a standard formula. Simultaneous measurements of PeCO2 and VD/VT were obtained using volumetric capnography. RESULTS: VD/VT measured by volumetric capnography was strongly correlated with both the uncorrected (r2 = 0.93, p CONCLUSION: Volumetric capnography measurements of VD/VT in mechanically-ventilated patients with ARDS are as accurate as those obtained by metabolic monitor technique.

Differential effects of sustained inflation recruitment maneuvers on alveolar epithelial and lung endothelial injury.

Abstract: Objective:The role of recruitment maneuvers in mechanical ventilation for patients with the acute respiratory distress syndrome and acute lung injury remains uncertain in part due to a lack of data on the effects of specific recruitment maneuvers on lung injury severity. The primary objective of thi

VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema

Abstract: Although overexpression of vascular endothelial growth factor (VEGF) 165 in the lung causes pulmonary oedema, its role in human acute lung injury (ALI) is unclear. VEGF levels are reported to be lower in bronchoalveolar lavage from ALI patients compared with normals, but these studies did not include a comparably ill control group with noninflammatory pulmonary oedema. The current authors hypothesised that VEGF levels in pulmonary oedema fluid would be lower in ALI patients compared with control patients with severe hydrostatic pulmonary oedema. VEGF was measured in pulmonary oedema fluid and plasma from 56 patients with ALI and 46 controls with severe hydrostatic pulmonary oedema. Pulmonary oedema fluid levels of VEGF did not differ between patients with hydrostatic oedema (median 799 pg·mL −1 , interquartile range (IQR) 226–2,281) and ALI (median 507, IQR 0.8–1,031). Plasma levels were also the same (median 20.5 pg·mL −1 , IQR 0–152 versus 4.8, IQR 0–99.8). There was no association between plasma or oedema fluid VEGF levels and outcomes including mortality. Vascular endothelial growth factor levels in pulmonary oedema fluid were depressed both in acute lung injury and hydrostatic pulmonary oedema. The decrease in air space concentrations of vascular endothelial growth factor in acute lung injury may not be a function of the degree of lung injury, but rather may result from alveolar flooding.

Decreased expression of both the α1- and α2-subunits of the Na-K-ATPase reduces maximal alveolar epithelial fluid clearance

Abstract: Impaired epithelial sodium channel function predisposes to delayed resorption of pulmonary edema and more severe experimental lung injury, whereas even a small fraction of the normal Na-K-ATPase ac...

High prevalence of pulmonary arterial thrombi in donor lungs rejected for transplantation.

Abstract: Background Donor hypoxemia is a common reason for the rejection of lungs for transplantation. Organ donors are at high risk for venous thromboembolism. Pulmonary arterial thrombosis could contribute to donor hypoxemia. The primary objective of this study was to prospectively quantify the incidence of pulmonary arterial thrombosis in organ donors whose lungs were rejected for transplantation. The secondary objective was to better define the spectrum of histologic abnormalities in the same group of lungs. Methods A complete gross pathologic and histologic analysis of whole lung specimens was done on lungs from 17 donors whose lungs were rejected for transplantation. Lungs had not been flushed with a pulmonary preservation solution. Results Overall, 35% of the donors had gross or microscopic evidence of either pulmonary arterial thrombosis, pulmonary infarction, or both. Clinical characteristics, including oxygenation, were not significantly different between donors who had thrombi or infarction and donors who did not. Other pathologic findings included bronchopneumonia (focal or early in 4/17, moderate or severe in 8/17), respiratory bronchiolitis (7/17) and centriacinar emphysema (7/17). Conclusions Pulmonary arterial thrombosis and/or pulmonary infarction are very common in organ donors whose lungs are rejected for transplantation and might contribute to lung dysfunction both in lung donors and lung recipients. Further studies are needed to define the incidence of pulmonary arterial thrombosis in organ donors whose lungs are used for transplantation and to better assess the adverse clinical consequences of donor pulmonary arterial thrombosis in lung recipients.

