Mortality In Acute Lung Injury Research Articles

Senescence in Alveolar Epithelial Type II Cells Promotes Acute Lung Injury and Impairs Regeneration.

Mortality of acute lung injury (ALI) increases with age. Alveolar epithelial type 2 cells (AEII) are the progenitor cells of the alveolar epithelium and crucial for repair after injury. We hypothesize that telomere dysfunction-mediated AEII senescence impairs regeneration and promotes the development of ALI. To discriminate between the impact of old age and AEII senescence in ALI, young (3 months) and old (18 months) Sftpc-Ai9 mice and young Sftpc-Ai9-Trf1 mice with inducible Trf1 knockout-mediated senescence in AEII were treated with 1 µg lipopolysaccharide (LPS)/g BW (n=9-11). Control mice received saline (n=7). Mice were sacrificed 4 or 7 days later. Lung mechanics, pulmonary inflammation and proteomes were analyzed and parenchymal injury, AEII proliferation and AEI differentiation rate were quantified using stereology. Old mice showed 55% mortality by day 4, whereas all young mice survived. Pulmonary inflammation was most severe in old mice, followed by Sftpc-Ai9-Trf1 mice. Young Sftpc-Ai9 mice recovered almost completely by day 7, while Sftpc-Ai9-Trf1 mice still showed mild signs of injury. An expansion of AEII was only measured in young Sftpc-Ai9 mice at day 7. Aging and telomere dysfunction-mediated senescence had no impact on AEI differentiation rate in controls, but the reduced number of AEII in Sftpc-Ai9-Trf1 mice also affected de-novo differentiation after injury. In conclusion, telomere dysfunction-mediated AEII senescence promoted parenchymal inflammation in ALI, but did not enhance mortality like old age. While Differentiation rate remained functional with old age and AEII senescence, AEII proliferative capacity was impaired in ALI, affecting the regenerative ability.

Aqueous extract of Descuraniae Semen attenuates lipopolysaccharide-induced inflammation by inhibiting ER stress and WNK4-SPAK-NKCC1 pathway.

Sepsis causes systemic inflammatory responses and acute lung injury (ALI). Despite modern treatments, sepsis-related ALI mortality remains high. Aqueous extract of Descuraniae Semen (AEDS) exerts anti-endoplasmic reticulum (ER) stress, antioxidant and anti-inflammatory effects. AEDS alleviates inflammation and oedema in ALI. Sodium-potassium-chloride co-transporter isoform 1 (NKCC1) is essential for regulating alveolar fluid and is important in ALI. The NKCC1 activity is regulated by upstream with-no-lysine kinase-4 (WNK4) and STE20/SPS1-related proline/alanine-rich kinase (SPAK). This study aimed to investigate the effects of AEDS on lipopolysaccharide (LPS)-induced ALI model in A549 cells, considering the regulation of ER stress, WNK4-SPAK-NKCC1 cascades, inflammation and apoptosis. Cell viability was investigated by the CCK-8 assay. The expressions of the proteins were assessed by immunoblotting analysis assays. The levels of pro-inflammatory cytokines were determined by ELISA. The expression of cytoplasmic Ca2+ in A549 cells was determined using Fluo-4 AM. AEDS attenuates LPS-induced inflammation, which is associated with increased pro-inflammatory cytokine expression and activation of the WNK4-SPAK-NKCC1 pathway. AEDS inhibits the WNK4-SPAK-NKCC1 pathway by regulating of Bcl-2, IP3R and intracellular Ca2+. WNK4 expression levels are significantly higher in the WNK4-overexpressed transfected A549 cells and significantly decrease after AEDS treatment. AEDS attenuates LPS-induced inflammation by inhibiting the WNK4-SPAK-NKCC1 cascade. Therefore, AEDS is regarded as a potential therapeutic agent for ALI.

Decreased LPS-induced lung injury in pigs treated with a lung surfactant protein A-derived nonapeptide that inhibits peroxiredoxin 6 activity and subsequent NOX1,2 activation.

