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Acute Lung Injury (acute + lung_injury)
Selected AbstractsRole of Protease Activated Receptor 2 in Experimental Acute Lung Injury and Lung FibrosisTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 4 2009Xiao Su Abstract Protease activated receptor 2 (PAR2) is widely-distributed (lung, liver, kidney, etc.) and expressed by variety of cells (i.e. leukocytes, epithelial cells, endothelial cells, and fibroblast). PAR2 may participate in many pathological processes, such as, inflammation, injury, as well as fibrosis. Therefore, in this study, we tested whether PAR2 would exert a role in acid-induced acute lung injury, E. coli pneumonia, bleomycin-induced acute lung injury and fibrosis. Acid, E. coli, or bleomycin were intratracheally instilled into the lungs of both wildtype and PAR2 knockout mice to detect differences in pulmonary edema, lung vascular permeability, lung fibrosis, and other parameters. Knockout of PAR2 did not affect the extent of pulmonary edema and lung vascular permeability in acid-induced acute lung injury. Also, both activation of PAR2 in the airspaces of the lung and deletion of PAR2 did not alter the magnitude of pulmonary edema and lung vascular permeability in E. coli pneumonia. Finally, PAR2 deficiency did not affect the severity of lung inflammation and lung fibrosis in bleomycin-induced acute lung injury and lung fibrosis models. Thus, PAR2 does not appear to play a critical role in the pathogeneses of experimental acid-induced acute lung injury, E. coli pneumonia, and bleomycin-induced acute lung injury and pulmonary fibrosis in mice. Anat Rec, 2009. © 2009 Wiley-Liss, Inc. [source] Therapeutic Effects and Anti-inflammatory Mechanisms of Heparin on Acute Lung Injury in RabbitsACADEMIC EMERGENCY MEDICINE, Issue 7 2008Meitang Wang MD Abstract Objectives:, The objectives were to investigate the potential beneficial effects and molecular mechanisms of heparin and low-molecular-weight heparin (LMWH) on acute lung injury (ALI). Methods:, Forty-eight rabbits were randomized into four groups: normal control group (Group A), lipopolysaccharide (LPS) group (Group B), LPS + heparin group (Group C), and LPS + LMWH group (Group D). The rabbit ALI model was established by intravenous (IV) injection with LPS. Alveolar,arterial O2 difference (PA-aO2), serum tumor necrosis factor , (TNF-,), circulating p38 mitogen-activated protein kinase (p38 MAPK) levels, lung nuclear factor (NF)-,B levels, and lung dry/wet (D/W) ratio were measured, and the lung injury scores were calculated. Results:, Lipopolysaccharide caused significant increases in PA-aO2, serum TNF-,, expression of p38 MAPK in polymorphonuclear neutrophils (PMNs), the lung injury scores, and nuclear factor-,B (NF-,B) activity in the lung tissue and caused a decrease in lung D/W ratio. A positive linear correlation was found between p38 MAPK and TNF-, at 1, 2, 4, and 6 hours (r = 0.68, 0.92, 0.93, and 0.93, respectively) and between NF-,B and p38 MAPK and TNF-, at 6 hours (r = 0.94 and 0.83, respectively). IV heparin or LMWH given after LPS treatment attenuated these changes in inflammatory response, oxygenation, p38 MAPK expression, and NF-,B activation. Conclusions:, The anti-inflammatory mechanisms of heparin in ALI may be inhibiting p38 MAPK and NF-,B activities, and then TNF-, overexpression, thus alleviating the inflammatory reaction. [source] Acute lung injury and acute respiratory distress syndrome: fashionable names for old conditions or new clinical entities in their own right?EQUINE VETERINARY JOURNAL, Issue 5 2005E. JOSE-CUNILLERAS No abstract is available for this article. [source] N -Acetylcysteine Improves Group B Streptococcus Clearance in a Rat Model of Chronic Ethanol IngestionALCOHOLISM, Issue 7 2009Sonja M. Tang Background:, Sepsis is the most common risk factor associated with acute respiratory distress syndrome (ARDS) and results in a 40,60% mortality rate due to respiratory failure. Furthermore, recent epidemiological studies have demonstrated that a history of alcohol abuse increases the risk of ARDS by 3.6-fold. More recently, group B streptococcus (GBS) infections in nonpregnant adults have been increasing, particularly in alcoholics where there is an increased risk of lobular invasion and mortality. We have shown in an established rat model that chronic ethanol ingestion impaired macrophage internalization of inactivated infectious particles in vitro and enhanced bidirectional protein flux across the alveolar epithelial-endothelial barriers, both of which were attenuated when glutathione precursors were added to the diet. We hypothesized that chronic ethanol ingestion would increase the risk of infection even though GBS is less pathogenic but that dietary N -acetylcysteine (NAC), a glutathione precursor, would improve in vivo clearance of infectious particles and reduce systemic infection. Methods:, After 6 weeks of ethanol feeding, rats were given GBS intratracheally and sacrificed 24 hours later. GBS colony-forming units were counted in the lung, liver, spleen, and bronchoalveolar lavage fluid. Acute lung injury in response to GBS was also assessed. Results:, Chronic ethanol exposure decreased GBS clearance from the lung indicating an active lung infection. In addition, increased colonies formed within the liver and spleen indicated that ethanol increased the risk of systemic infection. Ethanol also exacerbated the acute lung injury induced by GBS. NAC supplementation normalized GBS clearance by the lung, prevented the appearance of GBS systemically, and attenuated acute lung injury. Conclusions:, These data suggested that chronic alcohol ingestion increased the susceptibility of the lung to bacterial infections from GBS as well as systemic infections. Furthermore, dietary NAC improved in vivo clearance of GBS particles, attenuated acute lung injury, and disseminated infection. [source] Bilirubin influence on oxidative lung damage and surfactant surface tension propertiesPEDIATRIC PULMONOLOGY, Issue 3 2004Carlo Dani MD Abstract To study the hypothesis that hyperbilirubinemia might reduce in vivo oxidative lung damage while also diminishing lung surfactant surface tension properties during acute lung injury, we performed a randomized