Intrapulmonary Administration of Leukotriene B₄Enhances Pulmonary Host Defense against Pneumococcal Pneumonia

Abstract

Leukotriene B 4 (LTB 4 ) 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) LTB 4 is 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 LTB 4 augments antimicrobial functions in phagocytes. Here, we sought to determine whether the administration of LTB 4 has therapeutic potential in a mouse model of pneumonia. Wild-type and 5-LO knockout mice were challenged with Streptococcus pneumoniae via the intranasal route, and bacterial burdens, leukocyte counts, and cytokine levels were determined. LTB 4 was administered via the intraperitoneal, intravenous, and intranasal routes prior to pneumococcal infection and by aerosol 24 h following infection. Leukocytes recovered from mice given S. pneumoniae and treated with aerosolized LTB 4 were evaluated for expression levels of the p47phox subunit of NADPH oxidase. Intrapulmonary but not systemic pretreatment with LTB 4 significantly reduced the lung S. pneumoniae burden in wild-type mice. Aerosolized LTB 4 was 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 LTB 4 was 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 LTB 4 as an immunostimulatory strategy in patients with bacterial pneumonia.

Leukotrienes Target F-actin/Cofilin-1 to Enhance Alveolar Macrophage Anti-fungal Activity

“…We have previously confirmed the role of NADPH oxidase in LTB 4 -mediated killing of K. pneumoniae as suggested by pharmacologic studies with AMs derived from gp91phox Ϫ/Ϫ mice (14). In addition, LTB 4 can promote NADPH oxidase activation by various mechanisms, including enhancement of phosphorylation and membrane translocation of the NADPH oxidase subunit p47phox (14) and also by enhancing the expression of the gp91phox subunit (80). Interestingly, LTD 4 -induced C. albicans killing was only partially dependent on NADPH oxidase activation.…”

Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression

“…Administration of LTB 4 by aerosol augmented nuclear p50 staining in macrophages from both genotypes, restoring the p50 translocation response in 5-LO -/-mice to the level observed in infected WT animals. Consistent with these results, we recently reported that administration of LTB 4 using this protocol also enhances lung bacterial clearance in 5-LO -/-animals (27). Interestingly, we did not observe p50 nuclear translocation in neutrophils from either genotype in the absence or presence of aerosolized LTB 4 (data not shown).…”

“…pneumoniae infection. S. pneumoniae serotype 3, 6,303 (ATCC) was grown, and mice were infected, as described previously (27).…”

Monocyte Chemoattractant Protein 1 Regulates Pulmonary Host Defense via Neutrophil Recruitment during Escherichia coli Infection

“…These observations suggest that there is a complex interplay between CC and CXC chemokines. LTB 4 is a known neutrophil chemotactic lipid which can be generated by leukocytes from arachidonic acid (19) and act via G protein-coupled receptors to cause leukocyte accumulation, microbial killing, and generation of proinflammatory mediators (26,36). In an earlier study using the CLP model, it has been shown that MCP-1 inhibition attenuated neutrophil influx via the downregulation of LTB 4 production (37).…”