This study addressed the efficacy of a liposome-encapsulated nine amino acid peptide [peroxiredoxin 6 PLA2 inhibitory peptide-2 (PIP-2)] for the prevention or treatment of acute lung injury (ALI) +/- sepsis. PIP-2 inhibits the PLA2 activity of peroxiredoxin 6 (Prdx6), thereby preventing rac release and activation of NADPH oxidases (NOXes), types 1 and 2. Female Yorkshire pigs were infused intravenously with lipopolysaccharide (LPS) + liposomes (untreated) or LPS + PIP-2 encapsulated in liposomes (treated). Pigs were mechanically ventilated and continuously monitored; they were euthanized after 8 h or earlier if preestablished humane endpoints were reached. Control pigs (mechanical ventilation, no LPS) were essentially unchanged over the 8 h study. LPS administration resulted in systemic inflammation with manifestations of clinical sepsis-like syndrome, decreased lung compliance, and a marked decrease in the arterial Po2 with vascular instability leading to early euthanasia of 50% of untreated animals. PIP-2 treatment significantly reduced the requirement for supportive vasopressors and the manifestations of lung injury so that only 25% of animals required early euthanasia. Bronchoalveolar lavage fluid from PIP-2-treated versus untreated pigs showed markedly lower levels of total protein, cytokines (TNF-α, IL-6, IL-1β), and myeloperoxidase. Thus, the porcine LPS-induced sepsis-like model was associated with moderate to severe lung pathophysiology compatible with ALI, whereas treatment with PIP-2 markedly decreased lung injury, cardiovascular instability, and early euthanasia. These results indicate that inhibition of reactive oxygen species (ROS) production via NOX1/2 has a beneficial effect in treating pigs with LPS-induced ALI plus or minus a sepsis-like syndrome, suggesting a potential role for PIP-2 in the treatment of ALI and/or sepsis in humans.NEW & NOTEWORTHY Currently available treatments that can alter lung inflammation have failed to significantly alter mortality of acute lung injury (ALI). Peroxiredoxin 6 PLA2 inhibitory peptide-2 (PIP-2) targets the liberation of reactive O2 species (ROS) that is associated with adverse cell signaling events, thereby decreasing the tissue oxidative injury that occurs early in the ALI syndrome. We propose that treatment with PIP-2 may be effective in preventing progression of early disease into its later stages with irreversible lung damage and relatively high mortality.

Blood coagulation system in experimental acute lung injury and its treatment with dexamethasone

The effects of short- and long-term administrations of dexamethasone on survival, severity of pulmonary edema, and hemostasis on experimental lipopolysaccharide-induced acute lung injury in rats were analyzed. Acute lung injury in rats was modeled by the intratracheal injection of lipopolysaccharide from the Salmonella enterica cell wall. White male rats were randomly divided into nine groups: the intact group consisted of 10 animals; two control groups of 20 animals each, in which acute lung injury was simulated without further treatment and removed from the experiment on day 3 or 7; six comparison groups of 20 animals each, in which, 3 h after modeling of acute lung injury and then once a day for 3 days (short mode of administration) or 7 days (long mode of administration), dexamethasone solution was administered intraperitoneally in the following doses: 0. 52 (equivalent to 6 mg/day for humans), 1. 71 (20 mg/day for humans), and 8 mg/kg/day (94 mg/day, pulse therapy for humans). On days 3 and 7, the survival rate, coagulogram values (active partial thromboplastin time, prothrombin time, activity of antithrombin, and soluble fibrin monomer complexes), and low-frequency piezotromboelastography data were assessed in the surviving animals. The results revealed that dexamethasone reduces mortality in acute lung injury and has a dose-dependent effect on the hemostasis system: with an increase in the dose administered, blood clotting processes increase and fibrinolysis is inhibited. Low-frequency piezothromboelastography with a conventional coagulogram allows for a comprehensive assessment of the hemostasis system, identifying violations, and timely drug correction.

