Setting Of Lung Injury Research Articles

PLEURITIS AND EMPYEMA AFTER TRANSARTERIAL CHEMOEMBOLIZATION OF HEPATOCELLULAR CARCINOMA

PLEURITIS AND EMPYEMA AFTER TRANSARTERIAL CHEMOEMBOLIZATION OF HEPATOCELLULAR CARCINOMA

The Interplay between Aquaporin-1 and the Hypoxia-Inducible Factor 1α in a Lipopolysaccharide-Induced Lung Injury Model in Human Pulmonary Microvascular Endothelial Cells.

Aquaporin-1 (AQP1), a water channel, and the hypoxia-inducible factor 1α (HIF1A) are implicated in acute lung injury responses, modulating among others pulmonary vascular leakage. We hypothesized that the AQP1 and HIF1A systems interact, affecting mRNA, protein levels and function of AQP1 in human pulmonary microvascular endothelial cells (HPMECs) exposed to lipopolysaccharide (LPS). Moreover, the role of AQP1 in apoptosis and wound healing progression was examined. Both AQP1 mRNA and protein expression levels were higher in HPMECs exposed to LPS compared to untreated HPMECs. However, in the LPS-exposed HIF1A-silenced cells, the mRNA and protein expression levels of AQP1 remained unaltered. In the permeability experiments, a statistically significant volume increase was observed at the 360 s time-point in the LPS-exposed HPMECs, while LPS-exposed HIF1A-silenced HPMECs did not exhibit cell swelling, implying a dysfunctional AQP1. AQP1 did not seem to affect cell apoptosis yet could interfere with endothelial migration and/or proliferation. Based on our results, it seems that HIF1A silencing negatively affects AQP1 mRNA and protein expression, as well as AQP1 function, in the setting of lung injury.

Assessment of spontaneous breathing during pressure controlled ventilation with superimposed spontaneous breathing using respiratory flow signal analysis

Integrating spontaneous breathing into mechanical ventilation (MV) can speed up liberation from it and reduce its invasiveness. On the other hand, inadequate and asynchronous spontaneous breathing has the potential to aggravate lung injury. During use of airway-pressure-release-ventilation (APRV), the assisted breaths are difficult to measure. We developed an algorithm to differentiate the breaths in a setting of lung injury in spontaneously breathing ewes. We hypothesized that differentiation of breaths into spontaneous, mechanical and assisted is feasible using a specially developed for this purpose algorithm. Ventilation parameters were recorded by software that integrated ventilator output variables. The flow signal, measured by the EVITA® XL (Lübeck, Germany), was measured every 2 ms by a custom Java-based computerized algorithm (Breath-Sep). By integrating the flow signal, tidal volume (VT) of each breath was calculated. By using the flow curve the algorithm separated the different breaths and numbered them for each time point. Breaths were separated into mechanical, assisted and spontaneous. Bland Altman analysis was used to compare parameters. Comparing the values calculated by Breath-Sep with the data from the EVITA® using Bland–Altman analyses showed a mean bias of − 2.85% and 95% limits of agreement from − 25.76 to 20.06% for MVtotal. For respiratory rate (RR) RRset a bias of 0.84% with a SD of 1.21% and 95% limits of agreement from − 1.53 to 3.21% were found. In the cluster analysis of the 25th highest breaths of each group RRtotal was higher using the EVITA®. In the mechanical subgroup the values for RRspont and MVspont the EVITA® showed higher values compared to Breath-Sep. We developed a computerized method for respiratory flow-curve based differentiation of breathing cycle components during mechanical ventilation with superimposed spontaneous breathing. Further studies in humans and optimizing of this technique is necessary to allow for real-time use at the bedside.

Prevention or Treatment of Ards With Aspirin: A Review of Preclinical Models and Meta-Analysis of Clinical Studies.

The acute respiratory distress syndrome (ARDS) is a life-threating disorder that contributes significantly to critical illness. No specific pharmacological interventions directed at lung injury itself have proven effective in improving outcome of patients with ARDS. Platelet activation was identified as a key component in ARDS pathophysiology and may provide an opportunity for preventive and therapeutic strategies. We hypothesize that use of acetyl salicylic acid (ASA) may prevent and/or attenuate lung injury. We conducted a systematic review of preclinical studies and meta-analysis of clinical studies investigating the efficacy of ASA in the setting of lung injury. Medline, embase, and cochrane databases were searched. The literature search yielded 1,314 unique articles. Fifteen preclinical studies and eight clinical studies fulfilled the in- and exclusion criteria. In the animal studies, the overall effect of ASA was positive, e.g., ASA improved survival and attenuated inflammation and pulmonary edema. Mechanisms of actions involved, among others, are interference with the neutrophil-platelets interaction, reduction of leukotrienes, neutrophil extracellular traps, and prostaglandins. High-dose ASA may be the drug of choice. A meta-analysis of three clinical studies showed an association between ASA use and a reduced incidence of ARDS (OR 0.59, 95% CI 0.36-0.98), albeit with substantial between-study heterogeneity. All studies had their own shortcomings in methodological quality. This systematic review of preclinical studies and meta-analysis of clinical studies suggests a beneficial role for ASA in ARDS prevention and treatment. However, the currently available data is insufficient to justify an indication for ASA in ARDS. The body of literature does support further studies in humans. We suggest clinical trials in which the mechanisms of action of ASA in lung injury models are being evaluated to guide optimal timing and dose, before prospective randomized trials.

The Effect of Cholesterol on the Biophysical Inhibition of Pulmonary Surfactant by Albumin

Pulmonary surfactant is a mixture of 85% phospholipids, 5–8% cholesterol and 5–8% surfactant proteins which forms a surface tension reducing lipid film at the air‐liquid interface of the alveoli. By reducing the surface tension to near 0mN/m values during compression (i.e. exhalation) surfactant maintains alveolar stability at low lung volumes and maintains proper lung compliance. The importance of surfactant is evident in Acute Respiratory Distress Syndrome (ARDS) in which the dysfunction of surfactant contributes to hypoxemia, regional areas of collapse and reduced lung compliance. Specifically, serum proteins, such as Albumin, leaking into the lung during ARDS have been shown to interfere with surfactant's ability to reach low surface tension. In addition, recent studies suggest that elevated cholesterol within surfactant also contribute to surfactant dysfunction in the setting of lung injury. Although the effects of cholesterol and serum proteins with surfactant have been studied independently, the interaction between the two has not previously been investigated. It was hypothesized that elevated levels of cholesterol within surfactant will make surfactant more susceptible to serum protein inhibition.MethodsBovine Lipid Extract Surfactant (BLES), a commercially available exogenous surfactant, was utilized and modified to generate samples with concentrations of 0, 2.5, 5 and 10% (w/w) cholesterol. Varying amounts of Bovine Serum Albumin (BSA) were subsequently added to each sample to attain concentrations of 0, 20, 30, 40 and 50 mg/ml. A constrained sessile drop surfactometer was used to determine the minimal achievable surface tensions during dynamic compression/expansion cycles.ResultsSamples with various levels of cholesterol, in the absence of BSA, reached minimum surface tension values of near 0mN/m during compression. At moderate levels of BSA (20 & 30mg/ml), minimum surface tensions were lower in surfactant samples containing cholesterol as compared to samples containing no cholesterol. Finally, at high BSA values, all surfactant samples had surface tension values that were higher than those at the lower BSA concentration but were not significantly different among the sample with different cholesterol concentrations.DiscussionContrary to the hypothesis, values of up to 10% cholesterol within surfactant do not appear to increase the susceptibility of surfactant to serum protein inhibition. In fact, the results suggest that cholesterol mitigates the effect of moderate levels of BSA on surfactant function. It is concluded that cholesterol within surfactant contributes to its resistance against inhibition by albumin.Support or Funding InformationCanadian Institutes for Health Research.

Central cyclooxygenase inhibition during the course of lung injury attenuates breathing frequency

Ventilatory pattern is a neurally integrated output that is altered by lung injury. Work in our lab has provided evidence that ventilatory pattern changes persist in situ, and are concurrent with elevated IL‐1β expression, astrogliosis and altered synaptic efficacy in the nucleus of the tractus solitarii (nTS), a brainstem region critical for viscerosensory integration. Most recently, we observed that microinjection of exogenous IL‐1β into the nTS of naïve rats evokes some of the ventilatory pattern changes observed during lung injury. Collectively, these findings suggest that lung injury exerts influence over the neural control of breathing in part through the action of neuroinflammation. We therefore hypothesized that inhibiting neuroinflammation during the course of lung injury would attenuate breathing frequency (FR) and reduce IL‐β expression in the nTS. To test this hypothesis, we continuously administered either vehicle or indomethacin (IND), a cyclooxygenase‐1/2 (COX‐1/2) inhibitor, into the right lateral ventricle of bleomycin lung‐injured rats (bleo) via Alzet pump. We plethysmographically recorded breathing pattern and densitometrically measured brainstem IL‐1β immunoreactivity (IR) at day 7 of lung injury. We observed a significant (P<0.05) attenuation of FR in bleo rats receiving IND (161±56bpm, n=10) as compared to bleo rats receiving vehicle (217±66bpm, n=10). The level of IL‐1β IR detected within the nTS of IND treated bleo rats was reduced. Taken together, our results indicate that ventilatory pattern changes, which occur in the setting of lung injury, are in part dependent upon the central action of COX‐1/2, and are associated with decreased IL‐1β expression in the nTS.

Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

BackgroundData from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications.MethodWe performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans.ResultsThe efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings.ConclusionLocal anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.

Blocking TGFβvia Inhibition of theαvβ6 Integrin: A Possible Therapy for Systemic Sclerosis Interstitial Lung Disease

Interstitial lung disease (ILD) is a commonly encountered complication of systemic sclerosis (SSc) and accounts for a significant proportion of SSc-associated morbidity and mortality. Its pathogenesis remains poorly understood, and therapies that treat SSc ILD are suboptimal, at best. SSc ILD pathogenesis may share some common mechanisms with other fibrotic lung diseases, in which dysregulation of lung epithelium can contribute to pathologic fibrosis via recruitment or in situ generation and activation of fibroblasts. TGFβ, a master regulator of fibrosis, is tightly regulated in the lung by the integrin αvβ6, which is expressed at low levels on healthy alveolar epithelial cells but is highly induced in the setting of lung injury or fibrosis. Here we discuss the biology of αvβ6 and present this integrin as a potentially attractive target for inhibition in the setting of SSc ILD.

Twist: A Regulator of Epithelial-Mesenchymal Transition in Lung Fibrosis

BackgroundSeveral studies have implicated viral infection as an important factor in the pathogenesis of IPF and related fibrotic lung disorders. Viruses are thought to cause epithelial cell injury and promote epithelial-mesenchymal transition (EMT), a process whereby differentiated epithelial cells undergo transition to a mesenchymal phenotype, and considered a source of fibroblasts in the setting of lung injury. We have demonstrated an association between the epithelial injury caused by chronic herpes virus infection with the murine γ-herpes virus, MHV68, and lung fibrosis. We hypothesize that EMT in this model of virus-induced pulmonary fibrosis is driven by the expression of the transcription factor Twist.Methods/Findings In vitro MHV68 infection of murine lung epithelial cells induced expression of Twist, and mesenchymal markers. Stable overexpression of Twist promoted EMT in MLE15 lung epithelial cells. Transient knockdown expression of Twist resulted in preservation of epithelial phenotype after in vitro MHV68 infection. In concordance, high expression of Twist was found in lung epithelial cells of MHV68 infected mice, but not in mock infected mice. Alveolar epithelial cells from lung tissue of idiopathic pulmonary fibrosis (IPF) patients were strongly positive for Twist. These cells demonstrated features of EMT with low expression of E-cadherin and upregulation of the mesenchymal marker N-cadherin. Finally, IPF tissue with high Twist protein levels was also positive for the herpesvirus, EBV.Conclusions/SignificanceWe conclude that Twist contributes to EMT in the model of virus-induced pulmonary fibrosis. We speculate that in some IPF cases, γ-herpes virus infection with EBV might be a source of injury precipitating EMT through the expression of Twist.

Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling

The ingestion of apoptotic cells (ACs; termed “efferocytosis”) by phagocytes has been shown to trigger the release of molecules such as transforming growth factor β, interleukin-10 (IL-10), nitric oxide, and prostaglandin E2 (PGE2). Although the antiinflammatory actions of these mediators may contribute to the restoration of homeostasis after tissue injury, their potential impact on antibacterial defense is unknown. The lung is highly susceptible to diverse forms of injury, and secondary bacterial infections after injury are of enormous clinical importance. We show that ACs suppress in vitro phagocytosis and bacterial killing by alveolar macrophages and that this is mediated by a cyclooxygenase–PGE2–E prostanoid receptor 2 (EP2)–adenylyl cyclase–cyclic AMP pathway. Moreover, intrapulmonary administration of ACs demonstrated that PGE2 generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo. These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses. They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE2 or ligation of EP2.