study in a rabbit model of acute lung injury. Twenty rabbits were randomized to receive bilirubin or saline intravenously. Acute lung injury was induced by lung lavages with saline. Lung tissue oxidation was evaluated by measuring total hydroperoxide (TH), advanced oxidation protein products (AOPP), and protein carbonyls (PC) in bronchial aspirate (BA) samples. Surface surfactant activity was studied in BA samples using a capillary surfactometer. Bilirubin BA concentration increased in bilirubin-treated rabbits, while it remained undetectable in controls. A similar increase in TH, AOPP, and PC bronchial aspirate concentrations was found in both the study and control groups, while surfactant surface activity was lower in the bilirubin than in the control group. We conclude that during hyperbilirubinemia, bilirubin enters the lung tissue, where it can be detected in BA fluid. Bilirubin is not effective as an antioxidant agent and exerts a detrimental effect on lung surfactant surface tension properties. These findings may have relevance to the management of premature neonates suffering from respiratory distress syndrome and hyperbilirubinemia. Pediatr Pulmonol. © 2004 Wiley-Liss, Inc. [source] Panax notoginseng saponins attenuate acute lung injury induced by intestinal ischaemia/reperfusion in ratsRESPIROLOGY, Issue 6 2009Ling RONG ABSTRACT Background and objective: Acute lung injury remains a challenge for both clinicians and scientists. The effects of Panax notoginseng saponins (PNS) on acute lung injury induced by intestinal ischaemia/reperfusion (II/R) were studied in rats. Methods: Forty-eight Wistar rats were randomly assigned to four groups: (1) a sham-operated group that received laparotomy without II/R (n= 12); (2) a sham + PNS group, which was identical to group 1 except for PNS treatment (n= 12); (3) an II/R group that had 1 h of intestinal ischaemia followed by 3 h of reperfusion (n= 12); and (4) an II/R + PNS group that received 100 mg/kg of PNS, i.v., 15 min before reperfusion (n= 12). The effects of PNS administration on lung tissue histology, activities of oxidant and antioxidant enzymes, levels of malondialdehyde, nitric oxide and inducible nitric oxide synthase activity were examined. Levels of surfactant protein B, cell numbers in BAL fluid and plasma levels of pro-inflammatory cytokines were also examined. Results: Compared with the II/R group, pulmonary parenchymal damage, activities of oxidant enzymes, levels of malondialdehyde and nitric oxide, inducible nitric oxide synthase activity in lung tissue, and plasma levels of pro-inflammatory cytokines were significantly reduced by PNS treatment. In addition, the decreases in antioxidant enzyme activities were prevented in the II/R + PNS group. Total leukocyte and neutrophil counts were significantly decreased by PNS treatment. The decline in surfactant protein B levels in BAL fluid was reduced in the II/R + PNS group compared with the II/R group. Conclusions: Administration of PNS before reperfusion injury alleviates acute lung injury induced by II/R, and this is attributable to the antioxidant and anti-inflammatory effects of PNS. [source] Baicalin attenuates air embolism-induced acute lung injury in rat isolated lungsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2009Min-Hui Li Background and purpose:, Baicalin has been reported to have anti-inflammatory effects and protect against various tissue injuries. However, the effect of baicalin on air embolism-induced acute lung injury has not been tested yet. Experimental approach:, Acute lung injury was induced by infusion of air at a rate of 0.25 mL·min,1 for 1 min into the pulmonary artery of rat isolated lungs. At the end of the experiment, samples were collected for assessment of lung injury, biochemical analysis and histology. Different doses of baicalin (1, 2 and 4 mg·kg,1) were given into the perfusate before air infusion. Key results:, Air embolism elicited a significant increase in microvascular permeability (Kf), lung weight gain, wet/dry weight ratio, pulmonary artery pressure and protein concentration in the bronchoalveolar lavage fluid. Levels of the cytokines, tumour necrosis factor , and cytokine-induced neutrophil chemoattractant-1 in perfusate, and malondialdehyde levels and myeloperoxidase activities in lung tissue were also significantly increased. In addition, histological examination showed increased neutrophil infiltration in lung tissues. Furthermore, nuclear factor-,B activity and degradation of I,B-, were significantly increased in lungs. Pretreatment of the lungs with baicalin (4 mg·kg,1) showed a statistically significant difference in all of the assessed parameters, except for alteration in the pulmonary artery pressure. Conclusions and implications:, Our study suggests that baicalin attenuated air embolism-induced acute lung injury and may be considered a useful adjunct drug therapy in this clinical condition. [source] Meconium aspiration syndrome: a role for phospholipase A2 in the pathogenesis?ACTA PAEDIATRICA, Issue 4 2001P KääpäArticle first published online: 2 JAN 200 The pathophysiology of neonatal meconium aspiration syndrome (MAS), often resulting in severe respiratory failure, is complex and still largely unclear. Factors involved in the propagation of acute lung injury after perinatal aspiration of meconium include obstruction of the airways, ventilation/perfusion mismatch, increase of the pulmonary vascular resistance and a rapidly developing parenchymal and alveolar inflammatory reaction with associated surfactant dysfunction. Conclusion: Although the early pulmonary inflammatory response is believed to play a central pathogenetic role in the meconium-induced acute lung damage, its initiating mechanisms are still poorly defined. However, increasing evidence indicates a direct toxic effect of meconium. [source] Responses of the bronchial and pulmonary circulations to short-term nitric oxide inhalation before and after endotoxaemia in the pigACTA PHYSIOLOGICA, Issue 1 2002R. J. M. Middelveld ABSTRACT The physiological responses of the bronchial circulation to acute lung injury and endotoxin shock are largely unexplored territory. This study was carried out to study the responsiveness of the bronchial circulation to nitric oxide (NO) inhalation before and after endotoxaemia, in comparison with the pulmonary circulation, as well as to study changes in bronchial blood flow during endotoxaemia. Six anaesthetized pigs (pre-treated with the cortisol-synthesis inhibitor metyrapone) received an infusion of 10 µg/kg endotoxin during 2 h. Absolute bronchial blood flow was measured via an ultrasonic flow probe around the bronchial artery. The pigs received increasing doses of inhaled NO over 5 min each (0, 0.2, 2 and 20 ppm) before and after 4 h of endotoxaemia. The increase in bronchial vascular conductance during 5 min of inhalation of 20 ppm NO before endotoxin shock was significantly higher (area under curve (AUC) 474.2 ± 84.5% change) than after endotoxin shock (AUC 118.2 ± 40.4%, P < 0.05 Mann,Whitney U -test). The reduction of the pulmonary arterial pressure by 20 ppm NO was not different. A short rebound effect of the pulmonary arterial pressure occurred after discontinuation of inhaled NO before endotoxaemia (AUC values above baseline 54.4 ± 19.7% change), and was virtually abolished after endotoxaemia (AUC 6.1 ± 4.0%, P = 0.052, Mann,Whitney U -test). Our results indicate that the responsiveness of the bronchial circulation to inhalation of increasing doses of inhaled NO during endotoxin shock clearly differ from the responsiveness of the pulmonary circulation. The reduced responsiveness of the bronchial circulation is probably related to decreased driving pressure for the bronchial blood flow. The absence of the short rebound effect on pulmonary arterial pressure (PAP) after induction of shock could be related to maximum constriction of the pulmonary vessels at 4 h. [source] Serum concentrations of high-mobility group box chromosomal protein 1 before and after exposure to the surgical stress of thoracic esophagectomy: a predictor of clinical course after surgery?DISEASES OF THE ESOPHAGUS, Issue 1 2006K. Suda SUMMARY., High-mobility group box chromosomal protein 1 (HMGB-1) has recently been shown as an important late mediator of endotoxin shock, intra-abdominal sepsis, and acute lung injury. However, its role in the systemic inflammatory response syndrome after major surgical stress, which may lead to multiple organ dysfunction syndrome, has not been thoroughly investigated. We hypothesized that serum HMGB-1 participates in the pathogenesis of postoperative organ system dysfunction after exposure to major surgical stress. A prospective clinical study was performed to consecutive patients (n = 24) with carcinoma of the thoracic esophagus who underwent transthoracic esophagectomy with three field lymph node resection between 1998 and 2003 at Keio University Hospital, Japan. Serum HMGB-1 concentrations were measured by enzyme-linked immunosorbent assay. Preoperative serum HMGB-1 levels correlated with postoperative duration of SIRS, mechanical ventilation, and intensive care unit stay. Three of the 24 patients had serious postoperative complications: sepsis in two, and acute lung injury in one. Serum HMGB-1 levels in patients without complications increased within the first 24 h postoperatively, remained high during postoperative days 2,3, and then decreased gradually by postoperative day 7. In patients with serious complications, serum HMGB-1 was significantly higher than that found in patients without postoperative complications at every time point except postoperative day 2. Preoperative serum HMGB-1 concentration seems to be an important predictor of the postoperative clinical course. Transthoracic esophagectomy induces an increase in HMGB-1 in serum even in patients without complications. Postoperative serum HMGB-1 concentrations were higher in patients who developed complications, and may be a predictive marker for complications in this setting. [source] Both Fc,RIV and Fc,RIII are essential receptors mediating type II and type III autoimmune responses via FcR,-LAT-dependent generation of C5aEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2009Shahzad N. Syed Abstract Fc,RIV is a relatively new IgG Fc receptor (Fc,R) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to Fc,RIII, complement and IgG2 subclasses remains uncertain. Here we define Fc,RIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of Fc,RIV and Fc,RIII is critical to mediate certain type II/III autoimmune responses. Fc,RIII-deficient mice display compensatory enhanced Fc,RIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased Fc,RIV alone is not sufficient to trigger these diseases in the absence of Fc,RIII. Importantly, however, blockade of Fc,RIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b-induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that Fc,RIII and Fc,RIV are each essential to trigger an FcR,-linker for activation of T-cell-dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for Fc,RIII and Fc,RIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked Fc,R and C5a anaphylatoxin receptor activation to generate inflammation. [source] Behaviours of pulmonary sensory receptors during development of acute lung injury in the rabbitEXPERIMENTAL PHYSIOLOGY, Issue 4 2007Shuxin Lin We tested the hypothesis that oleic acid-induced acute lung injury activates pulmonary nociceptors, that is, C fibre receptors (CFRs) and high-threshold A, fibre receptors (HTARs). Single-unit activity was recorded in the cervical vagus nerve and assessed before and after injecting oleic acid (75 ,l kg,1i.v.) into anaesthetized, open-chest, mechanically ventilated rabbits. Unit activities increased within seconds and peaked within a few minutes (from 0.3 ± 0.1 to 1.4 ± 0.9 impulses s,1 for CFRs and from 0.5 ± 0.1 to 1.7 ± 0.3 impulses s,1 for HTARs, both n= 8 and P < 0.05). These activities were sustained while pulmonary oedema developed and dynamic lung compliance decreased over the 90 min observation period. Activities in slowly adapting receptors and rapidly adapting receptors were also increased; however, their responsiveness to airway pressure stimulation decreased progressively. We conclude that pulmonary nociceptors are stimulated during acute lung injury. The dual nociceptor system, consisting of both non-myelinated CFRs and myelinated HTARs, may play an important role in the pathophysiological process of acute lung