ABSTRACT
COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, ß2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-κB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/pharmacology , Chromans/pharmacology , Hypersensitivity/prevention & control , Piperazines/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Reactive Oxygen Species/antagonists & inhibitors , Animals , Cell Line, Transformed , Chromans/chemistry , Complex Mixtures/antagonists & inhibitors , Complex Mixtures/pharmacology , Disease Models, Animal , Gene Expression Regulation , Guinea Pigs , Humans , Hydrogen Sulfide/agonists , Hydrogen Sulfide/blood , Hypersensitivity/etiology , Hypersensitivity/immunology , Hypersensitivity/metabolism , Inflammation , Interleukin-8/antagonists & inhibitors , Interleukin-8/genetics , Interleukin-8/immunology , Lipopolysaccharides/administration & dosage , Lung , Male , Malondialdehyde/antagonists & inhibitors , Malondialdehyde/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/immunology , Myocytes, Smooth Muscle/pathology , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/immunology , Neutrophils/drug effects , Neutrophils/immunology , Neutrophils/pathology , Oxidative Stress , Piperazines/chemistry , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/physiopathology , Reactive Oxygen Species/metabolism , Tars/chemistry , Tars/toxicity , Transcription Factor RelA/antagonists & inhibitors , Transcription Factor RelA/genetics , Transcription Factor RelA/immunologyABSTRACT
This study establishes a proof-of-concept that a tattoo device can target intra-dermal drug delivery against cutaneous leishmaniasis (CL). The selected drug is oleylphosphocholine (OlPC) formulated as liposomes, particles known to be prone to macrophage ingestion. We first show that treatment of cultured Leishmania-infected macrophages with OlPC-liposomes results in a direct dose-dependent killing of intracellular parasites. Based on this, in vivo efficacy is demonstrated using a 10 day tattooing-mediated treatment in mice infected with L. major and L. mexicana. In both models this regimen results in rapid clinical recovery with complete regression of skin lesions by Day 28. Parasite counts and histopathology examination confirm high treatment efficacy at the parasitic level. Low amount of drug required for tattooing combined with fast clinical recovery may have a positive impact on CL patient management. This first example of tattoo-mediated drug delivery could open to new therapeutic interventions in the treatment of skin diseases.
