Dataset Information

Analysis of mechanical ventilation and lipopolysaccharide?induced acute lung injury using DNA microarray analysis.

ABSTRACT: Gene expression profiles of samples taken from patients with acute lung injury (ALI) induced by mechanical ventilation (MV) and lipopolysaccharide (LPS) were analyzed in order to identify key genes, and explore the underlying mechanisms. The GSE2411 microarray data set was downloaded from the Gene Expression Omnibus. This data set contained microarray data from 24 mouse lung samples, which were equally divided into four groups: Control group, MV group, LPS group and MV+LPS group. Differentially expressed genes (DEGs) were identified in the MV, LPS and MV+LPS groups, as compared with the control group, using packages of R software. Hierarchical clustering and between?group comparisons were performed for each group of DEGs. Overrepresented biological processes were revealed by functional enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery. Unique DEGs in the LPS and MV+LPS groups were selected, and pathway enrichment analyses were performed using the Kyoto Encyclopedia of Genes and Genomes Orthology Based Annotation system. A total of 32, 264 and 685 DEGs were identified in the MV, LPS and MV+LPS groups, respectively. The MV+LPS group had more DEGs, as compared with the other two treatment groups. Genes associated with the immune and inflammatory responses were significantly overrepresented in both the LPS and MV+LPS groups, suggesting that LPS dominated the progression of ALI. Unique DEGs in the LPS and MV+LPS groups were associated with cytokine?cytokine receptor interaction. The Janus kinase?signal transducer and activator of transcription signaling pathway was shown to be enriched in the LPS+MV?unique DEGs. The results of the present study demonstrated that MV could exaggerate the transcriptional response of the lungs to LPS. Numerous key genes were identified, which may advance knowledge regarding the pathogenesis of ALI.

SUBMITTER: Chen Y

PROVIDER: S-EPMC4394949 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Analysis of mechanical ventilation and lipopolysaccharide‑induced acute lung injury using DNA microarray analysis.

Chen Yuqing Y Zhou Xin X Rong Ling L

Molecular medicine reports 20150211 6

Gene expression profiles of samples taken from patients with acute lung injury (ALI) induced by mechanical ventilation (MV) and lipopolysaccharide (LPS) were analyzed in order to identify key genes, and explore the underlying mechanisms. The GSE2411 microarray data set was downloaded from the Gene Expression Omnibus. This data set contained microarray data from 24 mouse lung samples, which were equally divided into four groups: Control group, MV group, LPS group and MV+LPS group. Differentially ...[more]

PMID: 25672411

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Project description:Mechanical ventilation (MV) and lipopolysaccharide (LPS) infection are common causes of acute lung injury. The aim of the present study was to identify the key genes and potential mechanisms involved in mechanical ventilation (MV) and lipopolysaccharide (LPS)‑induced acute lung injury (ALI). Gene expression data of adult C57BL/6 mice with ALI induced by inhaling LPS, MV and LPS + MV were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) associated with MV, LPS and LPS + MV were screened, followed by functional enrichment analysis, protein‑protein interaction network construction, and prediction of transcription factors and small molecule drugs. Finally, the expression of key genes was verified in vivo using reverse transcription‑quantitative PCR. A total of 63, 538 and 1,635 DEGs were associated with MV, LPS and LPS + MV, respectively. MV‑associated genes were significantly enriched in the 'purine ribonucleotide metabolic process'. LPS and LPS + MV‑associated genes were significantly enriched in 'cellular response to cytokine stimulus' and 'cell chemotaxis'. All three conditions were enriched in 'TNF signaling pathway' and 'IL‑17 signaling pathway'. Expression levels of C‑X‑C motif chemokine ligand (CXCL)2, CXCL3 and CXCL10 were upregulated in the LPS and LPS + MV groups. Adenosine A2b receptor, zinc finger and BTB domain‑containing 16 and hydroxycarboxylic acid receptor 2 were identified as DEGs in the MV group. Compared with the control group, Early growth response 1 and activating TF 3 was upregulated in all three groups. Similarities and differences were observed among the MV‑ and LPS‑induced ALI, and MV may enhance the effects of LPS on gene expression. MV may affect urine ribonucleotide metabolic‑related processes, whereas LPS may cause cell chemotaxis and cytokine stimulus responses in ALI progression. The inflammatory response was shared by MV and LPS. The results of the present study may provide insight into a theoretical basis for the study and treatment of ALI.

Project description:BackgroundSurvival of patients with acute lung injury or the acute respiratory distress syndrome (ARDS) has been improved by ventilation with small tidal volumes and the use of positive end-expiratory pressure (PEEP); however, the optimal level of PEEP has been difficult to determine. In this pilot study, we estimated transpulmonary pressure with the use of esophageal balloon catheters. We reasoned that the use of pleural-pressure measurements, despite the technical limitations to the accuracy of such measurements, would enable us to find a PEEP value that could maintain oxygenation while preventing lung injury due to repeated alveolar collapse or overdistention.MethodsWe randomly assigned patients with acute lung injury or ARDS to undergo mechanical ventilation with PEEP adjusted according to measurements of esophageal pressure (the esophageal-pressure-guided group) or according to the Acute Respiratory Distress Syndrome Network standard-of-care recommendations (the control group). The primary end point was improvement in oxygenation. The secondary end points included respiratory-system compliance and patient outcomes.ResultsThe study reached its stopping criterion and was terminated after 61 patients had been enrolled. The ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen at 72 hours was 88 mm Hg higher in the esophageal-pressure-guided group than in the control group (95% confidence interval, 78.1 to 98.3; P=0.002). This effect was persistent over the entire follow-up time (at 24, 48, and 72 hours; P=0.001 by repeated-measures analysis of variance). Respiratory-system compliance was also significantly better at 24, 48, and 72 hours in the esophageal-pressure-guided group (P=0.01 by repeated-measures analysis of variance).ConclusionsAs compared with the current standard of care, a ventilator strategy using esophageal pressures to estimate the transpulmonary pressure significantly improves oxygenation and compliance. Multicenter clinical trials are needed to determine whether this approach should be widely adopted. (ClinicalTrials.gov number, NCT00127491.)