injury-induced respiratory responses. [source] Regulation of inflammation by PPARs: a future approach to treat lung inflammatory diseases?FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2006Julien Becker Abstract Lung inflammatory diseases, such as acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis, represent a major health problem worldwide. Although glucocorticoids are the most potent anti-inflammatory drug in asthma, they exhibit major side effects and have poor activity in lung inflammatory disorders such as ALI or COPD. Therefore, there is growing need for the development of alternative or new therapies to treat inflammation in the lung. Peroxisome proliferator-activated receptors (PPARs), including the three isotypes PPAR,, PPAR, (or PPAR,) and PPAR,, are transcription factors belonging to the nuclear hormone receptor superfamily. PPARs, and in particular PPAR, and PPAR,, are well known for their critical role in the regulation of energy homeostasis by controlling expression of a variety of genes involved in lipid and carbohydrate metabolism. Synthetic ligands of the two receptor isotypes, the fibrates and the thiazolidinediones, are clinically used to treat dyslipidaemia and type 2 diabetes, respectively. Recently however, PPAR, and PPAR, have been shown to exert a potent anti-inflammatory activity, mainly through their ability to downregulate pro-inflammatory gene expression and inflammatory cell functions. The present article reviews the current knowledge of the role of PPAR, and PPAR, in controlling inflammation, and presents different findings suggesting that PPAR, and PPAR, activators may be helpful in the treatment of lung inflammatory diseases. [source] Molecular mechanisms underlying inflammatory lung diseases in the elderly: Development of a novel therapeutic strategy for acute lung injury and pulmonary fibrosis,GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2005Takahide Nagase In the elderly, inflammatory lung diseases, including acute lung injury and pulmonary fibrosis, are significant in terms of both mortality and difficulty in management. Acute respiratory distress syndrome (ARDS) is an acute lung injury and the mortality rate for ARDS ranges from 40 to 70% despite intensive care. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder of the lung parenchyma. No useful drugs are currently available to treat IPF. However, molecular mechanisms underlying these lung diseases are little understood and the development of a novel therapeutic strategy is urgently needed. Platelet-activating factor (PAF) and metabolites of arachidonic acid, i.e. eicosanoids, are lipid mediators that have various biological effects. A key enzyme for the production of these inflammatory mediators, including eicosanoids and PAF, is phospholipase A2. In particular, cytosolic PLA2 (cPLA2) is especially important. The purpose of this article is to report novel findings regarding the role of PAF and cPLA2 in lung inflammatory diseases, especially, acute lung injury and pulmonary fibrosis. To address this question, we used mutant mice, i.e. PAFR transgenic mice, PAFR gene-disrupted mice and cPLA2 gene-disrupted mice. We have shown that PAF and eicosanoids, downstream mediators of cPLA2, may be involved in the pathogenesis of ARDS and IPF, which are important diseases in the elderly. Although there exist extreme differences in clinical features between ARDS and IPF, both diseases are fatal disorders for which no useful drugs are currently available. On the basis of recent reports using mutant mice, cPLA2 might be a potential target to intervene in the development of pulmonary fibrosis and acute lung injury in the elderly. [source] Response of lung ,, T cells to experimental sepsis in miceIMMUNOLOGY, Issue 1 2004Mark Hirsh Summary ,, T cells link innate and adaptive immune systems and may regulate host defence. Their role in systemic inflammation induced by trauma or infection (sepsis) is still obscured. The present study was aimed to investigate functions of lung ,, T cells and their response to experimental sepsis. Mice were subjected to caecal ligation and puncture (CLP) to induce sepsis and acute lung injury (ALI), or to the sham operation. Animals were killed 1, 4, and 7 days postoperatively; lungs were examined by histology, and isolated cells were studied by flow cytometry. Absolute number of ,, T cells progressively increased in lungs during sepsis, and reached a seven-fold increase at day 7 after CLP (3·84 ± 0·41 × 105/lung; P,=,0·0002 versus sham). A cellular dysfunction was revealed one day after CLP, as manifested by low cytolytic activity (22·3 ± 7·1%; P,<,0·05 versus sham), low interferon-, (IFN-,; 8·5 ± 2·5%; P,<,0·05 versus control) and interleukin-10 (IL-10) expression, and high tumour necrosis factor-, expression (19·5 ± 1·7%; P,<,0·05 versus control). The restoration of cytotoxicity, and increase in IFN-, and IL-10 expression was observed at day 7 of CLP-induced sepsis. In summary, our results demonstrate significant progressive accumulation of ,, T cells in lungs during CLP-induced ALI. The temporary functional suppression of lung ,, T cells found early after CLP may influence the outcome of sepsis, possibly being associated with uncontrolled inflammatory lung damage. [source] Early predictors of morbidity and mortality in trauma patients treated in the intensive care unitACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2010O. BRATTSTRÖM Background: We investigated the incidence and severity of post-injury morbidity and mortality in intensive care unit (ICU)-treated trauma patients. We also identified risk factors in the early phase after injury that predicted the later development of complications. Methods: A prospective observational cohort study design was used. One hundred and sixty-four adult patients admitted to the ICU for more than 24 h were included during a 21-month period. The incidence and severity of morbidity such as multiple organ failure (MOF), acute lung injury (ALI), severe sepsis and 30-day post-injury mortality were calculated and risk factors were analyzed with uni- and multivariable logistic regression analysis. Results: The median age was 40 years, the injury severity score was 24, the new injury severity score was 29, the acute