Aerosolized Bovine Lactoferrin Counteracts Infection, Inflammation and Iron Dysbalance in A Cystic Fibrosis Mouse Model of Pseudomonas aeruginosa Chronic Lung Infection.

Antimo Cutone,Mellani Jinnett Scotti,Ida De Fino,Alice Rossi,Luigi Rosa,Piera Valenti,Giovanni Musci,Maria Stefania Lepanto,Alessandra Bragonzi,Serena Ranucci,Francesca Berlutti

doi:10.3390/ijms20092128

Abstract

Cystic fibrosis (CF) is a genetic disorder affecting several organs including airways. Bacterial infection, inflammation and iron dysbalance play a major role in the chronicity and severity of the lung pathology. The aim of this study was to investigate the effect of lactoferrin (Lf), a multifunctional iron-chelating glycoprotein of innate immunity, in a CF murine model of Pseudomonas aeruginosa chronic lung infection. To induce chronic lung infection, C57BL/6 mice, either cystic fibrosis transmembrane conductance regulator (CFTR)-deficient (Cftrtm1UNCTgN(FABPCFTR)#Jaw) or wild-type (WT), were intra-tracheally inoculated with multidrug-resistant MDR-RP73 P. aeruginosa embedded in agar beads. Treatments with aerosolized bovine Lf (bLf) or saline were started five minutes after infection and repeated daily for six days. Our results demonstrated that aerosolized bLf was effective in significantly reducing both pulmonary bacterial load and infiltrated leukocytes in infected CF mice. Furthermore, for the first time, we showed that bLf reduced pulmonary iron overload, in both WT and CF mice. In particular, at molecular level, a significant decrease of both the iron exporter ferroportin and iron storage ferritin, as well as luminal iron content was observed. Overall, bLf acts as a potent multi-targeting agent able to break the vicious cycle induced by P. aeruginosa, inflammation and iron dysbalance, thus mitigating the severity of CF-related pathology and sequelae.

Highlights

Cystic fibrosis (CF) is a genetic disorder affecting several organs and reducing expectancy and quality of life
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It has not been established whether iron dyshomeostasis in lung is a cause or a consequence of P. aeruginosa infection in CF, while it is known that decreasing available iron generally ameliorates lung injury associated to inflammation states [42,43]

Summary

Introduction

Cystic fibrosis (CF) is a genetic disorder affecting several organs and reducing expectancy and quality of life. The most relevant damages are observed in the airways that are inherently prone to infection. Airway infections begin in early life [1] and by adulthood, they became chronic. Even though the microbial epidemiology has changed in the last years, it is well established that the chronic airway infections are often sustained by Pseudomonas aeruginosa [2,3]. During CF-induced airway infection progress, P. aeruginosa gradually shifts from the virulent pathogen form of early infection to the host-adapted pathogen form typical of the chronic phase, characterized by biofilm lifestyle and antibiotic resistance [4]. P. aeruginosa chronic infection correlates to increased rate of lung function decline, morbidity, and mortality [5]

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