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Updated: Feb 28, 2026
Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury
Benkun Zou1, Wei Jiang1, Han Han2
1Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China.
Abstract:
Pulmonary infection is the most common risk factor for acute lung injury (ALI). Innate immune responses induced by Microbe-Associated Molecular Pattern (MAMP) molecules are essential for lung defense but can lead to tissue injury. Little is known about how MAMP molecules are degraded in the lung or how MAMP degradation/inactivation helps prevent or ameliorate the harmful inflammation that produces ALI. Acyloxyacyl hydrolase (AOAH) is a host lipase that inactivates Gram-negative bacterial endotoxin (lipopolysaccharide, or LPS). We report here that alveolar macrophages increase AOAH expression upon exposure to LPS and that Aoah+/+ mice recover more rapidly than do Aoah-/- mice from ALI induced by nasally instilled LPS or Klebsiella pneumoniae. Aoah-/- mouse lungs had more prolonged leukocyte infiltration, greater pro- and anti-inflammatory cytokine expression, and longer-lasting alveolar barrier damage. We also describe evidence that the persistently bioactive LPS in Aoah-/- alveoli can stimulate alveolar macrophages directly and epithelial cells indirectly to produce chemoattractants that recruit neutrophils to the lung and may prevent their clearance. Distinct from the prolonged tolerance observed in LPS-exposed Aoah-/- peritoneal macrophages, alveolar macrophages that lacked AOAH maintained or increased their responses to bioactive LPS and sustained inflammation. Inactivation of LPS by AOAH is a previously unappreciated mechanism for promoting resolution of pulmonary inflammation/injury induced by Gram-negative bacterial infection.
Insights
Acyloxyacyl hydrolase (AOAH) inactivates lipopolysaccharide (LPS), a key factor in lung injury. AOAH-deficient mice show prolonged inflammation and delayed recovery from bacterial pneumonia, highlighting AOAH
Area of Science:
- Immunology
- Pulmonology
- Microbiology
Background:
- Pulmonary infections are a primary cause of acute lung injury (ALI).
- Microbe-Associated Molecular Patterns (MAMPs) trigger innate immune responses crucial for lung defense but can cause tissue damage.
- Mechanisms of MAMP degradation and their role in preventing ALI are not well understood.
Purpose of the Study:
- To investigate the role of Acyloxyacyl hydrolase (AOAH) in inactivating lipopolysaccharide (LPS) and its impact on acute lung injury (ALI).
- To determine how AOAH function influences inflammatory responses and recovery following Gram-negative bacterial infection in the lungs.
Main Methods:
- Investigated AOAH expression in alveolar macrophages upon LPS exposure.
- Compared ALI development and resolution in wild-type (Aoah+/+) and AOAH-deficient (Aoah-/-) mice challenged with LPS or Klebsiella pneumoniae.
- Analyzed leukocyte infiltration, cytokine expression, alveolar barrier integrity, and macrophage responses in vivo and in vitro.
Main Results:
- Alveolar macrophages upregulate AOAH in response to LPS.
- Aoah-/- mice exhibited prolonged leukocyte infiltration, elevated pro- and anti-inflammatory cytokines, and sustained alveolar barrier damage compared to Aoah+/+ mice.
- Persistently bioactive LPS in Aoah-/- mice stimulated alveolar macrophages and epithelial cells, promoting neutrophil recruitment and hindering clearance.
Conclusions:
- AOAH-mediated inactivation of LPS is a critical, previously unrecognized mechanism for resolving pulmonary inflammation and injury.
- AOAH deficiency leads to sustained inflammatory responses and impaired recovery from Gram-negative bacterial pneumonia.
- Targeting AOAH may offer a therapeutic strategy for mitigating ALI caused by bacterial infections.
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