Is there a role for beta-adrenoceptor agonists in the management of acute lung injury and the acute respiratory distress syndrome?

Abstract: Despite improvements in general supportive care and ventilatory strategies designed to limit lung injury, no specific pharmacological therapy has yet proven to be efficacious in the management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Based on experimental studies, as well as studies of the ex-vivo human lung, pulmonary edema fluid clearance from the alveolar space can be augmented by both inhaled and systemic beta2-adrenoceptor agonists (beta2-agonists). Additionally, in the presence of lung injury, beta2-agonists may reduce lung vascular permeability. Treatment with beta2-agonists may also increase the secretion of surfactant and have anti-inflammatory effects. In view of these potentially beneficial effects, beta2-agonist therapy should be evaluated for the treatment of lung injury in humans, particularly because they are already in wide clinical use and do not seem to have serious adverse effects in critically ill patients.

Leukotrienes in acute lung injury: a potential therapeutic target?

Abstract: A rapidly growing body of literature has begun to clarify the role of plasma membrane–derived mediators, including metabolites of arachidonic acid, sphingomyelin, lysophospholipid, ceramide, and platelet-activating factor (PAF), in the pathogenesis of acute lung injury. For example, PAF causes increased permeability pulmonary edema by inducing ceramide synthesis and cyclooxygenase activity (1). Endothelial barrier integrity is maintained in experimental ventilator-induced lung injury (VILI) by sphingosine-1 phosphate (2). Injurious ventilation increases lung phospholipase A2 activity, a major source of arachidonic acid release from the plasma membrane (3). The 5-lipoxygenase (5-LO) metabolite leukotriene (LT) D4 increases alveolar epithelial sodium transport by increasing sodium potassium ATPase activity and membrane abundance of the transporter (4). Although the precise mechanisms by which these interrelated pathways affect the balance of forces responsible for edema formation in acute lung injury have not been entirely resolved, it is clear that these lipid mediators play a larger role in lung endothelial and alveolar epithelial barrier function than previously recognized. Twenty years ago, it was reported that patients with acute lung injury had markedly elevated levels of LTs in pulmonary edema fluid compared with control patients with hydrostatic pulmonary edema, although the role of the LTs in the pathogenesis of lung injury was not clear at that time (5). In this issue of the Journal, Caironi and colleagues (pp. 334–343) provide new information on the role of 5-LO metabolites in acute lung injury resulting from sustained high Vt ventilation (6). These studies were designed to determine the contribution of impaired hypoxic pulmonary vasoconstriction (HPV) to hypoxemia resulting from VILI and to determine the wider role of LTs in the pathogenesis of VILI. Vasoconstriction is the normal pulmonary vascular response to hypoxemia and results in the redirection of blood flow to areas with greater ventilation. This intrinsic vascular response is in part mediated through LTs. Using mice that lack 5-LO, these investigators found that ventilation with high Vt for 6 hours resulted in an impaired vasoconstriction response via a 5-LO–dependent pathway. HPV was measured as the change in pulmonary vascular resistance in response to occlusion of the left mainstem bronchus. Interestingly, impaired HPV was detected despite normal arterial oxygen partial pressures before the hypoxic challenge. Normal pulmonary vasoconstriction was preserved by pretreatment with LT inhibitors and was restored by infusion of angiotensin II. In separate studies, high Vt ventilation for up to 10 hours resulted in increased alveolar epithelial permeability, elevated bronchoalveolar lavage levels of cysteinyl LTs (LTC4, LTD4, LTE4), and an influx of neutrophils into the airspaces. Importantly, 5-LO–deficient mice had better preservation of alveolar epithelial permeability, higher arterial oxygen tensions, and improved survival over the 10-hour study period. Pharmacologic inhibition of 5-LO activity produced similar effects in wild-type