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Updated: Jun 2, 2026

Pseudomonas aeruginosa Induced Lung Injury Model
Published on: October 29, 2014
Hemolytic phospholipase C inhibition protects lung function during Pseudomonas aeruginosa infection
Matthew J Wargo1, Maegan J Gross, Sathish Rajamani
1Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT 05405, USA. Matthew.Wargo@med.uvm.edu
Rationale:
The opportunistic pathogen Pseudomonas aeruginosa causes both acute and chronic lung infections and is particularly problematic in patients with cystic fibrosis and those undergoing mechanical ventilation. Decreased lung function contributes significantly to morbidity and mortality during P. aeruginosa infection, and damage inflicted by P. aeruginosa virulence factors contributes to lung function decline.
Objectives:
We sought to describe direct contribution of a bacterial phospholipase C/sphingomyelinase, PlcHR, to alteration of host lung physiology and characterize a potential therapeutic for protection of lung function.
Methods:
We infected C57Bl/6 mice with P. aeruginosa wild-type or isogenic plcHR deletion strains and measured lung function using computer-controlled ventilators. For in vivo testing, miltefosine was delivered intraperitoneally 1 hour after infection. Infection and respiratory endpoints were at 24 hours after infection.
Measurements And Main Results:
P. aeruginosa wild-type infection caused significant lung function impairment, whereas the effects of a ΔplcHR strain infection were much less severe. Surfactometry analysis of bronchoalveolar lavage fluid indicated that PlcHR decreased pulmonary surfactant function. Miltefosine has structural similarity to the PC and sphingomyelin substrates of PlcHR, and we found that it inhibits the cleavage of these choline-containing lipids in vitro. Miltefosine administration after P. aeruginosa infection limited the negative effects of PlcHR activity on lung function.
Conclusions:
We have directly linked production of a single virulence factor in P. aeruginosa with effects on lung function, and demonstrated that the inhibitor miltefosine protects lung function from PlcHR-dependent surfactant dysfunction.
Insights
Pseudomonas aeruginosa PlcHR damages lung function by impairing surfactant. The drug miltefosine inhibits PlcHR, protecting lung function during P. aeruginosa infection.
Area of Science:
- Microbiology
- Pulmonary Physiology
- Pharmacology
Background:
- Pseudomonas aeruginosa is an opportunistic pathogen causing severe lung infections, especially in cystic fibrosis patients.
- P. aeruginosa virulence factors significantly contribute to lung function decline, increasing morbidity and mortality.
- Understanding specific bacterial factors and their impact on host physiology is crucial for developing effective treatments.
Purpose of the Study:
- To elucidate the direct role of the phospholipase C/sphingomyelinase, PlcHR, in altering lung physiology during P. aeruginosa infection.
- To evaluate miltefosine as a potential therapeutic agent to protect lung function against PlcHR-mediated damage.
Main Methods:
- Mice were infected with wild-type or ΔplcHR P. aeruginosa strains.
- Lung function was assessed using computer-controlled mechanical ventilation.
- Miltefosine was administered intraperitoneally post-infection to evaluate its protective effects.
Main Results:
- P. aeruginosa wild-type infection severely impaired lung function, while the ΔplcHR strain caused significantly less damage.
- PlcHR was shown to reduce pulmonary surfactant function in bronchoalveolar lavage fluid.
- Miltefosine inhibited PlcHR's lipid cleavage activity in vitro and protected lung function in vivo.
Conclusions:
- This study directly links the P. aeruginosa virulence factor PlcHR to impaired lung function.
- Miltefosine effectively protects lung function by inhibiting PlcHR-dependent surfactant dysfunction.
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