physiology and chronic health evaluation II score was 15, sequential organ failure assessment maximum was 7 and ICU length of stay was 3.1 days. The incidences of post-injury MOF were 40.2%, ALI 25.6%, severe sepsis 31.1% and 30-day mortality 10.4%. The independent risk factors differed to some extent between the outcome parameters. Age, severity of injury, significant head injury and massive transfusion were independent risk factors for several outcome parameters. Positive blood alcohol was only a predictor of MOF, whereas prolonged rescue time only predicted death. Unexpectedly, injury severity was not an independent risk factor for mortality. Conclusions: Although the incidence of morbidity was considerable, mortality was relatively low. Early post-injury risk factors that predicted later development of complications differed between morbidity and mortality. [source] Radiographic lung density assessed by computed tomography is associated with extravascular lung water contentACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2010V. V. KUZKOV Background: We hypothesized that in acute lung injury (ALI), the volume of pulmonary tissue with aqueous density, as determined by spiral computed tomography (CT), is associated with extravascular lung water content. Our aim was to compare tissue volume index, as assessed by CT, before and after oleic acid-induced ALI, with extravascular lung water indexes (EVLWI), determined with single transpulmonary thermodilution (EVLWISTD), thermal-dye dilution (EVLWITDD), and postmortem gravimetry (EVLWIG). Methods: Seven instrumented sheep received an intravenous infusion of oleic acid 0.08 ml/kg (OA group) and four animals had vehicle only (Control group). The day before, and immediately after the experiment, sheep were anesthetized to undergo quantitative CT examinations during a short breath hold. Hemodynamics, oxygenation, EVLWISTD, and EVLWTDD were registered. Linear regression analysis was used to assess the relationships between EVLWISTD, EVLWTDD, EVLWIG, and lung tissue volume index (TVICT) determined with CT. Results: In the OA group, total lung volume increased compared with Controls. Poorly and non-aerated lung volumes increased a 3.6- and 4.9-fold, respectively, and TVICT almost doubled. EVLWISTD, EVLWITDD, and TVICT were associated significantly with EVLWIG (r=0.85, 0.90, and 0.88, respectively; P<0.001). TVICT deviated from the reference EVLWIG values to the greatest extent with a mean bias ± 2SD of 4.0 ± 6.0 ml/kg. Conclusions: In ovine oleic acid-induced ALI, lung tissue volume, as assessed by quantitative CT, is in close agreement with EVLWI, as determined by indicator dilution methods and postmortem gravimetry, but overestimates lung fluid content. [source] Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injuryINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 6 2007Dieudonnée Togbe Summary Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation. [source] Diagnosing acute lung injury in the critically ill: a national survey among critical care physiciansACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 10 2009A. P. J. VLAAR Background: Incidence reports on acute lung injury (ALI) vary widely. An insight into the diagnostic preferences of critical care physicians when diagnosing ALI may improve identification of the ALI patient population. Methods: Critical care physicians in the Netherlands were surveyed using vignettes involving hypothetical patients and a questionnaire. The vignettes varied in seven diagnostic determinants based on the North American European Consensus Conference and the lung injury score. Preferences were analyzed using a mixed-effects logistic regression model and presented as an odds ratio (OR) with a 95% confidence interval. Results: From 243 surveys sent to 30 hospitals, 101 were returned (42%). ORs were as follows: chest X-ray consistent with ALI: OR 1.7 (1.3,2.3), high positive end-expiratory pressure (PEEP) (15 cmH2O): OR 5.0 (3.9,6.6), low pulmonary artery occlusion pressures (PAOP) (<18 mmHg): OR 4.7 (3.6,6.1), low compliance (30 ml/cmH2O): OR 0.7 (0.5,0.9), low PaO2/FiO2 (<250 mmHg): OR 9.2 (6.9,12.3), absence of heart failure: OR 1.2 (0.9,1.5), presence of a risk factor for ALI (sepsis): OR 1.0 (0.8,1.3). The questionnaire revealed that critical care physicians with an anesthesiology background differed from physicians with an internal medicine background with regard to hemodynamic variables when considering an ALI diagnosis (P<0.05). Conclusions: Dutch critical care physicians consider the PEEP level, but not the presence of a risk factor for ALI, as an important factor to diagnose ALI. Background specialty of critical care physicians influences diagnostic preferences and may account for variance in the reported incidence of ALI. [source] Electrical impedence tomography and heterogeneity of pulmonary perfusion and ventilation in porcine acute lung injuryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 10 2009A. FAGERBERG Background: The heterogeneity of pulmonary ventilation (V), perfusion (Q) and V/Q matching impairs gas exchange in an acute lung injury (ALI). This study investigated the feasibility of electrical impedance tomography (EIT) to assess the V/Q distribution and matching during an endotoxinaemic ALI in pigs. Methods: Mechanically ventilated, anaesthetised pigs (n=11, weight 30,36 kg) were studied during an infusion of endotoxin for 150 min. Impedance changes related to ventilation (ZV) and perfusion (ZQ) were monitored globally and bilaterally in four regions of interest (ROIs) of the EIT image. The distribution and ratio of ZV and ZQ were assessed. The alveolar,arterial oxygen difference, venous admixture, fractional alveolar dead space and functional residual capacity (FRC) were recorded, together with global and regional lung compliances and haemodynamic parameters. Values are mean±standard deviation (SD) and regression coefficients. Results: Endotoxinaemia increased the heterogeneity of ZQ but not ZV. Lung compliance progressively decreased with a ventral redistribution of ZV. A concomitant dorsal redistribution of ZQ resulted in mismatch of global (from ZV/ZQ 1.1±0.1 to 0.83±0.3) and notably dorsal (from ZV/ZQ 0.86±0.4 to 0.51±0.3) V and Q. Changes in global ZV/ZQ correlated with changes in the alveolar,arterial oxygen difference (r2=0.65, P<0.05), venous admixture (r2=0.66, P<0.05) and fractional alveolar dead space (r2=0.61, P<0.05). Decreased end-expiratory ZV correlated with decreased FRC (r2=0.74, P<0.05). Conclusions: EIT can be used to assess the heterogeneity of regional pulmonary ventilation and perfusion and V/Q matching during endotoxinaemic ALI, identifying pivotal pathophysiological changes. [source] Comparison of the effects of erdosteine and N-acetylcysteine on apoptosis regulation in endotoxin-induced acute lung injuryJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2006Rezan Demiralay Abstract This study was carried out to investigate comparatively the frequency of apoptosis in lung epithelial cells after intratracheal instillation of endotoxin [lipopolysaccharide (LPS)] in rats and the role of tumor necrosis factor alpha (TNF- ,) on apoptosis, and the effects of erdosteine and N-acetylcysteine on the regulation of apoptosis. Female Wistar rats were given oral erdosteine (10,500 mg kg,1) or N-acetylcysteine (10,500 mg kg,1) once a day for 3 consecutive days. Then the rats were intratracheally instilled with LPS (5 mg kg,1) to induce acute lung injury. The rats were killed at 24 h after LPS administration. Lung tissue samples were stained with hematoxylin-eosin for histopathological assessments. The apoptosis level in the lung bronchial and bronchiolar epithelium was determined using the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling) method. Cytoplasmic TNF- , was evaluated by immunohistochemistry. Pretreatment with erdosteine and pretreatment with N-acetylcysteine at a dose of 10 mg kg,1 had no protective effect on LPS-induced lung injury. When the doses of drugs increased, the severity of the lung damage caused by LPS decreased. It was found that as the pretreatment dose of erdosteine was increased, the rate of apoptosis induced by LPS in lung epithelial cells decreased and this decrease was statistically significant in doses of 300 mg kg,1 and 500 mg kg,1. Pretreatment with N-acetylcysteine up to a dose of 500 mg kg,1 did not show any significant effect on apoptosis regulation. It was noticed that both antioxidants had no significant effect on the local production level of TNF- ,. These findings suggest that erdosteine could be a possible therapeutic agent for acute lethal lung injury and its mortality. Copyright © 2006 John Wiley & Sons, Ltd. [source] Attenuation of half sulfur mustard gas-induced acute lung injury in ratsJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2006Shannon D. McClintock Abstract Airway instillation into rats of 2-chloroethyl ethyl sulfide (CEES), the half molecule of sulfur mustard compound, results in acute lung injury, as measured by the leak of plasma albumin into the lung. Morphologically, early changes in the lung include alveolar hemorrhage and fibrin deposition and the influx of neutrophils. Following lung contact with CEES, progressive accumulation of collagen occurred in the lung, followed by parenchymal collapse. The co-instillation with CEES of liposomes containing pegylated (PEG)-catalase (CAT), PEG-superoxide dismutase (SOD), or the combination, greatly attenuated the development of lung injury. Likewise, the co-instillation of liposomes containing the reducing agents, N-acetylcysteine (NAC), glutathione (GSH), or resveratrol (RES), significantly reduced acute lung injury. The combination of complement depletion and airway instillation of liposomes containing anti-oxidant compounds maximally attenuated CEES-induced lung injury by nearly 80%. Delayed airway instillation of anti-oxidant-containing liposomes (containing NAC or GSH, or the combination) significantly diminished lung injury even when instillation was delayed as long as 1 h after lung exposure to CEES. These data indicate that CEES-induced injury of rat lungs can be substantially diminished by the presence of reducing agents or anti-oxidant enzymes delivered via liposomes. Copyright © 2005 John Wiley & Sons, Ltd. [source] The central role of Fas-ligand cell signaling in inflammatory lung diseasesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2004G. A. DosReis Abstract Following inflammation and injury in the lung, loss of epithelial cell precursors could determine the balance between tissue regeneration and fibrosis. This review discusses evidence that proapoptotic Fas-Fas ligand (FasL) signaling plays a central role in pulmonary inflammation, injury and fibrosis. FasL signaling induces inflammatory apoptosis in epithelial cells and alveolar macrophages, with concomitant IL-1, and chemokine release, leading to neutrophil infiltration. FasL signaling plays a critical role in models of acute lung injury, idiopathic pulmonary fibrosis and silicosis; blockade of Fas-FasL interactions either prevents or attenuates pulmonary inflammation and fibrosis. Serologic and immunohistochemical studies in patients support a major pathogenic role of Fas and FasL molecules in inflammatory lung diseases. Identification of the pathogenic role of FasL could facilitate the discovery of more effective treatments for currently untreatable inflammatory lung diseases. [source] Modelling survival in acute severe illness: Cox versus accelerated failure time modelsJOURNAL OF EVALUATION IN CLINICAL PRACTICE, Issue 1 2008John L. Moran MBBS FRACP FJFICM MD Abstract Background, The Cox model has been the mainstay of survival analysis in the critically ill and time-dependent covariates have infrequently been incorporated into survival analysis. Objectives, To model 28-day survival of patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), and compare the utility of Cox and accelerated failure time (AFT) models. Methods, Prospective cohort study of 168 adult patients enrolled at diagnosis of ALI in 21 adult ICUs in three Australian States with measurement of survival time, censored at 28 days. Model performance was assessed as goodness-of-fit [GOF, cross-products of quantiles of risk and time intervals (P , 0.1), Cox model] and explained variation (,R2', Cox and ATF). Results, Over a 2-month study period (October,November 1999), 168 patients with ALI were identified, with a mean (SD) age of 61.5 (18) years and 30% female. Peak mortality