Intrapulmonary Administration of Leukotriene B4Enhances Pulmonary Host Defense against Pneumococcal Pneumonia
Open Access
- 1 May 2010
- journal article
- research article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 78 (5), 2264-2271
- https://doi.org/10.1128/iai.01323-09
Abstract
Leukotriene B4(LTB4) is a potent lipid mediator of inflammation formed by the 5-lipoxygenase (5-LO)-catalyzed oxidation of arachidonic acid. We have previously shown that (i) LTB4is generated during infection, (ii) its biosynthesis is essential for optimal antimicrobial host defense, (iii) LT deficiency is associated with clinical states of immunocompromise, and (iv) exogenous LTB4augments antimicrobial functions in phagocytes. Here, we sought to determine whether the administration of LTB4has therapeutic potential in a mouse model of pneumonia. Wild-type and 5-LO knockout mice were challenged withStreptococcus pneumoniaevia the intranasal route, and bacterial burdens, leukocyte counts, and cytokine levels were determined. LTB4was administered via the intraperitoneal, intravenous, and intranasal routes prior to pneumococcal infection and by aerosol 24 h following infection. Leukocytes recovered from mice givenS. pneumoniaeand treated with aerosolized LTB4were evaluated for expression levels of the p47phox subunit of NADPH oxidase. Intrapulmonary but not systemic pretreatment with LTB4significantly reduced the lungS. pneumoniaeburden in wild-type mice. Aerosolized LTB4was effective at improving lung bacterial clearance when administered postinoculation in animals with established infection and exhibited greater potency in 5-LO knockout animals, which also exhibited greater baseline susceptibility. Augmented bacterial clearance in response to LTB4was associated with enhanced monocyte recruitment and leukocyte expression of p47phox. The results of the current study in an animal model serve as a proof of concept for the potential utility of treatment with aerosolized LTB4as an immunostimulatory strategy in patients with bacterial pneumonia.Keywords
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