Design, synthesis and anti-inflammatory activity study of lansiumamide analogues for treatment of acute lung injury

Acute lung injury (ALI) is an inflammation-mediated respiratory disease with a high mortality rate. Medications with anti-inflammatory small molecules have been demonstrated in phase I and II clinical trials to considerably reduce the ALI mortality. In this study, two series of lansiumamide analogues were designed, synthesized, and evaluated for anti-inflammatory activity for ALI treatment. We found that compound 8n exhibited the best anti-inflammatory activity through inhibiting LPS-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) in Raw264.7 cells and activating the Nrf2/HO-1 pathway. Furthermore, we discovered in a LPS-induced ALI mice model that compound 8n significantly reduced the infiltration of inflammatory cells into lung tissue to achieve the effect of protecting lung tissues and improving ALI. Additionally, our mice model study revealed that compound 8n had a good expectorant effect. These results consistently support that lansiumamide analogue 8n represents a new class of anti-inflammatory agents with potential as a lead compound for further development into a therapeutic drug for ALI treatment.

Prevention of mortality in acute lung injury induced by oleic acid: Application of polyherbal decoction (bronco T).

Acute lung injury (ALI) is a lethal respiratory disorder; directed uncontrolled inflammation, sloughing of the alveolar cells and their diffusion, and altered cardiorespiratory parameters with a global mortality rate of 40%. This study was designed to assess the preventive effect of a polyherbal decoction (Bronco T, 1.5 g/kg b. w.) on cardiorespiratory variables in oleic acid-induced ALI in rats. Oleic acid increases the level of neutrophil infiltration leading to pulmonary edema and alters the cardiorespiratory dynamics. The adult male rats were surgically cannulated and treated with intravenous oleic acid (0.38 ml/kg b. w.) to establish the ALI model. Bronco T was pre-administered orally 3 hours before oleic acid. The biophysical, histological, biochemical, and molecular effects were compared with dexamethasone (5 mg/kg b. w. i. p.). The animals were randomly divided into control, lethal, standard, and treatment groups. Respiratory frequency (RF), heart rate (HR), and mean arterial pressure (MAP) were recorded on a computerized chart recorder; arterial blood sample was collected to determine PaO2/FiO2, TNF-α, and MPO. Lipid peroxidation, superoxide dismutase, and catalase activity were evaluated to measure oxidative stress in bronchoalveolar lavage. Additionally, the pulmonary water content, COX-2 expression and histological examination were determined in the lung. A molecular docking study of the active phytoconstituent of BT obtained from HR-LCMS analysis against reported targets (IL-6, COX-2, TNFα, MPO and ENaC) of ALI was carried out. The B.T. pretreatment prevents mortality in comparison to the oleic acid group. It protects the lungs and heart from the detrimental effect of oleic acid, on par with dexamethasone. COX-2 mRNA expression was significantly down-regulated in the treatment group. The reduced level of TNF-α, MPO, SOD and catalase supported the protective effect of B.T. The in silico study revealed strong binding interaction between the phytoconstituent (Galangin 3- [galactosyl-(1–4)-rhamnoside and Beta solamarine] of BT and the reported target. The B.T. pre-administration attenuates the oleic acid-induced mortality and cardiorespiratory toxicity.

Inhibition of KLF6 reduces the inflammation and apoptosis of type II alveolar epithelial cells in acute lung injury.

