Outcome Of Acute Lung Injury Research Articles

Thr92Ala-DIO2 heterozygosity is associated with skeletal muscle mass and myosteatosis in patients with COVID-19.

The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and coronavirus disease 2019 (COVID-19). The objective was to identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. In total, 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5%. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (P = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan-Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥92 cm² exhibited the best survival rate. Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.

Persistent Hyperglycemia Worsens the Oleic Acid Induced Acute Lung Injury in Rat Model of Type II Diabetes Mellitus.

This research aimed to study the impacts of persistent hyperglycemia on oleic acid (OA)-induced acute lung injury (ALI) in a rat model of type II diabetes mellitus. Healthy adult male albino rats that weigh 150 to 180 g were divided into four groups (n = 6). Group I-saline (75 μL i.v.) was injected and served as a control; group II-OA (75 μL i.v.) was injected to induce ALI. Group III-pretreated with a high-fat diet and streptozotocin (35 mg/kg), was injected with saline, and served as a control for group IV. Group IV was pretreated with a high-fat diet, and streptozotocin (35 mg/kg) was injected with OA (75 μL i.v). Urethane was used to anesthetize the animal. The jugular venous cannulation was done for drug/saline administration, carotid artery cannulation was done to record blood pressure, and the tracheal cannulation was done to maintain the respiratory tract's patent. Heart rate, mean arterial pressure, and respiratory frequency were recorded on a computerized chart recorder; an arterial blood sample was collected to measure PaO2/FiO2. Additionally, the pulmonary water content and lung histology were examined. Hyperglycemic rats showed no significant change in the cardio-respiratory parameter. Histology of the lungs shows fibroblastic proliferation; however, rats survived throughout the observation period. There was an early deterioration of all the cardio-respiratory parameters in hyperglycemic rats when induced ALI (OA- induced), and survival time was significantly less compared to nonhyperglycemic rats. Persistent hyperglycemia may cause morphological changes in the lungs, which worsens the outcome of acute lung injury.

RNA-Sequencing approach for exploring the therapeutic effect of umbilical cord mesenchymal stem/stromal cells on lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is significantly associated with morbidity and mortality in patients with critical diseases. In recent years, studies have identified that mesenchymal stem/stromal cells (MSCs) ameliorate ALI and pulmonary fibrosis. However, the mechanism underlying this outcome in ALI has not yet been investigated. In this study, RNA sequencing technology was used to analyze the gene expression profile of lung tissue in lipopolysaccharide (LPS)-induced ALI rats following treatment with human umbilical cord MSC (HUCMSC). Differential expression analyses, gene ontology annotation, Kyoto Encyclopedia of Genes and Genomes enrichment, protein-protein interaction network identification, and hub gene analysis were also performed. HUCMSC treatment decreased inflammatory factor production and alveolar exudates, and attenuated lung damage in LPS-induced ALI rats. The RNA-Seq data indicated that HUCMSC treatment activated the IL-17, JAK-STAT, NF-κB, and TNF-α signaling pathways, increased oxygen transport, and decreased extracellular matrix organization. HUCMSC exert beneficial effects on ALI via these signaling pathways by reducing inflammation, inhibiting pulmonary fibrosis, and improving lung ventilation. Moreover, our study further revealed the hub genes (Tbx2, Nkx2-1, and Atf5) and signaling pathways involved in HUCMSC treatment, thus providing novel perspectives for future research into the molecular mechanisms underlying cell treatment of ALI. HUCMSC can regulate multiple genes and signaling pathways, which can prevent LPS-induced lung damage in an ALI rat model.

An mTOR siRNA-Loaded Spermidine/DNA Tetrahedron Nanoplatform with a Synergistic Anti-Inflammatory Effect on Acute Lung Injury.