The complex role of fibrin in acute lung injury

in the last decade there have been many advances in our understanding of the pathogenesis of acute lung injury (ALI), but there have been frustratingly few successful therapeutic interventions. In fact, the only treatment proven to reduce mortality is low tidal volume lung-protective mechanical

Pressure- versus volume-cycled ventilation in liquid-ventilated neonatal piglet lungs

Background/Purpose: If the goal of partial liquid ventilation (PLV) with perfluorocarbons in the management of respiratory failure is to improve dynamic lung compliance (C dyn) and pulmonary vascular resistance (PVR) while sustaing O 2 delivery, the optimal ventilatory management is unclear. The authors asked if volume-cycled or pressure-limited ventilation had different effects on PVR, cardiac index (CI), and C dyn in uninjured and injured neonatal piglet lungs. Methods: Anesthetized piglets (6 to 8 kg) were ventilated after tracheostomy. C dyn was measured by in-line Fleisch pneumotach/PC data acquisition terminal. Thermodilution instrumentation allowed determination of both Cl and PVR. Volume-control or pressure-limited ventilation was established in uninjured or injured (surfactant deficiency induced by saline lavage at 18 mL/kg) animals. After a stable 30-minute baseline, animals were assigned randomly to one of four groups: group I (n = 9), uninjured animals plus volume-cycled ventilation (intermittent mandatory ventilation [IMV], 10 bpm; tidal volume [TV], 15 mL/kg, positive end-expiratory pressure [PEEP], 5 cm H 2O; F io 2, 1.0; and PLV for 150 minutes); group II (n = 9), uninjured animals plus pressure-limited ventilation (IMV, 10 bpm; peak inspiratory pressure (PIP), 25 cm H 2O, PEEP, 5 cm H 2O, F io 2, 1.0; and PLV for 150 minutes); group III (n = 7), injured animals plus volume-cycled ventilation (IMV, 10 bpm; TV, 15 mL/kg; PEEP, 5 cm H 2O; F io 2, 1.0 for 30 minutes, followed by saline injury for 30 minutes, followed by PLV rescue for 120 minutes); group IV (n = 7), injured animals plus pressure-limited ventilation (IMV, 10 bpm; PIP, 25 cm H 2O; PEEP, 5 cm H 2O; F io 2, 1.0 for 30 minutes, followed by saline injury, and PLV rescue). Comparison within and between groups was accomplished by repeated measures analysis of variance (ANOVA) with Tukey correction. Results: There was no significant difference between volumecycled or pressure-limited ventilation in healthy lungs; however, in the setting of lung injury, dynamic compliance was 1.44 ± 0.15 after 180 minutes in the volume-cycled group and 0.91 ± 0.10 in the pressure-limited group after the same interval (mL/cm H 2O · kg ± SEM). Similarly, PVR was 100 ± 6 in the volume-cycled group and 145 ± 12 in the pressurelimited group after 180 minutes of lung injury (mm Hg/L/kg · min ± SEM). Cardiac index declined significantly in all groups independent of ventilatory mode. Conclusions: These results suggest that in the setting of lung injury, C dyn and PVR improved significantly when volume-cycled, compared with pressure-limited ventilation was used. Although no difference existed between ventilatory modes in healthy lungs, pressure-limited ventilation, when combined with PLV in injured lungs, had adverse effects on lung compliance and pulmonary vascular resistance. Volume-cycled ventilation may optimize the ability of perfluorocarbon to recruit collapsed or atelectatic lung regions.

Effect of Chronic and Acute Thyroid Hormone Reduction on Perioperative Outcome

Effect of Chronic and Acute Thyroid Hormone Reduction on Perioperative Outcome

Noninvasive determination of cardiac output using single breath CO2 analysis.

To examine the utility of single breath CO2 analysis as a noninvasive measure of cardiac output. An animal laboratory in a university-affiliated medical center. A prospective, animal cohort study comparing 21 parameters derived from single breath CO2 analysis with cardiac output determined by an ultrasonic flow probe. Six healthy adult sheep. The single breath CO2 analysis station consists of a mainstream capnometer, a variable orifice pneumotachometer, a signal processor, and computer software with capability for both on- and off-line data analysis. Twenty-one derived components of the CO2 expirogram were evaluated as predictors of cardiac output. Cardiac output was manipulated by successive injections of a hydraulic constrictor placed around the inferior vena cava. Thirty-four measurements of cardiac output were available for comparison with derived variables from the CO2 expirogram. Stepwise linear regression identified two variables that were most predictive of cardiac output: a) the angle between the slope lines for phase II and III of the CO2 expirogram divided by the volume of CO2 per breath (angle/mL CO2); and b) the slope of phase II. The multivariate equation was highly statistically significant and explained 94% of the variance (adjusted r2 = .94, p < .0001). The bias and precision of the calculated cardiac output were .00 and .23, respectively. The mean percent difference for the cardiac output estimate derived from the single breath CO2 analysis station was 0.36%. Our data indicate that analysis of the CO2 expirogram can yield accurate information about the cardiovascular system. Specifically, two variables derived from a plot of expired CO2 concentration vs. expired volume predict changes in cardiac output in healthy adult sheep with an adjusted coefficient of determination of .94. Prospective application of this technology in the setting of lung injury and rapidly changing physiology will be essential in determining the clinical usefulness of the technique.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Proliferation Presenting as Interstitial Lung Disease

