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A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.

ABSTRACT: Preclinical drug development studies currently rely on costly and time-consuming animal testing because existing cell culture models fail to recapitulate complex, organ-level disease processes in humans. We provide the proof of principle for using a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip that mimics pulmonary edema. The microfluidic device, which reconstitutes the alveolar-capillary interface of the human lung, consists of channels lined by closely apposed layers of human pulmonary epithelial and endothelial cells that experience air and fluid flow, as well as cyclic mechanical strain to mimic normal breathing motions. This device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame. Studies using this on-chip disease model revealed that mechanical forces associated with physiological breathing motions play a crucial role in the development of increased vascular leakage that leads to pulmonary edema, and that circulating immune cells are not required for the development of this disease. These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future.

SUBMITTER: Huh D

PROVIDER: S-EPMC8265389 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionCigarette smoking (CS) remains a major public health concern and has recently been associated with an increased risk of developing acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) experiments in human volunteers have demonstrated that active smokers develop increased alveolar-epithelial barrier permeability to protein after inhaling lipopolysaccharide (LPS). Here we tested the hypothesis that short-term whole-body CS exposure would increase LPS-induced lung edema in mice.MethodsAdult mice were exposed in a Teague TE-10 machine to CS from 3R4F cigarettes at 100 mg/m3 total suspended particulates for 12 days, then given LPS or saline intratracheally. Control mice were housed in the same room without CS exposure. Post-mortem measurements included gravimetric lung water and BAL protein, cell counts, and lung histology. Cytokines were measured in lung homogenate by ELISA and in plasma by Luminex and ELISA.ResultsIn CS-exposed mice, intratracheal LPS caused greater increases in pulmonary edema by gravimetric measurement and histologic scoring. CS-exposed mice also had an increase in BAL neutrophilia, lung IL-6, and plasma CXCL9, a T-cell chemoattractant. Intratracheal LPS concentrated blood hemoglobin to a greater degree in CS-exposed mice, consistent with an increase in systemic vascular permeability.ConclusionsThese results demonstrate that CS exposure in endotoxin injured mice increases the severity of acute lung injury. The increased lung IL-6 in CS-exposed LPS-injured mice indicates that this potent cytokine, previously shown to predict mortality in patients with ARDS, may play a role in exacerbating lung injury in smokers and may have utility as a biomarker of tobacco-related lung injury.ImplicationsOur results suggest that short-term CS exposure at levels that cause no overt lung injury may still prime the lung for acute inflammatory damage from a "second hit", a finding that mirrors the increased risk of developing ARDS in patients who smoke. This model may be useful for evaluating the acute pulmonary toxicity of existing and/or novel tobacco products and identifying biomarkers of tobacco-related lung injury.

Project description:Experimental acute lung injury models are often used to increase our knowledge on the acute respiratory distress syndrome (ARDS), however, existing animal models often do not take into account the impact of specific fluid strategies on the development of lung injury. In contrast, the current literature strongly suggests that fluid management strategies have a significant impact on clinical outcome of patients with ARDS. Thus, it is important to characterize the role of fluid management strategies in experimental models of lung injury. In this study we investigated the effect of two different fluid strategies on commonly used outcome variables in a short-term model of acute lung injury, in relation to age. Infant (2-3 weeks) and adult (3-4 months) Wistar rats received intratracheal instillations of lipopolysaccharide and 24 hours later were mechanically ventilated for 6 hours. During mechanical ventilation, rats from both age groups were randomized to either a standard or conservative intravenous fluid strategy. We found that the hemodynamic response in infant and adult rats was similar in both fluid strategies. Lung wet-to-dry ratios were lower in adult, but not in infant rats receiving the conservative fluid strategy as compared to the standard fluid strategy. There were age-related differences in markers of alveolar capillary barrier disruption and alveolar fluid clearance, yet these were unaffected by fluid strategy. Finally, we found significantly higher IL-1β and TNF-α concentrations in the adult rats treated with the conservative as compared to the standard fluid regimen. In conclusion, the choice of fluid strategy in mechanically ventilated rats with experimental LPS-induced acute lung injury has a significant effect on pulmonary extravascular water, an important and well-recognized lung injury marker, and on the local pro-inflammatory cytokine profiles. We advocate the use of a more uniform, conservative, fluid strategy regimen in experimental models of acute lung injury.

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A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.

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