Acute lung injury (ALI) is characterized by severe inflammation and damage to the lung air-blood barrier, resulting in respiratory function damage and life-threatening outcomes. Macrophage polarization plays an essential role in the occurrence, development, and outcome of ALI. As drug carriers, self-assembled DNA nanostructures can potentially overcome the drawbacks and limitations of traditional anti-inflammatory agents owing to their nontoxicity, programmability, and excellent structural control at the nanoscale. A small interfering RNA (siRNA) and drug dual therapy nanoplatform are proposed and constructed here to combat ALI. The nanoplatform consists of a spermidine-assembled DNA tetrahedron and four mammalian target of rapamycin siRNAs. Spermidine serves as a mediator of drug delivery vehicle synthesis and a drug that alters macrophage polarization. Both spermidine and siRNA exert anti-inflammatory effects in vitro and in vivo by regulating the macrophage phenotype. More importantly, these factors exhibit a synergistic anti-inflammatory effect by promoting macrophage autophagy. For the first time, an anti-inflammatory dual therapy strategy that uses self-assembled DNA nanostructures as nontoxic, programmable delivery vehicles is proposed and demonstrated through this work. Future work on utilizing DNA nanostructures for the treatment of noncancerous diseases such as ALI is highly promising and desirable.

Heterozygote Advantage of the Type II Deiodinase Thr92Ala Polymorphism on Intrahospital Mortality of COVID-19.

ContextThe type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and pulmonary fibrosis.ObjectiveOur objectives were to evaluate were cumulative mortality during admission according to Thr92Ala-DIO2 polymorphism.MethodsHere we conducted an observational, longitudinal, and prospective cohort study to investigate a possible association between the Thr92Ala-DIO2 polymorphism and intrahospital mortality from COVID-19 in adult patients admitted between June and August 2020. Blood biochemistry, thyroid function tests, length of stay, comorbidities, complications, and severity scores were also studied according to Thr92Ala-DIO2 polymorphism.ResultsIn total, 220 consecutive patients (median age 62; 48-74 years) were stratified into 3 subgroups: Thr/Thr (n = 79), Thr/Ala (n = 119), and Ala/Ala (n = 23). While the overall mortality was 17.3%, the lethality was lower in Ala/Thr patients (12.6%) than in Thr/Thr patients (21.7%) or Ala/Ala patients (23%). The heterozygous genotype (Thr/Ala) was associated with a 47% reduced risk of intrahospital mortality whereas univariate and multivariate logistic regression adjusted for multiple covariates revealed a reduction that ranged from 51% to 66%. The association of the Thr/Ala genotype with better clinical outcomes was confirmed in a metanalysis of 5 studies, including the present one.ConclusionHere we provide evidence for a protective role played by Thr92Ala-DIO2 heterozygosity in patients with COVID-19. This protective effect follows an inheritance model known as overdominance, in which the phenotype of the heterozygote lies outside the phenotypical range of both homozygous.

Inhibition of protein kinase C alpha attenuates lipopolysaccharide-triggered acute lung injury by alleviating the hyperinflammatory response and oxidative stress.

BackgroundThe currently available treatment methods are ineffective in reducing mortality or improving outcomes in acute lung injury (ALI). The activation of protein kinase C alpha (PKCα) has recently been implicated in ALI development. We explored the potential therapeutic outcomes of PKCα inhibition in cases of ALI and to elucidate the related mechanisms.MethodsIndexes of lung inflammation and injury were examined in lipopolysaccharide (LPS)-treated C57BL/6J mice (male) and macrophages after pretreatment with a PKCα inhibitor. Tissues were collected to assess lung injury by hematoxylin and eosin (H&E) staining. Bronchoalveolar lavage fluid was used to measure the pulmonary edema, hyperinflammatory response, and oxidative stress by bicinchoninic acid (BCA) method and enzyme-linked immunosorbent assay (ELISA). We tested the effect of PKCα inhibition on LPS-induced proliferation, cytotoxicity, oxidative damage, and the release of inflammatory cytokines in macrophages using the Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) cytotoxicity assay kit, flow cytometry, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and ELISA. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway related proteins were detected by Western blot, immunohistochemistry (IHC), and immunofluorescence staining.ResultsWe observed that LPS upregulated PKCα phosphorylation, induced a hyperinflammatory response, and caused lung injury. However, PKCα inhibition effectively attenuated the changes caused by LPS. Moreover, we confirmed that inhibiting PKCα weakened the activity of the NF-κB pathway under LPS-induced ALI. These findings indicated that inhibition of PKCα is protective against LPS-induced hyperinflammatory response in ALI, this effect is likely to attributed to the downregulation of NF-κB signaling pathways.ConclusionsThe results showed that PKCα inhibition could attenuate ALI which may closely related to its anti-inflammatory and anti-oxidative effects.