The development of acute lung injury (ALI) into a severe stage leads to acute respiratory distress syndrome (ARDS). The morbidity and mortality of ALI and ARDS are very high. Objective: This study is aimed to explore the effect of Krüppel-like factor 6 (KLF6) on lipopolysaccharide (LPS)-induced type II alveolar epithelial cells in ALI by interacting with cysteine-rich angiogenic inducer 61 (CYR61). ALI mice model and LPS-induced type II alveolar epithelial cells were conducted to simulate ALI in vivo and in vitro. The messenger RNA (mRNA) and protein expression of KLF6 in lung tissues were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Pathological changes in lung tissues were observed by hematoxylin and eosin (H&E) staining. The viability and KLF6 expression of A549 cells treated with different concentrations of LPS were detected by cell counting kit-8 (CCK-8) assay, RT-qPCR, and Western blot analysis. After indicated treatment, the viability and apoptosis of A549 cells were analyzed by CCK-8 and TUNEL assays, and the inflammation factors of A549 cells were detected by Enzyme-linked-immunosorbent serologic assay, RT-qPCR, and Western blot analysis. The combination of KLF6 and CYR61 was determined by chromatin immunoprecipitation (ChIP)-PCR and dual-luciferase reporter assay. KLF6 expression was increased in lung tissues of ALI mice and LPS-induced A549 cells. Interference with KLF6 improved the viability, reduced the inflammatory damage, and promoted the apoptosis of LPS-induced A549 cells. In addition, KLF6 could bind to CYR61. Interference with KLF6 could decrease CYR61 expression in LPS-induced A549 cells. LPS also enhanced the TLR4/MYD88 signaling pathway, which was reversed by KLF6 interference. The above phenomena in LPS-induced A549 cells transfected with Si-KLF6 could be reversed by overexpression of CYR61. Inhibition of KLF6 promoted the viability and reduced the inflammation and apoptosis of LPS-induced A549 cells, which was reversed by CYR61.

Actin fence therapy with exogenous V12Rac1 protects against acute lung injury.

High mortality in acute lung injury (ALI) results from sustained proinflammatory signaling by alveolar receptors, such as TNF-α receptor type 1 (TNFR1). Factors that determine the sustained signaling are not known. Unexpectedly, optical imaging of live alveoli revealed a major TNF-α–induced surge of alveolar TNFR1 due to a Ca2+-dependent mechanism that decreased the cortical actin fence. Mouse mortality due to inhaled LPS was associated with cofilin activation, actin loss, and the TNFR1 surge. The constitutively active form of the GTPase, Rac1 (V12Rac1), given intranasally (i.n.) as a noncovalent construct with a cell-permeable peptide, enhanced alveolar filamentous actin (F-actin) and blocked the TNFR1 surge. V12Rac1 also protected against ALI-induced mortality resulting from i.n. instillation of LPS or of Pseudomonas aeruginosa. We propose a potentially new therapeutic paradigm in which actin enhancement by exogenous Rac1 strengthens the alveolar actin fence, protecting against proinflammatory receptor hyperexpression, and therefore blocking ALI.

Phosphoproteome profiling provides insight into the mechanisms of ventilator-induced lung injury.

The incidence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is a common health problem in the clinic and is projected to increase in prevalence in the future. Mechanical ventilation is commonly used to provide respiratory support and has become indispensable in emergency and critical medicine. However, ventilator use can result in lung tissue damage, collectively termed ventilator-induced lung injury (VILI). In the present study, phosphoprotein profiling of blood and tissue samples from ventilated and non-ventilated mice was performed and key changes in protein levels and cell signaling during VILI were identified. Activation of the PI3K/AKT and mitogen activated protein kinase signaling pathways, in addition to changes in expression of cancer, inflammatory and cell-death related proteins were detected in response to mechanical ventilation. Focal adhesion-related protein levels and signaling pathways were also significantly altered in an injury model compared with control. VILI can affect patient mortality in ALI and ARDS cases, and no targeted treatment options currently exist. Identifying biomarkers and understanding the signaling pathways associated with VILI is critical for the development of future therapies.

Therapeutic Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury Mice

The incidence and mortality of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are still very high, but stem cells show some promise for its treatment. Here we found that intratracheal administration of human umbilical cord-mesenchymal stem cells (UC-MSCs) significantly improved survival and attenuated the lung inflammation in lipopolysaccharide (LPS)-induced ALI mice. We also used the proteins-chip and bioinformatics to analyze interactions between UC-MSCs treatment and immune-response alternations of ALI mice. Then we demonstrated that UC-MSCs could inhibit the inflammatory response of mouse macrophage in ALI mice, as well as enhance its IL-10 expression. We provide data to support the concept that the therapeutic capacity of UC-MSCs for ALI was primarily through paracrine secretion, particularly of prostaglandin-E2 (PGE2). Furthermore, we showed that UC-MSCs might secrete a panel of factors including GM-CSF, IL-6 and IL-13 to ameliorate ALI. Our study suggested that UC-MSCs could protect LPS-induced ALI model by immune regulation and paracrine factors, indicating that UC-MSCs should be a promising strategy for ALI/ARDS.

Fibrocytes Ameliorate Acute Lung Injury by Decreasing Inflammatory Cytokine and Chemokine Levels and Reducing Neutrophil Accumulation in the Lung

Background/Aims: Acute lung injury (ALI) remains a severe disease that threatens human life around the world. To decrease the mortality of ALI and improve ALI treatment efficacy, the development of more ALI treatments is urgently needed. Whether fibrocytes directly participate in ALI has not been studied. Therefore, a mouse model of ALI was induced with lipopolysaccharide (LPS). Methods: Fibrocytes were harvested from peripheral blood mononuclear cells of bleomycin mice and identified by using flow cytometry to detect the expression of molecular makers. The fibrocytes were injected for the treatment of acute lung injury mice. The curative effects were evaluated by using ELISA to determine the cytokines (including TNF-α, IL-6 and IFN-γ) concentrations in bronchoalveolar lavage fluid (BALF) supernatant. Results: The concentrations of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) were increased in mice with ALI induced with LPS. The concentrations of TNF-α, IL-6, and IFN-γ as well as their mRNA and protein expression levels were decreased by administration of fibrocytes. The effect of fibrocytes in ameliorating ALI was time dependent. LPS treatment induced an increase in myeloperoxidase (MPO) activity, whereas the fibrocyte treatment caused inhibition of MPO activity as well as expression of the neutrophil-chemoattractant chemokine macrophage inflammatory protein 2 (MIP-2). Conclusion: Taken together, these data suggest that fibrocytes ameliorated ALI by suppressing inflammatory cytokines and chemokines as well as by decreasing the accumulation of neutrophils in the lung.

Neutralization of osteopontin attenuates neutrophil migration in sepsis-induced acute lung injury.

IntroductionSepsis refers to severe systemic inflammation leading to acute lung injury (ALI) and death. Introducing novel therapies can reduce the mortality in ALI. Osteopontin (OPN), a secretory glycoprotein produced by immune reactive cells, plays a deleterious role in various inflammatory diseases. However, its role in ALI caused by sepsis remains unexplored. We hypothesize that treatment with an OPN-neutralizing antibody (anti-OPN Ab) protects mice against ALI during sepsis.MethodsSepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Anti-OPN Ab or non-immunized IgG as control, at a dose of 50 μg/mouse, was intravenously injected at the time of CLP. After 20 hours, the expression of OPN and proinflammatory cytokines in tissues and plasma was examined by real-time PCR, Western blot, and ELISA. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) and the lung myeloperoxidase (MPO) levels were determined by colorimetric assays. Lung damage and neutrophil infiltrations were determined by histological H&E and Gr-1 staining, respectively. The effect of recombinant mouse OPN (rmOPN) on human neutrophil-like cell (HL-60) migration was performed by Boyden chamber assays and the involvement of intracellular signaling molecules in HL-60 cells was revealed by Western blot.ResultsAfter 20 hours of sepsis, mRNA and protein levels of OPN were significantly induced in lungs, spleen, and plasma. Treatment with an anti-OPN Ab in septic mice significantly reduced the plasma levels of ALT, AST, and LDH, and the proinflammatory cytokines IL-6, IL-1β and the chemokine MIP-2, compared with the vehicle group. Similarly, the lung mRNA and protein expressions of proinflammatory cytokines and chemokine were greatly reduced in anti-OPN Ab-treated animals. The lung histological architecture, MPO and neutrophil infiltration were significantly improved in anti-OPN Ab-treated mice compared with the vehicle animals. Treatment of rmOPN in HL-60 cells significantly increased their migration, in vitro. The neutrophils treated with rmOPN remarkably increased the levels of phospho focal adhesion kinase (pFAK), phospho extracellular signal-regulated kinase (pERK) and phospho p38.ConclusionsOur findings clearly demonstrate the beneficial outcomes of anti-OPN Ab treatment in protecting against ALI, implicating a novel therapeutic strategy in sepsis.