Pulmonary neuroendocrine cell (PNEC) hyperplasia typically occurs as an adaptive response in persons living at high altitudes and as a reactive response in the setting of lung injury. However, previous studies suggest that PNEC hyperplasia can occur in the absence of preexisting lung disease and may even give rise to airway disease through the development of pulmonary tumorlets and airway fibrosis and perhaps the release of paracrine secretions. We describe a patient with diffuse PNEC proliferation of a probable hyperplastic nature developing in the absence of a chronic pulmonary disorder who presented clinically with an interstitial lung process. Open lung biopsy displayed a florid intraepithelial population of PNEC diffusely involving the distal airways and alveoli with desquamation and filling of alveolar spaces by nests of PNEC. The presence of alveolar thickening was attributable to the intraepithelial proliferation of PNEC associated with interstitial fibrosis and accounted for mild reductions in the pulmonary diffusing capacity. The neuroendocrine differentiation of this proliferation was evident by light microscopic and ultrastructural examination. The absence of airway fibrosis and pulmonary tumorlets was in agreement with the lack of clinical airway disease in this case. The intraepithelial growth and absence of parenchymal invasion in this lesion favor a diffuse, florid PNEC hyperplasia with mild dysplastic features over a pulmonary neuroendocrine neoplasm.

Mechanism by which the prone position improves oxygenation in acute lung injury.

The mechanism by which oxygenation improves when patients with ARDS are turned from supine to prone position is not known. From results of our previous studies we reasoned that (1) when supine, in the setting of lung injury, transpulmonary pressure will be less than airway opening pressure and (2) atelectasis will develop preferentially in dorsal lung areas, and (3) both ventilation and ventilation/perfusion ratios would improve in these regions on turning prone. To study this directly, we measured regional ventilation and perfusion using 81mKr and 99mTc-MAA, respectively, and single photon emission computed tomography, both prone and supine, in four control animals and four given oleic acid. After oleic acid, the prone position improved (1) oxygenation (mean +/- SD PaO2 = 140 +/- 112 versus 453 +/- 54 mm Hg), (2) median ventilation/perfusion ratios (0.77 versus 0.95), (3) ventilation/perfusion heterogeneity (coefficient of variation 86 +/- 15 versus 61 +/- 6), and (4) the gravitational ventilation/perfusion gradient (dependent to non-dependent slopes of 0.22 versus -0.02, all p < 0.05). The prone position generates a transpulmonary pressure sufficient to exceed airway opening pressure in dorsal lung regions, i.e., in regions where atelectasis, shunt, and ventilation/perfusion heterogeneity are most severe, without adversely affecting ventral lung regions.

Effect of hydralazine on cardiac output and venous admixture in experimental lung injury.

The mechanism by which hydralazine increases venous admixture (QVA/QT) in the setting of lung injury was investigated in a canine model of noncardiogenic pulmonary edema. Permeability pulmonary edema was produced by administration of oleic acid, 0.08 ml/kg given intravenously to 9 mongrel dogs. After stabilization of lung injury, hydralazine was administered intravenously in a loading dose of 1 mg/kg and followed by a constant infusion at 0.05 mg/kg/h. To control for the effect of increased cardiac output (QT) on QVA/QT, a balloon catheter was placed in the inferior vena cava, and stepwise inflation of the balloon was used to impede venous return and maintain QT at predrug levels. Prior to inflation of the balloon catheter, administration of hydralazine produced a 51% decrease in total systemic resistance (TSR) and a 23% decrease in mean arterial pressure (Pa). In contrast, pulmonary vascular resistance (PVR) showed no significant change, and mean pulmonary artery pressure (Ppa) increased 47%. Cardiac output increased from 3.4 +/- 0.3 to 5.5 +/- 0.4 L/min (mean +/- SEM; p less than 0.01) after administration of hydralazine, and QVA/QT increased from 23 +/- 7 to 35 +/- 5% (p less than 0.05). Mean arterial oxygen tension (PaO2) showed no significant change. Inflation of the balloon in the inferior vena cava after hydralazine administration reduced QT to 3.1 +/- 0.4 L/min and QVA/QT to 28 +/- 4%. Neither of these values differed significantly from the prehydralazine levels. Similarly, values for Ppa and PVR after hydralazine administration plus balloon inflation did not differ significantly from predrug levels.(ABSTRACT TRUNCATED AT 250 WORDS)