Molecular programs of fibrotic change in aging human lung

Lung fibrosis is increasingly detected with aging and has been associated with poor outcomes in acute lung injury or infection. However, the molecular programs driving this pro-fibrotic evolution are unclear. Here we profile distal lung samples from healthy human donors across the lifespan. Gene expression profiling by bulk RNAseq reveals both increasing cellular senescence and pro-fibrotic pathway activation with age. Quantitation of telomere length shows progressive shortening with age, which is associated with DNA damage foci and cellular senescence. Cell type deconvolution analysis of the RNAseq data indicates a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts with age. Consistent with this pro-fibrotic profile, second harmonic imaging of aged lungs demonstrates increased density of interstitial collagen as well as decreased alveolar expansion and surfactant secretion. In this work, we reveal the transcriptional and structural features of fibrosis and associated functional impairment in normal lung aging.

Incidence and Outcomes of Acute Lung Injury in Patients With Isolated Traumatic Brain Injury

Background and Aim: Traumatic Brain Injury (TBI) is an essential cause of morbidity and mortality worldwide. TBI patients frequently encounter lung complications, such as Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), which is associated with poor clinical outcome because hypoxia causes additional injury to the brain. This study aimed to evaluate the frequency of ALI in patients with TBI and its consequences. Methods and Materials/Patients: In this descriptive cross-sectional study, data from all records of patients admitted to Poursina Hospital’s ICU (emergency and neurosurgery ICU) in 20 18-2019 were used. The evaluated data included age, gender, type of head trauma mechanism, kind of brain injury based on CT scan findings, the severity of brain injury based on Glasgow Coma Scale (GCS), underlying diseases, mean head AIS score, the number of pack cell units injected, as well as bilateral pulmonary infiltration in favor of ALI and brain injury. Results: Only 81 of the 557 TBI cases met the inclusion criteria of the present study. The highest frequency of ALI following TBI was observed on the first day of hospitalization, in men (0.41%) in the age group of 40-50 years (7%) with severe brain damage (6%) and subdural hematoma (12%), following a motorcycle accident, cars, as well as on the third day of hospitalization were seen in men (43.8%) with the age group of 20-30 years (55%) with severe brain damage (42%) and intra-parenchymal bleeding (57%), following a motorcycle accident. In addition, no significant correlation was detected between the incidence of ALI and mortality, the duration of hospitalization, GCS, mean head AIS score, or the extent of received blood units in our study. Conclusion: According to the obtained findings, men aged between 20 and 30 years with severe cerebral injury, epidural hematoma and a motorcycle accident presented the highest rate of progression toward ALI in the first to third days of hospitalization.

Impact of ENaC downregulation in transgenic mice on the outcomes of acute lung injury induced by bleomycin.