mice, whereas specific inhibition of the cysteinyl LT 1 (cLT1) receptor prevented the increase in permeability, but had less effect on airspace neutrophil infiltration. This apparent discrepancy is perhaps explained by the differential signaling of the cLT1 and cLT2 receptors because others have reported that the cLT2 receptor is sufficient for cLT-mediated interleukin-8 secretion in mast cells (7). The magnitude of the protective effect of cLT inhibition in this model of VILI is perhaps surprising in light of findings by numerous other groups, implicating a variety of seemingly unrelated cytokines, chemokines, neutrophils, and other mediators in the pathogenesis of endothelial and epithelial injury in VILI (8–10). However, it may be that 5-LO metabolites represent a common pathway in the cascade of inflammatory events during the development of VILI. Similarly, as these authors have previously reported, the effect of cLTs on HPV and lung injury is not specific to VILI, and cLT signaling may be a contributor to impaired HPV and increased lung permeability from a variety of causes, including endotoxin (11). Data from the present study indicate that the cLT-dependent impairment in HPV is an early event and develops before overt lung injury. It is tempting to speculate how this aberrant physiologic response may contribute to the forces governing pulmonary edema formation in VILI. However, it is notable that hypoxemia per se is a poor marker of lung injury severity in clinical acute lung injury and acute respiratory distress syndrome (ARDS). In the ARDS Clinical Trials Network study of low Vt ventilation, patients ventilated with lower Vt had a lower PaO2 than patients ventilated with conventional Vt, despite lower mortality in the low Vt group (12). Although infusion of angiotensin II restored HPV in the present VILI model, the authors did not report the effect of angiotensin II on lung injury severity. The specific effects of cLT inhibition on permeability and vascular tone may be context-specific and the cellular sources of cLTs in the VILI model remain to be investigated. Other investigators recently reported that inhibition of cyclooxygenase 2 (COX-2) delayed the resolution of acute lung injury in a mouse model of acid-aspiration–induced acute lung injury (13). Inhibition of COX-2 prolonged airspace neutrophilia and the increase in alveolar epithelial permeability. Interpreted in the context of the present study, these data support a complex relationship among both pro- and antiinflammatory derivatives of arachidonic acid. Nitric oxide (NO) may be an important contributor to pulmonary edema and neutrophil recruitment in acute lung injury and VILI. For example, the nonspecific NO synthase (NOS) inhibitor l-NAME prevented the increase in permeability associated with high Vt ventilation in isolated rabbit lungs (14). Presumably, inhibition of NO signaling would have some influence on HPV in VILI, although this has not been reported. Several of the authors of the present study recently reported that NO was required for the impaired HPV response in endotoxin-treated mice (15). In addition, inducible NOS (iNOS)–deficient mice have fewer neutrophils sequestered in the pulmonary circulation, but more neutrophils in the airspaces than wild-type mice after cecal ligation and puncture (16). High Vt ventilation can induce iNOS expression and activity in the airspace, and reactive nitrogen species contribute to impaired alveolar epithelial fluid transport and pulmonary edema in VILI (17). The mechanisms of cLT-mediated lung permeability are uncertain, and how cLTs may influence NO-mediated alteration in barrier function and neutrophil trafficking remains to be investigated. Caironi and colleagues (6) have further clarified our understanding of the pathogenesis of VILI. Early events, such as mechanical disruption of the basement membrane, disruption of the plasma membrane, or mechanically triggered chemical signaling, initiate an inflammatory program that culminates in neutrophil recruitment and activation that amplifies lung injury. The effects of lipid mediators, including arachidonic acid metabolites, in the pathogenesis of VILI appear to be greater than previously recognized and should stimulate renewed interest in 5-LO inhibitors for the treatment of acute lung injury.

HO-1 induction restores c-AMP-dependent lung epithelial fluid transport following severe hemorrhage in rats

Abstract: Inhibition of cAMP-dependent stimulation of the vectorial fluid transport across the lung epithelium following hemorrhagic shock is mediated by NO released within the airspaces of the lung. We tested here the hypothesis that prior induction of HO-1 would attenuate the release of NO in the airspaces, thus preventing the inhibition of the c-AMP stimulation of alveolar fluid clearance (ALC) in rats. Indeed, HO-1 induction restored the cAMP-mediated up-regulation of ALC after hemorrhage by decreasing NO released within the airspaces of the lung. In vitro studies demonstrated that HO-1 induction significantly reduced the iNOS-mediated release of NO by alveolar macrophages stimulated with endotoxin for 24 h. This effect is explained in part by a HO-1-dependent attenuation of the LPS-mediated nuclear translocation of NF-kappaB. In addition, HO-1 induction also significantly reduced the iNOS-mediated release of NO by MH-S cells that were stimulated with interferon-gamma by decreasing the phosphorylation of STAT 1, another transcription factor important for the activation of the iNOS promoter. In contrast, HO-1 induction did not affect the production of NO by rat alveolar epithelial type II cells that were stimulated with cytomix (a mixture of TNF-alpha, IL-1beta, and IFN-gamma) for 24 h. In summary, these results provide the first in vivo evidence that the induction of HO-1 in the lung restores a normal fluid transport capacity of the alveolar epithelium following hemorrhagic shock by inhibiting the iNOS-mediated release of NO by alveolar macrophages.

Effect of pharmacological inhibition of chloride transport on lung fluid balance in acute Escherichia coli pneumonia in mice

Abstract: Clearance of fluid from the alveolar spaces primary depends on the active sodium transport across distal lung epithelium. Some experimental studies supported a potential role for the cystic fibrosis transmembrane conductance regulator (CFTR), especially in the cAMP-mediated upregulation of fluid clearance. Hypothetically, pharmacological inhibition of Cl-channels could worsen lung edema by decreasing the clearance of alveolar edema. In this study, we tested the affect of chloride transport inhibition on lung edema formation in acute pneumonia.

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung

Abstract: Apoptosis of distal lung epithelial cells plays a pivotal role in the pathogenesis of acute lung injury. In this context, proteinases, either circulating or leukocyte-derived, may contribute to epithelial apoptosis and lung injury. We hypothesized that apoptosis of lung epithelial cells induced by leukocyte elastase is mediated via the proteinase activated receptor (PAR)-1. Leukocyte elastase, thrombin, and PAR-1–activating peptide, but not the control peptide, induced apoptosis in human airway and alveolar epithelial cells as assessed by increases in cytoplasmic histone-associated DNA fragments and TUNEL staining. These effects were largely prevented byaspecificPAR-1antagonistandbyshortinterferingRNAdirected against PAR-1. To ascertain the mechanism of epithelial apoptosis, we determined that PAR-1AP, thrombin, and leukocyte elastase dissipated mitochondrial membrane potential, induced translocation of cytochrome c to the cytosol, enhanced cleavage of caspase-9 and caspase-3, and led to JNK activation and Akt inhibition. In concert, these observations provide strong evidence that leukocyte elastase mediates apoptosis of human lung epithelial cells through PAR-1–dependent modulation of the intrinsic apoptotic pathway via alterations in mitochondrial permeability and by modulation of JNK and Akt.

Chapter 16 Looking to the future as keepers of the dam

Abstract: Publisher Summary Despite the extreme delicacy of the alveolar capillary membrane, the pulmonary microvascular endothelium normally functions faithfully as an effective and selective barrier, thereby protecting the lung parenchyma and the alveoli from excesses of the blood fluid, bioactive molecules, and cellular components, while allowing optimal exchange of oxygen and carbon dioxide critical to life. Advances in cellular, molecular, and biomechanical sciences have enabled the appreciation and understanding of the construction and function of the endothelial barrier, as well as the many important regulatory functions of the endothelium. Thus, as keepers of the dam, an intimate acquaintance with its composition, maintenance, and regulation is needed. There is a growing recognition that even moderate endothelial dysfunction in any anatomic site contributes to the pathological processes leading to diverse acute and chronic, vascular, and organ dysfunction. This chapter highlights integrated presentation of the advancements in endothelial biology and the development of a view toward the expansion of the comprehension of endothelial functional integrity.

