Nasally Administered Lactococcus lactis Secreting Heme Oxygenase-1 Attenuates Murine Emphysema.

Kentaro Yumoto,Takashi Sato,Fu Namai,Takeshi Kaneko,Takeshi Shimosato,Kentaro Nakashima,Suguru Shigemori

doi:10.3390/antiox9111049

Kentaro Yumoto, Takashi Sato + Show 5 more

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https://doi.org/10.3390/antiox9111049

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Journal: Antioxidants	Publication Date: Oct 27, 2020
Citations: 7	License type: CC BY 4.0

Affiliation: Yokohama City University, Shinshu University

Abstract

Emphysema, a type of lung-destroying condition associated with chronic obstructive pulmonary disease (COPD), is an inflammatory lung disease mainly due to cigarette smoke exposure. As there is no curative therapy, prevention should be considered first by cessation of smoking to avoid exposure to oxidative stresses and inflammatory mediators. In addition, therapies involving antioxidative and/or anti-inflammatory agents such as heme oxygenase (HO)-1 are candidate treatments. We developed a new tool using genetically modified Lactococcus lactis to deliver recombinant HO-1 to the lungs. Using an elastase-induced emphysema model mimicking COPD, we evaluated the effect of nasally administered L. lactis secreting HO-1 (HO-1 lactis) on cellular and molecular responses in the lungs and further disease progression. Nasally administered HO-1 lactis resulted in (1) overexpression of HO-1 in the lungs and serum and (2) attenuation of emphysema progression evaluated both physiologically and morphologically. There was a transient 5–10% weight loss compared to baseline through trafficking to the lungs when administering 1.0 × 109 cells/mouse; however, this did not impact either survival or final body weight. These results suggest that delivering HO-1 using genetically modified L. lactis through the airways could be a safe and potentially effective therapeutic approach for COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is a major chronic respiratory disease and the third leading cause of death globally, accounting for approximately 3.2 million deaths in 2015 worldwide [1,2]
No life-threatening effects or effects on the restoration of body weight were observed throughout 7 days after a single administration of 5.0 × 108, 10 × 108, or 50 × 108 L. lactis cells, the highest dose (50 × 108 cells) of L. lactis resulted in significant weight loss on day 2 (>12%) and greater area under the curve (AUC) of the body weight measurements during the week after administration (Figure 1; p < 0.05 compared to saline control)
This study showed for the first time that (1) nasal administration of genetically modified strains of LAB (gmLAB) could be a potential tool for delivering specific therapeutics to the lungs, and (2) the therapeutics could be further transferred to the systemic circulation

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a major chronic respiratory disease and the third leading cause of death globally, accounting for approximately 3.2 million deaths in 2015 worldwide [1,2]. COPD is characterized by chronic respiratory symptoms and airflow limitation due to long-term exposure to toxic substances such as cigarette smoke [3]. In addition to urging smokers to quit, avoiding exposure to other oxidative/inflammatory substances is important, as a prospective study demonstrated that the incidence of COPD increases with age in both current/former smokers and never smokers [5]. Inflammation associated with COPD involves inflammatory cells such as neutrophils, macrophages, and cytotoxic T cells [6]. These inflammatory and lung epithelial cells produce inflammatory mediators such as chemokines and cytokines and proteases and oxidants [7]

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