What is the central question of this study? How does the downregulation of ENaC, the major driving force for alveolar fluid clearance, impact acute lung injury outcomes induced by bleomycin, featuring alveolar damage, as observed during ARDS exudative phase? What is the main finding and its importance? ENaC downregulation in αENaC(-/-)Tg+ mice did not elicit a substantial worsening impact on the main bleomycin outcomes. In ARDS patients, both ENaC alteration and alveolar damage are observed. Thus, novel therapeutic avenues, favouring alveolar integrity restauration, in addition to lung oedema resolution capacity, mainly driven by ENaC, would be essential. The exudative phase of acute respiratory distress syndrome (ARDS) is characterized by extended alveolar damage, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Na+ reabsorption through ENaC channels is a major driving force for alveolar fluid clearance (AFC) in physiological and pathological conditions. It has previously been shown that partial αENaC impairment in transgenic (αENaC(-/-)Tg+) mice results in reduced AFC in basal conditions and increased wet/dry ratio after thiourea-induced lung oedema, a model in which the integrity of the alveolar epithelium is preserved. The goal of this study was to further investigate the impact of αENaC downregulation in αENaC(-/-)Tg+ mice using an experimental model of acute lung injury induced by bleomycin. A non-significant trend in enhanced weight loss and mortality rates was observed after the bleomycin challenge in αENaC(-/-)Tg+ compared to wild-type (WT) mice. Bronchoalveolar lavage analyses revealed increased TNFα levels and protein concentrations, as indexes of lung inflammation and alveolar damage, in αENaC(-/-)Tg+ mice, compared to WT, at day 3 post-bleomycin, although a statistical difference was no longer measured at day 7. Differential immune cell counts were similar in WT and αENaC(-/-)Tg+ mice challenged with bleomycin. Moreover, lung weight measurements indicated similar oedema levels in WT mice and in transgenic mice with impaired ENaC channels. Altogether, our data indicated that change in ENaC expression does not elicit a significant impact on lung oedema level/resolution in the bleomycin model, featuring alveolar damage.

Venetoclax nanomedicine alleviates acute lung injury via increasing neutrophil apoptosis.

Delayed neutrophil apoptosis has been proved to be closely associated with acute lung injury. A Bcl-2 inhibitor, venetoclax, can improve the clinical outcome of acute lung injury based on its pro-apoptotic effect. However, pulmonary delivery of free venetoclax is hindered by its water insolubility, which results in limited bioavailability and pharmacological effects. An amphipathic polymer-based nanodelivery system has been extensively used to improve the delivery of this insoluble drug and enhance its bioavailability. In this study, an amphiphilic poly(ethylene glycol) modified poly(α-lipoic acid) nanoparticle with an extended lung tissue-resident time was utilized to deliver venetoclax. Compared to free venetoclax, the nanoformulated venetoclax (Nf-venetoclax) presented better efficacy for acute lung injury through increasing neutrophil apoptosis in vivo. In addition, a stronger pro-apoptotic effect of Nf-venetoclax was also demonstrated in vitro. Our study provides encouraging evidence that Nf-venetoclax exhibits effective therapy for acute lung injury.

ACUTE LUNG INJURY FOLLOWING TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION WITH DRUG ELUTING BEADS LOADED WITH DOXORUBICIN

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Transcatheter arterial chemoembolization (TACE) is commonly used as palliative management of primary hepatocellular carcinoma (HCC). Acute lung injury after this procedure is very rarely reported but has been seen. We describe a case of TACE-induced pneumonitis. CASE PRESENTATION: A 60-year old female with significant past medical history of hepatocellular carcinoma, hepatitis C cirrhosis complicated by ascites, bleeding varices, and encephalopathy presented for scheduled transcatheter arterial chemoembolization (TACE). She received TACE of LC beads loaded with doxorubicin of the left hepatic artery. She had this procedure three times prior in the past year without any complications. On hospital day 3 she was noted to have an episode of desaturation to the mid-70s, chest x-ray was done and showed no acute pathology. She continued to require 1-2L of oxygen via nasal cannula and desaturation with ambulation. Pulmonary computed tomography angiography (CTA) was ordered due to continued oxygen requirement which showed new bilateral central ground-glass and reticular opacities with relative sparing of the lung bases, new since a CT chest performed 2 months prior. The patient had no infectious symptoms or leukocytosis, and remained hypoxemic despite aggressive diuresis- a workup for diffuse parenchymal lung disease included ANA, ANCA, CCP, RF, and hypersensitivity pneumonitis which were all negative. Bronchoscopic evaluation of the patient was considered, however she declined. She was started on prednisone for presumed TACE-induced pneumonitis and was discharged with home oxygen and follow-up with pulmonology. She was seen one month after discharge with repeat chest imaging which showed near complete resolution of the diffuse ground-glass opacities. She was no longer requiring supplemental oxygen at home and was started on a gradual steroid taper with plans to continue until subsequent follow-up in three months, however the patient passed away from complications of cirrhosis. DISCUSSION: TACE is commonly used as palliative treatment in primary HCC. The procedure involves occluding portions of the hepatic artery that supplies the tumor. Commonly reported complications of this procedure include postembolization syndrome which is characterized by fatigue and abdominal pain, other local complications such as ischemic necrosis which could result in liver failure, spontaneous rupture of tumor, and gallbladder infarction can occur. We described a case of acute lung injury three days after TACE with doxorubicin-eluting beads (DEB-TACE). Review of the literature revealed only a few case reports of such a complication. CONCLUSIONS: Although an unusual complication, this entity will be more important given the increasing prevalence of DEB-TACE. Reference #1: Aladdin, M. & Ilyas, M. (2011). Chemoembolization of Hepatocellular Carcinoma with Drug-Eluting Beads Complicated by Interstitial Pneumonitis. Seminars in Interventional Radiology, 28(2), 218-211. Reference #2: Alifakioti D. et al. (2014). Acute Eosinophilic and Neutrophilic Pneumonia Following Transarterial Chemoembolization with Drug-Eluting Beads loaded with Doxorubicin for Hepatocellular Carcinoma: A Case Report. Respiration 88, 426-429. Reference #3: Fang, LJ. et al. (2019). Clinical Characteristics and Outcomes of Acute Lung Injury Caused by Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A retrospectiveCohort Study from a Single Institution in China. Anal Cell Pathol. DISCLOSURES: No relevant relationships by Luan Nghiem, source=Web Response No relevant relationships by Sheshadrie Saha, source=Web Response no disclosure on file for Ryan Webster

