Hemolytic phospholipase C inhibition protects lung function during Pseudomonas aeruginosa infection.

ABSTRACT:

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 ?plcHR 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.

SUBMITTER: Wargo MJ 

PROVIDER: S-EPMC3175536 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature