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The endogenous capacity to produce proinflammatory mediators by the ex vivo human perfused lung.

ABSTRACT: BACKGROUND:The ex vivo human perfused lung model has enabled optimizing donor lungs for transplantation and delineating mechanisms of lung injury. Perfusate and airspace biomarkers are a proxy of the lung response to experimental conditions. However, there is a lack of studies evaluating biomarker kinetics during perfusion and after exposure to stimuli. In this study, we analyzed the ex vivo-perfused lung response to three key perturbations: exposure to the perfusion circuit, exogenous fresh whole blood, and bacteria. RESULTS:Ninety-nine lungs rejected for transplantation underwent ex vivo perfusion. One hour after reaching experimental conditions, fresh whole blood was added to the perfusate (n?=?55). Two hours after reaching target temperature, Streptococcus pneumoniae was added to the perfusate (n?=?42) or to the airspaces (n?=?17). Perfusate and airspace samples were collected at baseline (once lungs were equilibrated for 1?h, but before blood or bacteria were added) and 4?h later. Interleukin (IL)-6, IL-8, angiopoietin (Ang)-2, and soluble tumor necrosis factor receptor (sTNFR)-1 were quantified. Baseline perfusate and airspace biomarker levels varied significantly, and this was not related to pre-procurement PaO2:FiO2 ratio, cold ischemia time, and baseline alveolar fluid clearance (AFC). After 4?h of ex vivo perfusion, the lung demonstrated a sustained production of proinflammatory mediators. The change in biomarker levels was not influenced by baseline donor lung characteristics (cold ischemia time, baseline AFC) nor was it associated with measures of experimental epithelial (final AFC) or endothelial (percent weight gain) injury. In the presence of exogenous blood, the rise in biomarkers was attenuated. Lungs exposed to intravenous (IV) bacteria relative to control lungs demonstrated a significantly higher rise in perfusate IL-6. CONCLUSIONS:The ex vivo-perfused lung has a marked endogenous capacity to produce inflammatory mediators over the course of short-term perfusion that is not significantly influenced by donor lung characteristics or the presence of exogenous blood, and only minimally affected by the introduction of systemic bacteremia. The lack of association between biomarker change and donor lung cold ischemia time, final alveolar fluid clearance, and experimental percent weight gain suggests that the maintained ability of the human lung to produce biomarkers is not merely a marker of lung epithelial or endothelial injury, but may support the function of the lung as an immune cell reservoir.

SUBMITTER: Leligdowicz A

PROVIDER: S-EPMC7505905 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The endogenous capacity to produce proinflammatory mediators by the ex vivo human perfused lung.

Leligdowicz Aleksandra A Ross James T JT Nesseler Nicolas N Matthay Michael A MA

Intensive care medicine experimental 20200921 1

<h4>Background</h4>The ex vivo human perfused lung model has enabled optimizing donor lungs for transplantation and delineating mechanisms of lung injury. Perfusate and airspace biomarkers are a proxy of the lung response to experimental conditions. However, there is a lack of studies evaluating biomarker kinetics during perfusion and after exposure to stimuli. In this study, we analyzed the ex vivo-perfused lung response to three key perturbations: exposure to the perfusion circuit, exogenous f ...[more]

PMID: 32955627

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Project description:Rationale: Exposure to biomass smoke is believed to increase the risk of developing chronic obstructive pulmonary disease. However, little is known about the mechanisms underlying responses to biomass smoke in human lungs.Objectives: This study had two objectives: first, to quantify "real-life" exposures to particulate matter <2 ?m in diameter (PM2.5) and carbon monoxide (CO) measured during cooking on stoves in rural areas of Nepal in different geographical settings; and second, to assess the effect of biomass smoke extracts on inflammatory responses in ex vivo human lung tissue.Methods: Personal exposures to PM2.5 and indoor near-stove CO concentrations were measured during cooking on a range of stoves in 103 households in 4 different Nepalese villages situated at altitudes between ?100 and 4,000 m above sea level. Inflammatory profiles to smoke extracts collected in the field were assessed by incubating extracts with human lung tissue fragments and subsequent Luminex analysis.Results: In households using traditional cooking stoves, the overall mean personal exposure to PM2.5 during cooking was 276.1 ?g/m3 (standard deviation [SD], 265 ?g/m3), and indoor CO concentration was 16.3 ppm (SD, 19.65 ppm). The overall mean PM2.5 exposure was reduced by 51% (P?=?0.04) in households using biomass fuel in improved cook stoves, and 80% (P?<?0.0001) in households using liquefied petroleum gas. Similarly, the indoor CO concentration was reduced by 72% (P?<?0.001) and 86% (P?<?0.0001) in households using improved cook stoves and liquefied petroleum gas, respectively. Significant increases occurred in 7 of the 17 analytes measured after biomass smoke extract stimulation of human lung tissue (IL-8 [interleukin-8], IL-6, TNF-? [tumor necrosis factor-?], IL-1?, CCL2, CCL3, and CCL13).Conclusions: High levels of real-life exposures to PM2.5 and CO occur during cooking events in rural Nepal. These exposures induce lung inflammation ex vivo, which may partially explain the increased risk of chronic obstructive pulmonary disease in these communities.

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The endogenous capacity to produce proinflammatory mediators by the ex vivo human perfused lung.

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The endogenous capacity to produce proinflammatory mediators by the ex vivo human perfused lung.

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