Alveolar macrophage - derived exosomes modulate severity and outcome of acute lung injury

Severe acute lung injury (ALI) can cause death, and the survivals may develop acute respiratory distress syndrome (ARDS) due to fibrotic repair of the lung. Alveolar macrophages play a demonstrative role during the pathogenesis of ALI, and the timing and degree of differentially polarization of macrophages determine the severity of disease and outcome. Exosomes are important mediators of cellular communication and play critical roles during macrophage differentiation, proliferation and function. Nevertheless, the exact effects of alveolar macrophage - derived exosomes on ALI remain unknow. Here, we used lipopolysaccharide (LPS) to induce ALI in mice and analyzed the exosome population in bronchoalveolar lavage fluid (BALF) from macrophages, neutrophils and epithelial cells at different time points after treatment. Our data showed that macrophages were the major secretors for early secreted pro-inflammatory cytokines in the BALF-exosomes, which likely activated neutrophils to produce a variety of pro-inflammatory cytokines and IL-10. IL-10 by neutrophils in BALF-exosomes likely in turn polarized macrophages to M2c, which may be responsible for post-ALI fibrosis. Our study thus reveals a previous non-acknowledged role of BALF-exosomes as a mediator of inflammatory response and cell crosstalk during ALI.

Clinical Characteristics and Outcomes of Acute Lung Injury Caused by Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Retrospective Cohort Study from a Single Institution in China

Background Acute lung injury (ALI) is a rare but life-threatening pulmonary complication of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The aim of this study was to characterize the common risk factors, clinical features, imaging findings, treatments, and outcomes of acute lung injury caused by TACE. Methods A retrospective study was performed on all TACE-associated ALI cases that were diagnosed at authors' hospital from January 2015 to June 2018. Results The study included 14 ALI cases where the mean age of patients was 60.9 ± 11.7 years (range 41-82 years), with a mean onset time of 2.4 ± 1.6 d after TACE. Of the 14 patients, 8 patients (57.1%) developed acute respiratory distress syndrome (ARDS). 7 patients (50%) had underlying chronic respiratory disease and hepatic arteriovenous fistula was detected in 6 patients (42.6%), both of which were significantly higher than control group (P < 0.05). Dyspnea (92.9%) was the most common symptoms. Pleural effusion (64.3%), diffuse pulmonary infiltration (42.9%), and accumulation of Lipiodol in lung field (42.9%) were frequent radiologic abnormalities. 11 patients (78.6%) achieved remission after treatment, and the 30-day mortality rate was approximately 21.4%. Patient's median survival time after the development of ALI was merely 4.3 months, which was obviously worse than control group (4.3 months vs. 13.5 months, P < 0.05). Conclusion This study illustrates that TACE-associated ALI is a rare pulmonary complication with a high mortality rate. We infer that pulmonary Lipiodol embolization might be one of the main causes of TACE-associated ALI. Thus, HCC patients who are at high risk should be closely evaluated and monitored during TACE to avoid such potentially fatal complication.