Acute Respiratory Distress Syndrome: Mortality in a Single Center According to Different Definitions.

Mortality in acute lung injury (ALI) remains high, with outcome data arising mostly from multicenter studies. We undertook this investigation to determine hospital mortality in patients with ALI in a single center. We studied patients admitted between 2005 and 2012 with ALI and acute respiratory distress syndrome (ARDS) according to the American European Consensus Conference (AECC) criteria and recorded clinical variables. Thereafter, patients were classified as subgroups according to the AECC and Berlin definition in order to compare the clinical characteristics and outcomes. In the 93 patients comprising the study, hospital mortality was 38%. Mortality at 28 days was 36%. Multivariate analysis associated hospital mortality with age and Pao2/Fio2 on day 1 ( P < .001). Differences resulted between the subgroups of AECC (ALI vs ARDS) and Berlin (mild vs moderate vs severe ARDS) in the lung injury score, Pao2/Fio2, Pao2/PAo2, PaCo2 on day 1, and hospital mortality. The overall hospital mortality (38%) was similar to that of other studies and according to the presence of ARDS (Pao2/Fio2 ≤ 200), we found significant differences between ALI and ARDS (AECC) and between mild and moderate or severe ARDS (Berlin) in baseline respiratory variables and mortality.

Effect of sivelestat sodium on the prognosis of patients with acute lung injury and acute respiratory distress syndrome: a meta-analysis

To investigate the effect of sivelestat sodium on the prognosis in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Databases including PubMed, EBSCO, Springer, Ovid, Wanfang data, CNKI and China Biology Medicine (CBM) were searched to identify randomized controlled trials (RCTs) regarding sivelestat sodium treatment for ALI/ARDS published from 1985 to December 2014. The patients in treatment group received intravenous infusion of sivelestat sodium, and those in control group received normal saline. The items for analysis were 28-day mortality, duration of mechanical ventilation, length of intensive care unit (ICU) stay, and oxygenation index on day 3. According to the evaluation method of Cochrane system, data extraction and quality assessment from the literature were carried out. Meta-analysis was performed using RevMan 5.3. The publication bias was analyzed with funnel plot. Five RCTs with a total of 780 participants were included, with 389 patients in sivelestat sodium group, and 391 in control group. Meta analysis showed: compared with control group, sivelestat sodium could not lower the 28-day mortality [odds ratio (OR) = 0.91, 95% confidence interval (95% CI) = 0.66-1.26, P = 0.58], or shorten the duration of mechanical ventilation or length of ICU stay [duration of mechanical ventilation: mean difference (MD) = -0.02, 95% CI = -0.29 to 0.24, P = 0.87; length of ICU stay: MD = -9.63, 95% CI = -23.34 to 4.08, P = 0.17], but it could improve oxygenation index on day 3 (MD = 0.88, 95% CI = 0.39 to 1.36, P = 0.000 4). Heterogeneity was not significant for the main analysis and no publication bias was shown on funnel plot. Sivelestat sodium gave rise to a better oxygenation on day 3, but did not change the length of mechanical ventilation and ICU stay, and it did not improve 28-day mortality in ALI and ARDS.

Study of the expression of GABA(A) receptor in rats during acute lung injury caused by endotoxin.

