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Updated: Aug 16, 2026
Non-Invasive Endotracheal Administration of Lipopolysaccharide to Induce Acute Lung Injury in Rodents
Published on: December 5, 2025
Role of Kupffer cells in lung injury in rats administered endotoxin 1
Hiroshi Kono1, Hideki Fujii, Hidetake Amemiya
1First Department of Surgery, University of Yamanashi, Yamanashi, Japan. hkouno@res.yamanashi-med.ac.jp
Abstract:
The purpose of this study was to investigate the regulation of lung macrophages (Muvarphis) by Kupffer cells (KCs) in lung injury caused by endotoxemia. Phenotypic differences in tissue Muvarphis were also investigated. Muvarphis were isolated from gadolinium chloride (GdCl(3))- or saline-treated rats 2 h after saline or lipopolysaccharide (LPS) administration. Furthermore, rats were given GdCl(3) 24 h prior to LPS administration, and survival rate was assessed for 24 h. Moreover, lung edema was assessed 9 h after LPS injection. Expression of inflammatory mediators was measured in the liver and lung. KCs were divided into three subpopulations based on size and phagocytosis. The expression of TNF-alpha and MIP-2 was greater in the small KCs and lung Muvarphis, while the expression of IL-6, IL-10, and MCP-1 was greater in the large and intermediate KCs. GdCl(3) eliminated ED2-positive large KCs and did not have any effect on the lung Muvarphis. The number of ED1-positive KCs increased significantly in both organs after LPS challenge and was reduced by GdCl(3). The population of ED2-positive KCs did not change following LPS administration. GdCl(3) completely prevented increases in lung microvascular permeability and mortality after LPS infusion. After LPS administration, expression of TNF-alpha and IL-6 increased rapidly and then decreased gradually in both organs. GdCl(3) inhibited these increases in the liver significantly and enhanced the expression of MCP-1 and IL-10 in the lung 9 h after LPS administration. Thus, the heterogeneous response of KCs to endotoxin leads to production of certain cytokines and chemokines that affect lung function.
Insights
Kupffer cells (KCs) heterogeneity influences lung macrophages (Muvarphis) during endotoxemia. Gadolinium chloride (GdCl3) treatment protected against lung injury and mortality by modulating KC populations and inflammatory mediator expression.
Area of Science:
- Immunology
- Cell Biology
- Pulmonary Medicine
Background:
- Endotoxemia-induced lung injury involves complex immune cell interactions.
- Kupffer cells (KCs) in the liver and lung macrophages (Muvarphis) play critical roles in inflammatory responses.
- Understanding KC heterogeneity is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the regulatory role of Kupffer cells (KCs) on lung macrophages (Muvarphis) in endotoxemia-induced lung injury.
- To analyze phenotypic differences in lung Muvarphis.
- To assess the impact of Kupffer cell depletion on survival and lung edema.
Main Methods:
- Rats were treated with gadolinium chloride (GdCl3) or saline, followed by lipopolysaccharide (LPS) or saline administration.
- Lung macrophages and Kupffer cells were isolated and analyzed for phenotypic markers (ED1, ED2) and inflammatory mediator expression (TNF-alpha, IL-6, IL-10, MIP-2, MCP-1).
- Survival rates and lung microvascular permeability were assessed post-LPS challenge.
Main Results:
- Kupffer cells exhibited heterogeneity, with distinct subpopulations expressing different inflammatory mediators.
- GdCl3 treatment eliminated ED2-positive KCs and reduced ED1-positive KCs post-LPS.
- GdCl3 administration prevented increased lung microvascular permeability and mortality, and modulated cytokine/chemokine expression in the liver and lung.
Conclusions:
- Heterogeneity of Kupffer cells contributes to the production of cytokines and chemokines that impact lung function during endotoxemia.
- Targeting Kupffer cell populations with agents like GdCl3 offers a protective strategy against endotoxemia-induced lung injury.
- Modulating KC responses presents a potential therapeutic avenue for managing sepsis-related lung complications.