The role of bacterial and viral infection in exacerbation of bronchiectasis: a prospective study

BackgroundExacerbations are crucial events in the progression of bronchiectasis. Previous studies have documented associations between viral or bacterial infection and bronchiectasis exacerbations, but assays for viral or bacterial infection were conducted separately. No study has yet revealed an association between bacteria and viruses in bronchiectasis exacerbations. Moreover, the clinical correlates of bacterial with or without viral detections are unclear. We sought to explore associations between bacterial infection, viral infection and co-infection, and exacerbation of bronchiectasis. MethodsIn this prospective cohort study, we enrolled 108 patients from the outpatient clinics of The First Affiliated Hospital of Guangzhou Medical University (Guangzhou, China). The participants were followed up every 3–6 months and at exacerbation episodes, between March, 2017, and November, 2018. Each sputum sample was split into two for detection of bacteria (routine culture) and viruses (quantitative PCR). Clinical characteristics were assessed during exacerbation episodes. FindingsThe median exacerbation rate was 2·0 (interquartile range 1·0–2·5) per patient per year. Viral infection was correlated with significantly higher risks of exacerbation (29% [22 of 76] of exacerbation episodes; OR 3·28, 95% CI 1·76–6·12) than non-viral infection. Similarly, new occurrence of bacterial infection was correlated with significantly higher risks of exacerbation (eg, Haemophilus influenza was associated with 11% [eight of 26] of exacerbation episodes; 2·52, 1·35–4·71) than no new occurrence of bacterial infection, and likewise co-infection (2·24, 1·11–4·55) than all of the other groups combined. A positive bacterial culture alone was not correlated with exacerbations (p>0·778). Although coryza seemed to be more common in viral exacerbation than in unexplained and new bacterial exacerbation (p=0·053), lower airway symptoms were more severe in new bacterial exacerbation (visual analogue scale for cough, p=0·030; sputum volume, p=0·006; sputum purulence, p=0·025). Airway interleukin-1β levels were consistently higher in new bacterial exacerbation than in unexplained and viral exacerbation (p=0·007). A significantly greater number of coryza was correlated with co-infection at exacerbation (p=0·019). However, co-infection did not differ from bacterial or viral infection alone in lower airway symptoms (p=0·063), lung function decline (forced expiratory volume in one second, p=0·278; forced vital capacity, p=0·230), and sputum cytokine levels (interleukin-1β, p=0·445; CXC motif chmokine-8, p=0·279; tumour necrosis factor-α, p=0·055; and interferon-γ, p=0·555). InterpretationViral infection, new occurrence of bacterial infection and co-infection are associated with exacerbation of bronchiectasis. The clinical characteristics of bronchiectasis exacerbation might inform clinicians of the possible underlying pathogens. FundingThis work was supported by the National Natural Science Foundation (no. 81870003), Pearl River S&T Nova Program of Guangzhou (no. 201710010097) and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme 2017 (to W-JG), and the Impact and Mechanisms of Physical, Chemical and Biological Interventions on the Development and Outcome of Acute Lung Injury (no. 81490534, to N-SZ).

