25-Hydroxycholesterol exacerbates vascular leak during acute lung injury

JCI Insight · 15 authors, 6 centres

AI SUMMARY

FIDELITY 100%

POPULATIONCh25h-/- mice and wild-type mice subjected to high-dose LPS inhalation, with parallel endothelial monolayer studies

INTERVENTIONGenetic deletion of Ch25h and/or pharmacologic 25HC exposure in a high-dose LPS acute lung injury model

COMPARISONCh25h-/- mice versus wild-type mice, and LXR-null mice versus wild-type mice

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

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TL;DR

Using Ch25h-/- mice and a high-dose LPS lung injury model, the study shows that 25-hydroxycholesterol promotes endothelial activation and vascular leak via an LXR-independent mechanism.

Full summary

1,174 CHARS

The paper investigates 25-hydroxycholesterol (25HC) produced by cholesterol-25-hydroxylase (CH25H) in a high-dose LPS mouse model of acute lung injury. Sustained reductions in BALF cytokines and microvascular leak were observed in Ch25h-/- mice compared with wild-type, whereas LXR-null mice did not show this protection, implicating an LXR-independent pathway. Systemically delivered 25HC was sufficient to induce lung Vcam1 and increase endothelial monolayer permeability but did not by itself cause BALF protein leak in naive mice, suggesting a required proinflammatory milieu. Bone marrow chimera experiments indicated that non-hematopoietic rather than hematopoietic CH25H drives vascular leak. An association between alveolar macrophage CH25H expression and ARDS severity markers is reported in human patients, although the human data are observational. Limitations include reliance on a single LPS model, imperfect selectivity of the ER stress inhibitor PBA, in vitro 25HC supplementation that does not model native CH25H/25HC, and lack of endothelial-specific Ch25h deletion. The authors propose ER stress as a candidate integrator of context-dependent 25HC effects.

PICO

PPOPULATION

Ch25h-/- mice and wild-type mice subjected to high-dose LPS inhalation, with parallel endothelial monolayer studies

IINTERVENTION

Genetic deletion of Ch25h and/or pharmacologic 25HC exposure in a high-dose LPS acute lung injury model

OOUTCOME

BALF cytokine levels, microvascular leak, endothelial activation markers, and endothelial monolayer permeability

STUDY TYPE

other

SPECIALTY

pulmonology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10132150

25-Hydroxycholesterol exacerbates vascular leak during acute lung injury

JCI Insight

READ THE FULL PAPER

ABSTRACT

Abstract Cholesterol-25-hydroxylase (CH25H), the biosynthetic enzyme for 25-hydroxycholesterol (25HC), is most highly expressed in the lung, but its role in lung biology is poorly defined. Recently, we reported that Ch25h is induced in monocyte-derived macrophages recruited to the airspace during resolution of lung inflammation and that 25HC promotes liver X receptor–dependent (LXR-dependent) clearance of apoptotic neutrophils by these cells. Ch25h and 25HC are, however, also robustly induced by lung-resident cells during the early hours of lung inflammation, suggesting additional cellular sources and targets. Here, using Ch25h –/– mice and exogenous 25HC in lung injury models, we provide evidence that 25HC sustains proinflammatory cytokines in the airspace and augments lung injury, at least in part, by inducing LXR-independent endoplasmic reticulum stress and endothelial leak. Suggesting an autocrine effect in endothelium, inhaled LPS upregulates pulmonary endothelial Ch25h , and non-hematopoietic Ch25h deletion is sufficient to confer lung protection. In patients with acute respiratory distress syndrome, airspace 25HC and alveolar macrophage CH25H were associated with markers of microvascular leak, endothelial activation, endoplasmic reticulum stress, inflammation, and clinical severity. Taken together, our findings suggest that 25HC deriving from and acting on different cell types in the lung communicates distinct, temporal LXR-independent and -dependent signals to regulate inflammatory homeostasis. Keywords: Inflammation, Pulmonology Keywords: Cell stress, Innate immunity, Mouse models

CITATION EXPORT

Jennifer H Madenspacher, Eric D Morrell, Jeffrey G McDonald et al.. 25-Hydroxycholesterol exacerbates vascular leak during acute lung injury. JCI Insight. (2023). https://doi.org/10.1172/jci.insight.155448

AUTHORS

15 · 6 CENTRES

Jennifer H Madenspacher, Eric D Morrell, Jeffrey G McDonald, Bonne M Thompson, Yue Li, Konstantin G Birukov, Anna A Birukova, Renee D Stapleton, Aidin Alejo, Peer W Karmaus, Julie M Meacham, Prashant Rai, Carmen Mikacenic, Mark M Wurfel, Michael B Fessler

1Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
2Section of Pulmonary, Critical Care, and Sleep Medicine, Harborview Medical Center, Seattle, Washington, USA.
3Center for Human Nutrition and
4Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
6Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.