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Effective Steroid-free Therapies for Chronic Inflammatory Lung Diseases: Targeting Leukotriene B4

Voelkel NF, Nicolls MR.

Respiratory Drug Delivery 2014. Volume 1, 2014: 39-48.

Abstract:

Chronic obstructive pulmonary diseases (COPD) present a clinical spectrum of chronic, and usually progressive, lung disorders that are defined by airflow limitation and associated with chronic inflammation. Presently, the inflammatory disease component is frequently treated with inhaled steroids. Antibiotics are also used during sporadic acute exacerbations. Overall, the available repertoire of drugs for the treatment of COPD is rather limited and new treatment targets need to be identified. The development of new anti-inflammatory drugs, preferably delivered via inhalation, remains an unmet need. Leukotrienes are lipid mediators of inflammation derived from the ubiquitous and abundant cell membrane arachidonic acid pool. The 5-lipoxygenase metabolite leukotriene B4 (LTB4) is increased in exhaled breath condensate and sputum samples from COPD patients. Bestatin, an inhibitor of LTB4 production by neutrophils and macrophages, has been shown to prevent the development of severe pulmonary hypertension in a rat model, as well as the reversal of established pulmonary arterial hypertension (PAH). The rationale for treatment with bestatin is inhibition of increased LTB4 generation and inhibition of chemotaxis of inflammatory cells. Inhalation of a microparticle dry powder formulation of bestatin was highly effective in decreasing lung LTB4 production in an animal model of PAH. This proof of principle study led to the postulate that inhaled bestatin may rationally be administered to patients with COPD, particularly to those that exhibit high levels of serum LTB4 or exhaled LTB4.