The objective of the present study was to investigate the role of γ-aminobutyric acid type A receptor (GABA(A)R) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. Thirty-two male wistar rats were randomly divided into four groups. Rats in the GABA group were pretreated with LPS and GABA, while those in the bicuculline (BIC) group were pretreated with LPS and bicuculline. We assessed the arterial blood gas, dry/wet ratio, and the level of tumor necrosis factor-α (TNF-α), IL-6, malondialdehyde, and superoxide dismutase 6 h after the immunization. Paraffin sections of samples were detected using the steptavidin-peroxidase method. Protein expression was detected using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blotting. PaO2 in the LPS group was significantly lower than that in the control rats. Activation of GABA-mediated signaling by GABA increased the expression of GABA(A)R in airway bronchial and alveolar epithelial cells. Blockade of the GABA(A)R by bicuculline limited the expression of this receptor. The GABA group rats had higher levels of tissue TNF-α and IL-6 than in ALI rats and control rats. The BIC group rats demonstrated an opposite expression level compared to the GABA group rats. Our results suggest that the GABA(A)R could aggravate the inflammatory response syndrome and oxidative stress in the lungs and play an essential role in LPS-induced acute lung injury. It provides a novel method to study the incidence and mortality of ALI during the peroperative period.

Incidence and outcome of acute lung injury and acute respiratory distress syndrome in the surgical intensive care unit.

Introduction:To determine the incidence and mortality of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in a cohort of patients with risk factors admitted to the Surgical Intensive Care Unit (SICU).Materials and Methods:A prospective observational inception cohort study with no intervention was conducted over 12 months. All patients with at least one known risk factor for ALI/ARDS admitted to the SICU were included in the study. The APACHE II severity of disease classification system scoring was performed within 1 h of admission. The ventilatory parameters and chest radiographs were recorded every 24 h. The P/F ratio, PEEP and Lung Injury Score were calculated each day until the day of discharge from the Intensive Care Unit or for the first 7 days of admission, whichever was shorter.Results:The incidence of ARDS among those who were mechanically ventilated was 11.4%. Sepsis was the most common (34.6%) etiology. Among those with risk factors, the incidence of ARDS was 30% and that of ALI was 32.7%. The mortality in those with ARDS was 41.8%. Those who develop ARDS had higher APACHE II scores, lower pH and higher PaCO2 at admission compared with those who developed ALI or no lung injury.Conclusion:The incidence and mortality of ARDS was similar to other studies. Identifying those with risk factors for ARDS or mortality will enable appropriate interventional measures.

Obesity, inflammation, and lung injury (OILI): the good.

Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5) were reduced significantly in obesity, which is associated with increased inflammation, indicated by increase of TNFα and IL-6, through activation of toll-like receptor (TLR4) and nuclear factor light chain κB (NF-κB) signaling pathways. Administration of these adipocytokines promotes weight loss and reduces inflammation. Zinc-α2-glycoprotein (ZAG), vaspin, IL-10, interleukin-1 receptor antagonist (IL-1RA), transforming growth factor β (TGF-β1), and growth differentiation factor 15 (GDF15) are also regarded as anti-inflammatories. There were controversial reports. Furthermore, there is a huge lack of studies for obesity related lung injury. The effects of adiponectin on lung transplantation, asthma, chronic obstructive pulmonary diseases (COPD), and pneumonia were anti-inflammatory and protective in lung injury. Administration of IL-10 agonist reduces mortality of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly through inhibiting proinflammation and strengthening host immunity. Very limited information is available for other adipocytokines.

Association of apolipoprotein A1 -75 G/A polymorphism with susceptibility to the development of acute lung injury after cardiopulmonary bypass surgery

IntroductionApolipoprotein A1 (apoA1) is the major apoprotein constituent of high density lipoprotein (HDL) which exerts innate protective effects in systemic inflammation. However, its role in the acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) has not been well studied. The objective of this study was to investigate the potential association between APOA1 -75 G/A polymorphism and the development of ALI after cardiopulmonary bypass (CPB) surgery.Materials and methodsA hospital-based case–control study was conducted in patients with ALI (n = 300), patients without ALI (n = 300) and healthy controls (n = 300). Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the APOA1 -75 G/A genotypes.ResultsPatients with ALI had a significantly higher frequency of APOA1 -75 AA genotype [odds ratio (OR) =1.75, 95% confidence interval (CI) = 1.04, 2.92; P = 0.03] than patients without ALI. APOA1 -75 AA genotype (OR =3.47, 95% CI = 1.60, 7.52; P = 0.002) and A allele (OR =1.92, 95% CI = 1.24, 2.96; P = 0.003) were the significant independent prognostic factors for the 30-day survival rate of patients with ALI after CPB surgery.ConclusionOur study suggested that APOA1 -75 AA genotype was associated with a higher ALI risk after CPB surgery. Patients with the APOA1 -75 AA genotype and A allele had higher 30-day mortality of ALI after CPB surgery. Additional studies are needed to confirm this finding.

TNF-Induced Death Signaling Triggers Alveolar Epithelial Dysfunction in Acute Lung Injury

The ability of the alveolar epithelium to prevent and resolve pulmonary edema is a crucial determinant of morbidity and mortality in acute lung injury (ALI). TNF has been implicated in ALI pathogenesis, but the precise mechanisms remain undetermined. We evaluated the role of TNF signaling in pulmonary edema formation in a clinically relevant mouse model of ALI induced by acid aspiration and investigated the effects of TNF p55 receptor deletion, caspase-8 inhibition, and alveolar macrophage depletion on alveolar epithelial function. We found that TNF plays a central role in the development of pulmonary edema in ALI through activation of p55-mediated death signaling, rather than through previously well-characterized p55-mediated proinflammatory signaling. Acid aspiration produced pulmonary edema with significant alveolar epithelial dysfunction, as determined by alveolar fluid clearance (AFC) and intra-alveolar levels of the receptor for advanced glycation end-products. The impairment of AFC was strongly correlated with lung caspase-8 activation, which was localized to type 1 alveolar epithelial cells by flow cytometric analysis. p55-deficient mice displayed markedly attenuated injury, with improved AFC and reduced caspase-8 activity but no differences in downstream cytokine/chemokine production and neutrophil recruitment. Caspase-8 inhibition significantly improved AFC and oxygenation, whereas depletion of alveolar macrophages attenuated epithelial dysfunction with reduced TNF production and caspase-8 activity. These results provide in vivo evidence for a novel role for TNF p55 receptor-mediated caspase-8 signaling, without substantial apoptotic cell death, in triggering alveolar epithelial dysfunction and determining the early pathophysiology of ALI. Blockade of TNF-induced death signaling may provide an effective early-phase strategy for ALI.

Epigallocatechin‐3‐Gallate inhibits the effects of TGF‐Beta and IL‐1B on ENaC expression in human alveolar epithelial cells.

Acute Lung Injury (ALI) is major clinical problem in the United States, affecting over 200,000 Americans a year. Increased mortality in ALI is attributed to pulmonary edema and decreased net fluid transport. Previous clinical studies from ALI patients have correlated the decrease net fluid transport with decreased expression of epithelium sodium channels (ENaC). Therefore drugs that enhance ENaC expression offer considerable therapeutic promise in ALI. Epigallocatechin‐3‐Gallate (EGCG), a green tea extract, has been shown to have potent anti‐inflammatory effects. However, its effect on ENaC expression in response to proinflammatory cytokines in ALI has not been shown. In this study, we investigated the hypothesis that EGCG rescues human alveolar epithelial cell (A549) ENaC expression following proinflammatory cytokine (IL‐1β and TGFβ) treatment. To test this, A549 cells were treated with TGF‐β and IL‐1β in the presence or absence of EGCG. Cell lysates as well as supernatants were collected for protein analysis. EGCG treatments resulted in increased expression of the alpha and beta subunits of ENaC in response to both TGF‐ β and IL‐ β. Further, EGCG treatments resulted in decreased cytokine secretion mediated through decreased NF‐kappaB and p‐38 MAP kinase activity in comparison to control. Our data suggests that EGCG up regulates ENaC, a major sodium channel involved in resolution of pulmonary edema in ALI.