Interventional low-dose azithromycin attenuates cigarette smoke-induced emphysema and lung inflammation in mice.

Matthew G Macowan,Marianne D Keller,Sandra Hodge,Rhys Hamon,Hong Liu,Hai B Tran,Miranda Ween

doi:10.14814/phy2.14419

Abstract

Cigarette smoke (CS)‐induced emphysema is an important contributor to chronic obstructive pulmonary disease (COPD). We have shown the efficacy of azithromycin in reducing airway inflammation in COPD and in reducing exacerbations in severe asthma; however, the effects of long‐term azithromycin on emphysema development have not been shown. We employed live animal imaging to monitor emphysema‐like development and the effects of interventional azithromycin treatment in CS‐exposed mice. BALB/c mice (female, 10 weeks; n = 10) were exposed to CS for 1 hr twice daily, 5 days/week, and for 12 weeks (CS). Half were cotreated with low‐dose azithromycin during weeks 7–12 (CS + Azi; 0.2 mg kg−1 day−1). Microcomputed tomography (CT) and magnetic resonance imaging (MRI) scans were acquired longitudinally. Histological examinations were performed post mortem (mean linear intercept (Lm) and leukocyte infiltration). CS increased median Lm (CS: 42.45 µm versus control: 34.7 µm; p = .0317), this was recovered in CS + Azi mice (33.03 µm). Average CT values were reduced in CS mice (CS: −399.5 Hounsfield units (HU) versus control: −384.9 HU; p = .0286) but not in CS + Azi mice (−377.3 HU). CT values negatively correlated with Lm (r = −.7972; p = .0029) and T2‐weighted MRI (r = −.6434; p = .0278). MRI also showed significant CS‐induced inflammatory changes that were attenuated by azithromycin in the lungs, and positively correlated with Lm (r = .7622; p = .0055) and inflammatory foci counts (r = .6503; p = .0257). Monitoring of emphysema development is possible via micro‐CT and MRI. Interventional azithromycin treatment in CS‐exposed mice attenuated the development of pulmonary emphysema‐like changes.

Highlights

Emphysema, alongside chronic bronchitis, is the most common condition in chronic obstructive pulmonary disease (COPD), for which cigarette smoke (CS) is the most common causative factor
Emphysema severity is highly variable among COPD patients and increased severity is associated with poorer quality of life (Makita et al, 2007)
We and others have previously highlighted the potential of macrolide antibiotics in COPD for reducing inflammation (Zarogoulidis et al, 2012) and pulmonary exacerbations (Albert et al, 2011; Pomares et al, 2011), improving bacterial clearance (Hodge et al, 2008; Hodge & Reynolds, 2012), and increasing the phagocytosis of apoptotic airway cells, that is, efferocytosis (Hodge et al, 2006)

Summary

| INTRODUCTION

Alongside chronic bronchitis, is the most common condition in chronic obstructive pulmonary disease (COPD), for which cigarette smoke (CS) is the most common causative factor. We have previously shown that low-dose azithromycin treatment in COPD patients improves macrophage clearance of apoptotic cells and bacteria, and reduces airway inflammation (Albert et al, 2011; Hodge et al, 2008; Hodge & Reynolds, 2012; Pomares et al, 2011). No study has investigated whether a macrolide can attenuate development of emphysema-like changes when administered at a low dosage following CS-induced development of an inflammatory, yet pre-emphysematous lung environment. This model is representative of a treatment that prevents emphysema development in a smoker experiencing minor lung distress. In this study, we utilized live animal imaging to monitor the inflammatory lung environment and emphysema-like changes development in CS-exposed mice treated with interventional inhaled azithromycin

| METHODS

| RESULTS

Findings

| DISCUSSION