Journal article
Lung Atelectasis Promotes Immune and Barrier Dysfunction as Revealed by Transcriptome Sequencing in Female Sheep
Anesthesiology (Philadelphia), Vol.133(5), pp.1060-1076
11/01/2020
DOI: 10.1097/ALN.0000000000003491
PMCID: PMC7572680
PMID: 32796202
Abstract
Background: Pulmonary atelectasis is frequent in clinical settings. Yet there is limited mechanistic understanding and substantial clinical and biologic controversy on its consequences. The authors hypothesize that atelectasis produces local transcriptomic changes related to immunity and alveolar-capillary barrier function conducive to lung injury and further exacerbated by systemic inflammation. Methods: Female sheep underwent unilateral lung atelectasis using a left bronchial blocker and thoracotomy while the right lung was ventilated, with (n = 6) or without (n = 6) systemic lipopolysaccharide infusion. Computed tomography guided samples were harvested for NextGen RNA sequencing from atelectatic and aerated lung regions. The Wald test was used to detect differential gene expression as an absolute fold change greater than 1.5 and adjustedPvalue (Benjamini-Hochberg) less than 0.05. Functional analysis was performed by gene set enrichment analysis. Results: Lipopolysaccharide-unexposed atelectaticversusaerated regions presented 2,363 differentially expressed genes. Lipopolysaccharide exposure induced 3,767 differentially expressed genes in atelectatic lungs but only 1,197 genes in aerated lungs relative to the corresponding lipopolysaccharide-unexposed tissues. Gene set enrichment for immune response in atelectasisversusaerated tissues yielded negative normalized enrichment scores without lipopolysaccharide (less than -1.23, adjustedPvalue less than 0.05) but positive scores with lipopolysaccharide (greater than 1.33, adjustedPvalue less than 0.05). Leukocyte-related processes (e.g., leukocyte migration, activation, and mediated immunity) were enhanced in lipopolysaccharide-exposed atelectasis partly through interferon-stimulated genes. Furthermore, atelectasis was associated with negatively enriched gene sets involving alveolar-capillary barrier function irrespective of lipopolysaccharide (normalized enrichment scores less than -1.35, adjustedPvalue less than 0.05). Yes-associated protein signaling was dysregulated with lower nuclear distribution in atelectaticversusaerated lung (lipopolysaccharide-unexposed: 10.0 +/- 4.2versus13.4 +/- 4.2 arbitrary units, lipopolysaccharide-exposed: 8.1 +/- 2.0versus11.3 +/- 2.4 arbitrary units, effect of lung aeration,P= 0.003). Conclusions: Atelectasis dysregulates the local pulmonary transcriptome with negatively enriched immune response and alveolar-capillary barrier function. Systemic lipopolysaccharide converts the transcriptomic immune response into positive enrichment but does not affect local barrier function transcriptomics. Interferon-stimulated genes and Yes-associated protein might be novel candidate targets for atelectasis-associated injury.
Details
- Title: Subtitle
- Lung Atelectasis Promotes Immune and Barrier Dysfunction as Revealed by Transcriptome Sequencing in Female Sheep
- Creators
- Congli Zeng - Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USAGabriel C. Motta-Ribeiro - Federal ReserveTakuga Hinoshita - Boston UniversityMarcos Adriano Lessa - University of Iowa, AnesthesiaTilo Winkler - Boston UniversityKira Grogg - Boston UniversityNathan M. Kingston - Boston UniversityJohn N. Hutchinson - Harvard UniversityLynette Marie Sholl - Boston UniversityXiangming Fang - Boston UniversityXaralabos Varelas - Boston UniversityMatthew D. Layne - Boston UniversityRebecca M. Baron - Boston UniversityMarcos F. Vidal Melo - Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA
- Resource Type
- Journal article
- Publication Details
- Anesthesiology (Philadelphia), Vol.133(5), pp.1060-1076
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1097/ALN.0000000000003491
- PMID
- 32796202
- PMCID
- PMC7572680
- ISSN
- 0003-3022
- eISSN
- 1528-1175
- Number of pages
- 17
- Grant note
- RO1 HL121228 / National Institutes of Health/National Heart, Lung, and Blood Institute (Bethesda, Maryland); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 11/01/2020
- Academic Unit
- Anesthesia
- Record Identifier
- 9984656528302771
Metrics
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