These studies demonstrate in vivo and in vitro protective effects of oxidized phospholipids on LPS-induced lung dysfunction.

Acute lung injury is a complex illness with a high mortality rate (>30%) and often requires the use of mechanical ventilatory support for respiratory failure. Mechanical ventilation can lead to clinical deterioration due to augmented lung injury in certain patients, suggesting the potential existence of genetic susceptibility to mechanical stretch (6, 48), the nature of which remains unclear. To identify genes affected by ventilator-induced lung injury (VILI), we utilized a bioinformatic-intense candidate gene approach and examined gene expression profiles from rodent VILI models (mouse and rat) using the oligonucleotide microarray platform. To increase statistical power of gene expression analysis, 2,769 mouse/rat orthologous genes identified on RG_U34A and MG_U74Av2 arrays were simultaneously analyzed by significance analysis of microarrays (SAM). This combined ortholog/SAM approach identified 41 up- and 7 downregulated VILI-related candidate genes, results validated by comparable expression levels obtained by either real-time or relative RT-PCR for 15 randomly selected genes. K-mean clustering of 48 VILI-related genes clustered several well-known VILI-associated genes (IL-6, plasminogen activator inhibitor type 1, CCL-2, cyclooxygenase-2) with a number of stress-related genes (Myc, Cyr61, Socs3). The only unannotated member of this cluster (n = 14) was RIKEN_1300002F13 EST, an ortholog of the stress-related Gene33/Mig-6 gene. The further evaluation of this candidate strongly suggested its involvement in development of VILI. We speculate that the ortholog-SAM approach is a useful, time- and resource-efficient tool for identification of candidate genes in a variety of complex disease models such as VILI.

Background Mechanical ventilation at high tidal volume (HTV) may cause pulmonary capillary leakage and acute lung inflammation resulting in ventilator-induced lung injury. Besides blunting the Toll-like receptor-4-induced inflammatory cascade and lung dysfunction in a model of lipopolysaccharide-induced lung injury, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exerts direct barrier-protective effects on pulmonary endothelial cells in vitro via activation of the small GTPases Rac and Cdc42. To test the hypothesis that OxPAPC may attenuate lung inflammation and barrier disruption caused by pathologic lung distension, we used a rodent model of ventilator-induced lung injury and an in vitro model of pulmonary endothelial cells exposed to pathologic mechanochemical stimulation.

Background The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

Use of consomic rats for genomic insights into ventilator-associated lung injury. Am J Physiol Lung Cell Mol Physiol 293: L292-L302, 2007. First published April 27, 2007; doi:10.1152/ajplung.00481.2006.-Increasing evidence supports the contribution of genetic influences on susceptibility/severity in acute lung injury (ALI), a devastating syndrome requiring mechanical ventilation with subsequent risk for ventilatorassociated lung injury (VALI). To identify VALI candidate genes, we determined that Brown Norway (BN) and Dahl salt-sensitive (SS) rat strains were differentially sensitive to VALI (tidal volume of 20 ml/kg, 85 breaths/min, 2 h) defined by bronchoalveolar lavage (BAL) protein and leukocytes. We next exploited differential sensitivities and phenotyped both the VALI-sensitive BN and the VALI-resistant SS rat strains by expression profiling coupled to a bioinformatic-intense candidate gene approach (Significance Analysis of Microarrays, i.e., SAM). We identified 106 differentially expressed VALI genes representing gene ontologies such as "transcription" and "chemotaxis/cell motility." We mapped the chromosomal location of the differentially expressed probe sets and selected consomic SS rats with single BN introgressions of chromosomes 2, 13, and 16 (based on the highest density of probe sets) while also choosing chromosome 20 (low probe sets density). VALI exposure of consomic rats with introgressions of BN chromosomes 13 and 16 resulted in significant increases in both BAL cells and protein (compared to parental SS strain), whereas introgression of BN chromosome 2 displayed a large increase only in BAL protein. Introgression of BN chromosome 20 had a minimal effect. These results suggest that genes residing on BN chromosomes 2, 13, and 16 confer increased sensitivity to high tidal volume ventilation. We speculate that the consomic-microarray-SAM approach is a time-and resource-efficient tool for the genetic dissection of complex diseases including VALI.

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Aim: To test the hypothesis that PI3K/Akt/eNOS signaling has a protective role in a murine model of ventilation associated lung injury (VALI) through down-regulation of p38 MAPK signaling. Methods: Male C57BL/J6 (wild-type, WT) or eNOS knockout mice (eNOS -/-) were exposed to mechanical ventilation (MV) with low (LV T , 7 mL/kg) and high tidal volume (HV T , 20 mL/kg) for 0−4 h. A subset of WT mice was administered the specific inhibitors of PI3K (100 nmol/L Wortmannin [Wort], ip) or of p38 MAPK (SB203580, 2 mg/kg, ip) 1 h before MV. Cultured type II alveolar epithelial cells C10 were exposed to 18% cyclic stretch for 2 h with or without 20 nmol/L Wort pretreatment. At the end of the experiment, the capillary leakage in vivo was assessed by extravasation of Evans blue dye (EBD), wet/dry weight ratio and lung lavage protein concentration. The lung tissue and cell lysate were also collected for protein and histological review. Results: MV decreased PI3K/Akt phosphorylation and eNOS expression but increased phospho-p38 MAPK expression along with a lung leakage of EBD. Inhibitions of phospho-Akt by Wort worsen the lung edema, whereas inhibition of p38 MAPK kinase restored activation of Akt together with alleviated capillary leakage. eNOS -/-mice showed an exacerbated lung edema and injury. The stretched C10 cells demonstrated that Wort diminished the activation of Akt, but potentiated phosphorylation of MAPK p38. Conclusion: Our results indicate that PI-3K/Akt/eNOS pathway has significant protective effects in VALI by preventing capillary leakage, and that there is a cross-talk between PI3K/Akt and p38 MAPK pathways in vascular barrier dysfunction resulting from VALI.

Key PointsQuestionIn critically ill adult patients undergoing tracheal intubation, does intravenous infusion of a crystalloid solution as a 500-mL fluid bolus decrease the incidence of severely low blood pressure, cardiac arrest, or death (referred to as cardiovascular collapse) during or shortly after the procedure?FindingsIn this randomized clinical trial that included 1065 critically ill adults, the incidence of cardiovascular collapse was 21.0% with administration of a fluid bolus vs 18.2% without administration of a fluid bolus, a difference that was not statistically significant.MeaningAmong critically ill adults undergoing tracheal intubation, administration of a fluid bolus did not significantly decrease the incidence of cardiovascular collapse.