Administration of products of the 5-lipoxygenase metabolic pathway to enhance antimicrobial defense

Abstract

The use of leukotrienes and other products of the 5-lipoxygenase pathway to enhance bacterial defense and treat infections is described. The products are especially useful when administered to the lungs for the treatment of pneumonia and other lower respiratory tract infections. The products may be administered for treatment or prophylactic purposes and may be administered concomitantly with antibiotics to combat infection.

Description

[0001] This invention was made with United States government support awarded by the National Institute of Health (NIH), Grant Nos. HL 58200, HL 57243, AA 10571, P 50 HL 46487, CA 66180, HL 50057, and HL 47391.FIELD OF THE INVENTION [0002] The present invention relates generally to the administration of compounds to enhance antimicrobial defense, and more particularly to the administration of products of the 5-lipoxygenase metabolic pathway to enhance bacterial defense and to treat and prevent bacterial pneumonia. BACKGROUND OF THE INVENTION [0003] A. Pulmonary Host Defense and the Pathogenesis of Pneumonia [0004] In view of the constant challenge to the respiratory tract from inhaled or aspirated microbes, and the deleterious consequences of unchecked infection, an efficient system of pulmonary antimicrobial defense is obviously important to health. Microbes which elude the mechanical defenses offered by the upper respiratory tract and airways reach the alveoli. Here, the alveolar m...

AI Technical Summary

Benefits of technology

[0015] In order to evaluate the role of leukotrienes in bacterial pneumonia, the present inventors have employed a model of Klebsiella pneumonia in knockout mice rendered leukotriene-deficient by the targeted disruption of the 5-lipoxygenase gene. The present inventors found that leukotriene production was increased in the lungs of infected wild type mice, and that leukotriene-deficient animals manifested reduced bacterial clearance and enhanced lethality. Moreover, alveolar macrophages from knockout mice exhibited impaired in vitro phagocytosis and killing of K. pneumoniae, and this functional defect in leukotriene-deficient alveolar macrophages was overcome by the addition of exogenous leukotrienes such as LTB4. Importantly, intrapulmonary administration of LTB4 partially overcame the in vivo impairment in bacterial clearance observed in knockout mice.

[0017] The present invention contemplates the treatment of patients with a recognized predisposing factor (e.g., smoking, alcoholism, diabetes, HIV infection, known aspiration) for overwhelming pneumonia, or with early pneumonia, with administration via inhalation or an endotracheal tube of metabolic products of the 5-lipoxygenase pathway (e.g., leukotrienes). In addition, the present invention contemplates the use of the products of the 5-lipoxygenase pathway for prophylactic purposes. While an understanding of the mechanism by which the products act is not necessary for the successful practice of the present invention, the administration of such products, especially the intrapulmonary administration of leukotrienes, augments local endogenous host defense mechanisms and assists in bacterial infection eradication during antibiotic administration. The products have a relatively short duration of action (e.g., hours), do not cause antibody-mediated immune responses, and are relatively inexpensive.

Problems solved by technology

Unfortunately, qualitative or quantitative impairment of any component of these defenses can compromise bacterial clearance and predispose to pneumonia.

Antibiotic pressure in certain patient populations (e.g., patients with underlying systemic illness or impairments in host defense) has contributed to the development of infections with multi-drug resistant organisms, the eradication of which is increasingly difficult.

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