Project description:BackgroundPatients in intensive care units (ICUs) often received broad-spectrum antibiotic treatment and Acinetobacter baumannii (A.b.) and Pseudomonas aeruginosa (P.a.) were the most common pathogens causing ventilator-associated pneumonia (VAP). This study aimed to examine the effects and mechanism of mechanical ventilation (MV) on A.b.-induced lung injury and the involvement of alveolar macrophages (AMs).MethodsC57BL/6 wild-type (WT) and c-Jun N-terminal kinase knockout (JNK1-/-) mice received MV for 3 h at 2 days after nasal instillation of A.b., P.a. (1 × 106 colony-forming unit, CFU), or normal saline.ResultsIntranasal instillation of 106 CFU A.b. in C57BL/6 mice induced a significant increase in total cells and protein levels in the bronchoalveolar lavage fluid (BALF) and neutrophil infiltration in the lungs. MV after A.b. instillation increases neutrophil infiltration, interleukin (IL)-6 and vascular cell adhesion molecule (VCAM) mRNA expression in the lungs and total cells, IL-6 levels, and nitrite levels in the BALF. The killing activity of AMs against A.b. was lower than against P.a. The diminished killing activity was parallel with decreased tumor necrosis factor-α production by AMs compared with A.b. Inducible nitric oxide synthase inhibitor, S-methylisothiourea, decreased the total cell number in BALF on mice receiving A.b. instillation and ventilation. Moreover, MV decreased the A.b. and P.a. killing activity of AMs. MV after A.b. instillation induced less total cells in the BALF and nitrite production in the serum of JNK1-/- mice than those of WT mice.ConclusionA.b. is potent in inducing neutrophil infiltration in the lungs and total protein in the BALF. MV enhances A.b.-induced lung injury through an increase in the expression of VCAM and IL-6 levels in the BALF and a decrease in the bacteria-killing activity of AMs. A lower inflammation level in JNK1-/- mice indicates that A.b.-induced VAP causes lung injury through JNK signaling pathway in the lungs.

Project description:BackgroundThe mechanisms by which moderate tidal volume ventilation (MTV) exacerbates preexisting lung injury are unclear. We hypothesized that systemic endotoxemia via the gut-lung axis would lead to non-canonical and canonical inflammasome activation and pyroptosis in a two-hit model involving polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of dsRNA and MTV and that this would associate with acute lung injury (ALI).MethodsAnesthetized mice were administered Poly(I:C) intratracheally and then 6 h later, they were mechanically ventilated for 4 h with otherwise non-injurious MTV (10ml/kg). Changes in intestinal and alveolar capillary permeability were measured. Further documentation of ALI was assessed by evans blue albumin permeability, protein and IL-1 family concentration in bronchoalveolar lavage fluid (BALF) or plasma, and histopathology in cohorts of wildtype (WT), whole body genetically ablated caspase-11 (caspase-11-/-), caspase-1/caspase-11 double knockout (caspase-1/11-/-), gasdermin D (GSDMD)-/-, nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3)-/- and advanced glycosylation end product-specific receptor (RAGE) -/- mice.ResultsNon-injurious MTV exacerbated the mild lung injury associated with Poly(I:C) administration. This included the disruption of alveolar-capillary barrier and increased levels of interleukin (IL)-6, high mobility group proteins 1 (HMGB-1), IL-1β in BALF and IL-18 in plasma. Combined (Poly(I:C)-MTV) injury was associated with increase in gastrointestinal permeability and endotoxin in plasma and BALF. Poly(I:C)-MTV injury was sensitive to caspase-11 deletion with no further contribution of caspase-1 except for maturation and release of IL-18 (that itself was sensitive to deletion of NLRP3). Combined injury led to large increases in caspase-1 and caspase-11. Genetic ablation of GSDMD attenuated alveolar-capillary disruption and release of cytokines in combined injury model.ConclusionsThe previously noted exacerbation of mild Poly(I:C)-induced ALI by otherwise non-injurious MTV is associated with an increase in gut permeability resulting in systemic endotoxemia. The gut-lung axis resulted in activation of pulmonary non-canonical (cytosolic mediated caspase-11 activation) and canonical (caspase-1) inflammasome (NLRP3) mediated ALI in this two-hit model resulting in GSDMD sensitive alveolar capillary barrier disruption, pyroptosis (alveolar macrophages) and cytokine maturation and release (IL-1β; IL-18). Pharmacologic strategies aimed at disrupting communication between gut and lung, inhibition of inflammasomes or GSDMD in pyroptosis may be useful in ALI.

Dataset Information

Analysis of mechanical ventilation and lipopolysaccharide?induced acute lung injury using DNA microarray analysis.

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Analysis of mechanical ventilation and lipopolysaccharide‑induced acute lung injury using DNA microarray analysis.

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