hazard occurred at days 7,8 after onset of ALI/ARDS. In the Cox model, increasing age and female gender, plus interaction, were associated with an increased mortality hazard. Time-varying effects were established for patient severity-of-illness score (decreasing hazard over time) and multiple-organ-dysfunction score (increasing hazard over time). The Cox model was well specified (GOF, P > 0.34) and R2 = 0.546, 95% CI: 0.390, 0.781. Both log-normal (R2 = 0.451, 95% CI: 0.321, 0.695) and log-logistic (R2 0.470, 95% CI: 0.346, 0.714) AFT models identified the same predictors as the Cox model, but did not demonstrate convincingly superior overall fit. Conclusions, Time dependence of predictors of survival in ALI/ARDS exists and must be appropriately modelled. The Cox model with time-varying covariates remains a flexible model in survival analysis of patients with acute severe illness. [source] Additives in intravenous anesthesia modulates pulmonary inflammation in a model of LPS-induced respiratory distressACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2009J. J. HAITSMA Background: It has been suggested that propofol with ethylenediaminetetraacetic acid (EDTA) can modulate the systemic inflammatory response. Prolonged higher levels of pulmonary inflammation are associated with poor outcome of patients with acute lung injury. In the present study, we hypothesized that pulmonary inflammation could be modulated by propofol with EDTA compared with propofol with sulfite. Methods: Respiratory distress was induced in rats (n=25) by intratracheal nebulization of lipopolysaccharide (LPS). After 24 h, animals were randomized to either propofol with EDTA (PropofolEDTA), propofol with sulfite (Propofolsulfite) or ketamine/midazolam (Ket/Mid); control animals received saline (n=30). Animals were ventilated for 4 h and blood gases were measured hourly. Bronchoalveolar lavage (BAL) was performed for cytokine analysis of: tumor necrosis factor (TNF), interleukin (IL)-6 and macrophage inflammatory protein (MIP)-2. Results: LPS led to increased pulmonary inflammation in all groups compared with the control groups. Gas exchange deteriorated over time only in the LPS Propofolsulfite group and was significantly lower than the Ket/Mid group. Only IL-6 was significantly higher in the LPS Propofolsulfite group compared with both the Ket/Mid group and the PropofolEDTA group. Conclusion: Pulmonary IL-6 can be modulated by additives in systemic anesthesia. Implication Statement: This study demonstrates that pulmonary inflammation caused by direct lung injury can be modulated by intravenous anesthesia used in critically ill patients. [source] Hemodynamic effects of PEEP in a porcine model of HCl-induced mild acute lung injuryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2009C. K. MARUMO Background: Positive end-expiratory pressure (PEEP) and sustained inspiratory insufflations (SI) during acute lung injury (ALI) are suggested to improve oxygenation and respiratory mechanics. We aimed to investigate the hemodynamic effects of PEEP with and without alveolar recruiting maneuver in a mild ALI model induced by inhalation of hydrochloric acid. Methods: Thirty-two pigs were randomly allocated into four groups (Control,PEEP, Control,SI, ALI,PEEP and ALI,SI). ALI was induced by intratracheal instillation of hydrochloric acid. PEEP values were progressively increased and decreased from 5, 10, 15 and 20 cmH2O in all groups. Three SIs maneuvers of 30 cmH2O for 20 s were applied to the assignable groups between each PEEP level. Transesophageal echocardiography (TEE), global hemodynamics, oxygenation indexes and gastric tonometry were measured 5 min after the maneuvers had been concluded and at each established value of PEEP (5, 10, 15 and 20 cmH2O). Results: The cardiac index, ejection fraction and end-diastolic volume of right ventricle were significantly (P<0.001) decreased with PEEP in both Control and ALI groups. Left ventricle echocardiography showed a significant decrease in end-diastolic volume at 20 cmH2O of PEEP (P<0.001). SIs did not exert any significant hemodynamic effects either early (after 5 min) or late (after 3 h). Conclusions: In a mild ALI model induced by inhalation of hydrochloric acid, significant hemodynamic impairment characterized by cardiac function deterioration occurred during PEEP increment, but SI, probably due to low applied values (30 cmH2O), did not exert further negative hemodynamic effects. PEEP should be used cautiously in ALI caused by acid gastric content inhalation. [source] Involvement of thromboxane A2 (TXA2) in the early stages of oleic acid-induced lung injury and the preventive effect of ozagrel, a TXA2 synthase inhibitor, in guinea-pigsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2004Yoichi Ishitsuka ABSTRACT An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and pulmonary vascular hyper-permeability. Although oleic acid lung injury is used as a model of acute respiratory distress syndrome (ARDS), the precise mechanisms of the lung injury are still unclear. We have investigated whether thromboxane A2 (TXA2) participated in the lung injury and have evaluated the efficacy of ozagrel, a TXA2 synthase inhibitor, on the lung injury in guinea-pigs. Oleic acid injection increased the plasma level of TXB2, a stable metabolite of TXA2, and the time-course of plasma TXB2 was similar to that of the decreased partial oxygen pressure of arterial blood (Pao2) induced with oleic acid. Ozagrel administered intravenously 30 min before oleic acid injection prevented the decrease in Pao2 and pulmonary vascular hyper-permeability. It also prevented increases in lactate dehydrogenase activity, a measure of lung cell injury, TXB2 and its weight ratio to 6-keto prostaglandin F1 , in bronchoalveolar lavage fluid. Although ozagrel administered simultaneously with oleic acid ameliorated the decrease in Pao2, post treatment showed little effect. We suggest that TXA2 participated in the oleic acid lung injury, as an "early phase" mediator, and rapidly-acting TXA2 synthase inhibitors were effective in the prevention of acute lung injury. [source] N -Acetylcysteine Improves Group B Streptococcus Clearance in a Rat Model of Chronic Ethanol IngestionALCOHOLISM, Issue 7 2009Sonja M. Tang Background:, Sepsis is the most common risk factor associated with acute respiratory distress syndrome (ARDS) and results in a 40,60% mortality rate due to respiratory failure. Furthermore, recent epidemiological studies have demonstrated that a history of alcohol abuse increases the risk of ARDS by 3.6-fold. More recently, group B streptococcus (GBS) infections in nonpregnant adults have been increasing, particularly in alcoholics where there is an increased risk of lobular invasion and mortality. We have shown in an established rat model that chronic ethanol ingestion impaired macrophage internalization of inactivated infectious particles in vitro and enhanced bidirectional protein flux across the alveolar epithelial-endothelial barriers, both of which were attenuated when glutathione precursors were added to the diet. We hypothesized that chronic ethanol ingestion would increase the risk of infection even though GBS is less pathogenic but that dietary N -acetylcysteine (NAC), a glutathione precursor, would improve in vivo clearance of infectious particles and reduce systemic infection. Methods:, After 6 weeks of ethanol feeding, rats were given GBS intratracheally and sacrificed 24 hours later. GBS colony-forming units were counted in the lung, liver, spleen, and bronchoalveolar lavage fluid. Acute lung injury in response to GBS was also assessed. Results:, Chronic ethanol exposure decreased GBS clearance from the lung indicating an active lung infection. In addition, increased colonies formed within the liver and spleen indicated that ethanol increased the risk of systemic infection. Ethanol also exacerbated the acute lung injury induced by GBS. NAC supplementation normalized GBS clearance by the lung, prevented the appearance of GBS systemically, and attenuated acute lung injury. Conclusions:, These data suggested that chronic alcohol ingestion increased the susceptibility of the lung to bacterial infections from GBS as well as systemic infections. Furthermore, dietary NAC improved in vivo clearance of GBS particles, attenuated acute lung injury, and disseminated infection. [source] Increased Fibronectin Expression in Lung in the Setting of Chronic Alcohol AbuseALCOHOLISM, Issue 4 2007Ellen L. Burnham Rationale: The incidence and severity of the acute respiratory distress syndrome (ARDS) is increased in individuals who abuse alcohol. One possible mechanism by which alcohol increases susceptibility to acute lung injury is through alterations in alveolar macrophage function and induction of tissue remodeling activity. Our objective was to determine whether alcohol abuse, independent of other comorbidities, alters fibronectin and metalloproteinase gene expression in alveolar macrophages and in epithelial lining fluid (ELF) of the lung. Methods: Otherwise healthy subjects with alcohol abuse (n=21) and smoking-matched controls (n=17) underwent bronchoalveolar lavage. Alveolar macrophage fibronectin and matrix metalloproteinase (MMP) mRNA expression were measured via reverse transcription-polymerase chain reaction. The supernatant from cultured alveolar macrophages and lung ELF were tested for their ability to induce fibronectin and MMP-9 gene transcription in cell-based assays. Results: Alveolar macrophages from subjects with alcohol abuse demonstrated increased fibronectin mRNA expression (p<0.001), and their ELF also elicited more fibronectin gene transcription in lung fibroblasts compared with controls (p<0.001). In contrast, alveolar macrophages from subjects with alcohol abuse had decreased MMP-9 and MMP-2 mRNA expression (p<0.03 and p<0.005, respectively). Similarly, the supernatant (p<0.001) and ELF (p<0.01) from these subjects induced less MMP-9 gene transcription in THP-1 cells. Discussion: Alcohol abuse is associated with increased fibronectin mRNA expression in alveolar macrophages and increased fibronectin-inducing activity in the ELF. This appears to be a specific effect as other tissue remodeling genes, such as MMPs, were not equally affected. These findings suggest activation of tissue remodeling that may contribute to the increased susceptibility for the ARDS observed in alcoholism. [source] Mechanical Ventilation Exacerbates Alveolar Macrophage Dysfunction in the Lungs of Ethanol-Fed RatsALCOHOLISM, Issue 8 2005Pradip P. Kamat Background: Patients with alcohol abuse have a two- to three-fold increased risk of acute lung injury and respiratory failure after sepsis or trauma but are also at increased risk of nosocomial pneumonia. Mechanical ventilation exacerbates lung injury during critical illnesses. In this study we tested whether mechanical ventilation of the alcoholic lung promotes on balance a proinflammatory phenotype favoring ventilator-induced lung injury or an immunosuppressive phenotype favoring ventilator-associated pneumonia. Methods: Lungs from rats fed an isocaloric diet with or without ethanol (six weeks) were isolated and ventilated ex vivo with a low-volume (protective) or high-volume (injurious) strategy for two hours with or without prior endotoxemia (two hours). In other experiments, rats were subjected to high-volume ventilation in vivo. Airway levels of the proinflammatory cytokines tumor necrosis factor-,, macrophage inflammatory protein-2, and interleukin-1, were determined after mechanical ventilation ex vivo and compared with edematous lung injury after high-volume ventilation in vivo. In parallel, alveolar macrophage phagocytosis of bacteria and secretion of interleukin-12 during ventilation ex vivo and endotoxin-stimulated alveolar macrophage phagocytosis and tumor necrosis factor-, secretion in vitro were determined. Results: Ethanol ingestion suppressed the proinflammatory response to injurious mechanical ventilation and did not increase experimental ventilator-induced lung injury. In parallel, ethanol ingestion blunted the innate immune response of alveolar macrophages during injurious ventilation ex vivo and after endotoxin stimulation in vitro. Conclusions: Ethanol ingestion dampens ventilator-induced inflammation but exacerbates macrophage immune dysfunction. These findings could explain at least in part why alcoholic patients are at increased risk of ventilator-associated pneumonia. [source] | |||||||||||||||||||||||||||||||||||||