C5a receptor1 inhibition alleviates influenza virus-induced acute lung injury

Influenza A virus is an important human pathogen that causes 3 to 5 million severe cases of influenza worldwide each year. An aberrant innate immune response, particularly hypercytokinemia, is thought to play an important role in the disease, although the pathogenesis of severe influenza virus infection remains unclear and no specific and efficacious immunotherapy is available. This study reports dysregulated complement activation in mice after infection with A/Puerto Rico/8/34 (PR8). C5aR1-deficient mice and mice treated with an anti-C5aR1 antibody were used as models to study the C5a-C5aR1 axis during acute lung injury (ALI) induced by influenza virus infection. The results showed that blocking the C5a-C5aR1 axis alleviated ALI by inhibiting endothelial cell activation and dampening the host immune response (i.e., reduced TNF-α, IL-1β, IL-6, IP-10, MCP-1, IL-12p70, and IFN-γ concentrations in plasma), particularly CTL-mediated immunopathology. Furthermore, blockade of the C5a-C5aR1 axis inhibited viral replication in lung tissue. Taken together, the results indicate that the C5a-C5aR1 axis plays an important role in the outcome of ALI induced by influenza virus infection and that regulation of complement activation, particularly the C5aR1 inhibition, is a promising intervention and adjunctive treatment.

Abstract 21057: Combined Administration of DNMT and HDAC6 Inhibitors Suppress Endotoxemia Induced Macrophages Pro-Inflammatory Signaling Pathway

Background: Acute lung injury (ALI) is an common inflammatory disease that affects millions of people worldwide. Therapies based on a new understanding of disease pathogenesis are needed. Studies have shown that treatment with a single drug is not effective in controlling the pro-inflammatory response caused by ALI. Hypothesis: The combinatorial epigenetic treatment with 5-Aza-2’-deoxycytidine (Aza, a DNMT inhibitor) and Tubastatin-A (TBSA, a HDAC6 inhibitor) after LPS-induced ALI would mitigates the pro-inflammatory P38-MAPK signaling and rescues animal from ALI-induced death. Methods: Acute lung injury was induced in C57BL mice by intraperitoneal injection of LPS (10mg/kg). One hour later, the mice received either vehicle, Aza (1mg/kg), TBSA (0.25mg/kg), or Aza+TBSA. After 12 hours, the mice were sacrificed for further biochemical and histological analyses. To delineate the signaling mechanism, we have used macrophage cell line (RAW 264.7). For this, macrophages were treated with vehicle, LPS (1ug/ml), Aza (50nM), TBSA (750nM), or with combined treatment for 30 min and 24 hours for Western and qRT-PCR analyses. Results: We observed that all mice treated with LPS and LPS+Aza died within 24 hrs. The mice treated with LPS+TBSA exhibited 20% survival rate whereas the LPS+Aza+TBSA- treated group displayed 80% survival rate. Our results revealed that LPS significantly increases the expression of inflammatory cytokines such as iNOS, IL-6 and TNF-α in macrophages. However, the increased mRNA expression was significantly reduced after treatment with Aza+TBSA (Fig. A) . We also found that Aza+TBSA suppressed the LPS-induced P38-MAPK signaling pathway (Fig. B) . Conclusion: We report for the first time that Aza+TBSA together reverses the outcome of ALI induced by endotoxemia.

Incidence and outcomes of acute lung injury in the surgical intensive care unit of a tertiary care hospital in Bangkok, Thailand

Abstract Background Although the pathophysiology and treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are well established, the incidence and outcomes of ALI have not been extensively reported. Variations in healthcare systems, demographics, socioeconomics, and levels of intensive care units (ICU) may explain remarkable differences in outcomes reported. Objectives To evaluate the incidence and outcomes of ALI/ARDS at the surgical ICU (SICU) at Siriraj Hospital of Mahidol University, Bangkok. Methods We included patients aged ≥18 years admitted to the general SICU between June 1, 2010 and May 31, 2013 in this prospective, cohort observational study. All patients required ≥24 h of ventilatory support. The study outcomes were the incidence of ALI/ARDS, SICU length of stay, and mortality rate. Results Of 2523 patients admitted to the SICU, 495 (20%) required ≥24 h ventilatory support, and 15 (3%) developed ALI/ARDS. ALI/ARDS occurred on day 2 of ventilatory support. ARDS was caused by sepsis and pneumonia. The patients who developed ALI/ARDS had a higher APACHE II score (P = 0.001) and end-stage renal disease (P = 0.01). Pneumonia and acute kidney injury were more severe in patients with ALI and ARDS (40% vs 9%, P = 0.002; 33% vs 10%, P = 0.02, respectively). Ventilatory support duration, SICU lengths of stay and hospital mortality were higher in the ALI/ARDS group. Conclusions The incidence of ALI/ARDS in the SICU was low, but the mortality rate was high. A larger sample size is necessary to identify independent risk factors for ALI/ARDS.