Chapter 1 The cellular and molecular foundations of pulmonary edema

Abstract: Publisher Summary This chapter discusses the cellular and molecular foundations of pulmonary edema. The study of lung endothelium evolved from an early focus on barrier function to an intensive interest in the many interactive and regulatory functions of endothelium. However, the significance of the relationship between endothelial integrity and the clinically important problem of pulmonary edema is undiminished. To advance the treatment and prevention of alveolar flooding and inflammation, an improved and up-to-date mastery of the construction and maintenance of the dam is needed. The chapter presents the fundamentals of the structural elements of the endothelium and highlights the forces that challenge barrier integrity and the mechanisms of response. Detailed descriptions of the individual structural elements, their regulation, their contribution to barrier integrity or dysfunction, and the heterogeneity of endothelium are presented in the chapter. The interactions of endothelium with blood-borne cells, factors, infectious agents, and the injurious consequences are defined. Finally, the internal defenses and repair of the barrier by endothelium and the advances in the treatment to aid in resistance to activation, injury, and repair are reviewed.

Prone positioning in pediatric acute lung injury. results of a randomized controlled clinical trial

Abstract: SULTS OF A RANDOMIZED CONTROLLED CLINICAL TRIAL MAQ Curley, LD Fineman, N Cvijanovich, MJC Grant, FE Barr, D Steinhorn, P Luckett, JE Thompson, PL Hibberd, MA Matthay, JH Arnold Children’s Hospital Boston, MA; University of California, San Francisco, CA; Children’s Hospital Oakland, CA; Primary Children’s Medical Center, Salt Lake City, UT; Vanderbilt Children’s Hospital, Nashville, TN; Children’s Memorial Hospital, Chicago, IL; Children’s Medical Center of Dallas, TX; New England Medical Center, Boston, MA; USA Rationale: Uncontrolled clinical series have suggested that prone positioning (PP) improves oxygenation in infants and children with ALI/ARDS without significant complications. It is not known if improvements in oxygenation result in improvements in clinical outcomes. This randomized controlled clinical trial compared the proportion of children with ALI/ARDS who were treated with PP vs. supine positioning (SP) who were alive and ventilator-free after 28 days and the number of ventilator free days in the two treatment groups. Methods: The study design was a multi-center, randomized, non-crossover, controlled clinical trial (2001–2004) with an estimated N of 180 patients; 0.05, 0.10. Pediatric patients, 42-weeks post-conceptual age to 18 years, were enrolled within 48 hours of meeting ALI criteria. Patients randomized to PP were positioned within 4 hours of randomization and remained prone for 20 hours/day during the acute phase of their illness for a maximum of 7 days. Both groups were managed per ventilator protocol, extubation readiness testing, sedation protocol and hemodynamic, nutrition and skin care guidelines. Results: The study was stopped for futility after an interim analysis of 94 patients (47 SP and 47 PP). The two groups were well matched at study entry. Baseline oxygenation index (OI) was significantly higher in the prone group (27 vs. 20; P .04), but the number of ventilator free days in both groups was the same (15 days in each group). After controlling for age and baseline OI, PRISM III, and primary cause of ALI/ARDS in a multiple regression model, PP was not significantly better than SP. There were also no differences in secondary endpoints including time to recovery from lung injury, organ failure free days, mortality, functional outcome, or adverse events. Conclusion: PP does not improve clinical outcomes in pediatric patients with ALI/ARDS. Abstract funded by NIH/NINR RO1NR05336