Effect of Lung Recruitment Maneuver in Children with Acute Lung Injury

Background Acute lung injury (ALI) is defined as PaO2/FiO2 less than 300 with bilateral pulmonary infiltrates, without pressure is the top of the left atrium. Early diagnosis and treatment of pediatric ALI and find new cases is very important. Accurate diagnosis and effective steps to treating these patients is essential in the outcome of ALI. This study was conducted to show the impact of recruitment in the treatment of ALI patients. Materials and Methods This clinical trial study was conducted in Pediatric Educational-Medical center of Tabriz University of Medical Sciences (Tabriz, Iran) and 42 patients with ALI were enrolled. All patients were underwent echocardiography. The patients were divided in 2 groups randomly (intervention and control groups consisted of 21 patients for each group). Patients were followed for 6 months to be evaluated in terms of clinical status and mortality. Results Difference on level of PaO2 in intervention group was -26±4 in comparison to the control group which was -4±4 (P<0.05). Difference on time of dependence on mechanical ventilation in intervention group was 8.05±3 in comparison to control group which was 11.05±8 (P<0.05). Mortality rate of intervention group (28%) was lower than the control group (47%)(P<0.05). Conclusion Implementation of recruitment could play an important role in decreasing of mortality in patients with acute lung injury.

Infection site is predictive of outcome in acute lung injury associated with severe sepsis and septic shock.

Sepsis is a leading cause of acute lung injury (ALI); however, the characteristics and outcome of sepsis-associated ALI are poorly understood. We aimed to elucidate factors that predict patient outcome in sepsis-associated ALI. Secondary analysis of a multicenter, prospective, observational study was performed. Among 624 patients with severe sepsis and septic shock, 251 (40.2%) fulfilled the definition of American-European Consensus Conference definition of ALI. All-cause 28-day and in-hospital mortalities were 30.7% and 38.6%, respectively. More than 40% of ALI patients had neurological, cardiovascular and haematological dysfunctions or disseminated intravascular coagulation, all of which were associated with higher mortality. We report a significant correlation between infection site and mortality in patients with ALI, but not in those without ALI. The proportion of ALI was significantly higher in pulmonary sepsis; further, a complication of ALI was associated with higher mortality in sepsis from pulmonary and other sources, but not in abdominal sepsis. Among the other sepsis sites, urinary tract, central nervous system, catheter-related and undetermined foci of infection had worse outcomes when associated with ALI. None of the individual severe sepsis bundles, including fluid resuscitation and early antibiotic administration, correlated with mortality. Compliance with a set of sepsis management bundles was associated with better outcomes. In severe sepsis and septic shock, the proportion and effect on outcome was not uniform among infection sites. The infection site was predictive of outcome in patients with ALI but not in those without ALI.

The Prognostic Value of Soluble Intercellular Adhesion Molecule 1 Plasma Level in Children With Acute Lung Injury.

The objective of this study was to evaluate the prognostic significance of soluble intercellular adhesion molecule 1 (sICAM-1) measurement in plasma for the prediction of outcome of acute lung injury (ALI) in children that may allow early recognition of critical cases. The study was performed as a prospective, controlled cohort study involving 40 children with ALI and 30 healthy children. The plasma level of sICAM-1 was measured at days 1 and 3 of development of ALI for the patient group and measured only once for the control group. C-Reactive protein was measured in both groups on day 1 only. There was significant increase in sICAM-1 in the patient group than in the control group ( P = .001*). The mortality rate reached 55% in children with ALI. The ceased group had significantly higher plasma sICAM-1 levels both at days 1 and 3 than the survived group ( P < .001*), and there was positive correlation between plasma sICAM-1 level and both duration of mechanical ventilation and the death rate, but more significant correlation was observed with plasma sICAM-1 levels at day 3 than day 1. Plasma sICAM-1 level served as a good predictor biomarker for both mechanical ventilation duration and the mortality risk in children with ALI.