Attenuation of host defense function of lung phagocytes in young cystic fibrosis patients

Alexis, Neil E.; Muhlebach, Marianne S.; Peden, David B.; Noah, Terry L.

doi:10.1016/j.jcf.2005.11.001

Cited by 65 publications

(34 citation statements)

References 40 publications

(32 reference statements)

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“…The CFTR protein is present in human PMNs, and its dysfunction in CF may attenuate phagocytic competence. 40 Various aggravating mechanisms have been proposed, for instance, reduced phagocytic priming of PMNs recruited to the lungs, 41 defective production of intraphagosomal bactericidal hypochlorous acid (HOCl) 42 or the presence of high levels of human neutrophil peptides in sputum, which counteracts the phagocytic activity of PMNs in a negative feedback manner. 43 Nevertheless, the observed reduced phagocytic activity of CF PMNs is controversial, and while the ROS production by murine CFTR deficient alveolar macrophages is attenuated, 44 the intrinsic production of ROS by PMNs derived from CF patients is normal.…”

Section: Discussionmentioning

confidence: 99%

Anti-Pseudomonas aeruginosaIgY antibodies promote bacterial opsonization and augment the phagocytic activity of polymorphonuclear neutrophils

Thomsen

Christophersen

Jensen

et al. 2016

Human Vaccines & Immunotherapeutics

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Moderation of polymorphonuclear neutrophils (PMNs) as part of a critical defense against invading pathogens may offer a promising therapeutic approach to supplement the antibiotic eradication of Pseudomonas aeruginosa infection in non-chronically infected cystic fibrosis (CF) patients. We have observed that egg yolk antibodies (IgY) harvested from White leghorn chickens that target P. aeruginosa opsonize the pathogen and enhance the PMN-mediated respiratory burst and subsequent bacterial killing in vitro. The effects on PMN phagocytic activity were observed in different Pseudomonas aeruginosa strains, including clinical isolates from non-chronically infected CF patients. Thus, oral prophylaxis with anti-Pseudomonas aeruginosa IgY may boost the innate immunity against Pseudomonas aeruginosa in the CF setting by facilitating a rapid and prompt bacterial clearance by PMNs.

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Section: Discussionmentioning

confidence: 99%

Anti-Pseudomonas aeruginosaIgY antibodies promote bacterial opsonization and augment the phagocytic activity of polymorphonuclear neutrophils

Thomsen

Christophersen

Jensen

et al. 2016

Human Vaccines & Immunotherapeutics

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“…The neutrophilic response is worsened by defects in neutrophil apoptosis and impaired clearance of debris. Defects in mucociliary clearance and macrophage dysfunction lead to accumulation of neutrophils and their products 15,67 . Proteases, primarily NE, are released by neutrophils and overwhelm the normally counteracting anti-proteases (e.g.…”

Section: Host- Response In Cf Lung Diseasementioning

confidence: 99%

Cystic Fibrosis

Zemanick

Hoffman

2016

Pediatric Clinics of North America

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THE EARLIEST DESCRIPTIONS OF LUNG DISEASE IN PEOPLE WITH CYSTIC FIBROSIS (CF) DEMONSTRATED THE INVOLVEMENT OF THREE INTERACTING PATHOPHYSIOLOGICAL ELEMENTS IN CF AIRWAYS: MUCUS OBSTRUCTION, INFLAMMATION, AND INFECTION. OVER THE PAST 7 DECADES, OUR UNDERSTANDING OF CF RESPIRATORY MICROBIOLOGY AND INFLAMMATION HAS EVOLVED WITH THE INTRODUCTION OF NEW TREATMENTS, WITH INCREASED LONGEVITY, AND WITH INCREASINGLY SOPHISTICATED LABORATORY TECHNIQUES. IN THIS CHAPTER, WE WILL REVIEW THE CURRENT STATE OF UNDERSTANDING OF THE ROLES OF INFECTION AND INFLAMMATION AND THEIR ROLES IN DRIVING LUNG DISEASE. WE WILL ALSO DISCUSS HOW THIS CONSTANTLY EVOLVING INFORMATION IS USED TO INFORM CURRENT THERAPEUTIC STRATEGIES, MEASURES AND PREDICTORS OF DISEASE SEVERITY, AND RESEARCH PRIORITIES.

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“…Whether neutrophils in CF are intrinsically abnormal or if dysregulated cell activity is a result of chronic inflammation is still a matter of debate (8). However, potential defects in CF neutrophils have been proposed for several of the main neutrophil functions including cell chemotaxis (9), phagocytosis (10), oxidant production, and protease degranulation (11, 12). …”

mentioning

confidence: 99%

Galectin-9 Signaling through TIM-3 Is Involved in Neutrophil-Mediated Gram-Negative Bacterial Killing: An Effect Abrogated within the Cystic Fibrosis Lung

Vega-Carrascal

Bergin

McElvaney

et al. 2014

The Journal of Immunology

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The T cell Ig and mucin domain–containing molecule (TIM) family of receptors have emerged as potential therapeutic targets to correct abnormal immune function in chronic inflammatory conditions. TIM-3 serves as a functional receptor in structural cells of the airways and via the ligand galectin-9 (Gal-9) can modulate the inflammatory response. The aim of this study was to investigate TIM-3 expression and function in neutrophils, focusing on its potential role in cystic fibrosis (CF) lung disease. Results revealed that TIM-3 mRNA and protein expression values of circulating neutrophils were equal between healthy controls (n = 20) and people with CF (n = 26). TIM-3 was detected on resting neutrophil membranes by FACS analysis, and expression levels significantly increased post IL-8 or TNF-α exposure (p < 0.05). Our data suggest a novel role for TIM-3/Gal-9 signaling involving modulation of cytosolic calcium levels. Via TIM-3 interaction, Gal-9 induced neutrophil degranulation and primed the cell for enhanced NADPH oxidase activity. Killing of Pseudomonas aeruginosa was significantly increased upon bacterial opsonization with Gal-9 (p < 0.05), an effect abrogated by blockade of TIM-3 receptors. This mechanism appeared to be Gram-negative bacteria specific and mediated via Gal-9/ LPS binding. Additionally, we have demonstrated that neutrophil TIM-3/Gal-9 signaling is perturbed in the CF airways due to proteolytic degradation of the receptor. In conclusion, results suggest a novel neutrophil defect potentially contributing to the defective bacterial clearance observed in the CF airways and suggest that manipulation of the TIM-3 signaling pathway may be of therapeutic value in CF, preferably in conjunction with antiprotease treatment.

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Attenuation of host defense function of lung phagocytes in young cystic fibrosis patients

Cited by 65 publications

References 40 publications

Anti-Pseudomonas aeruginosaIgY antibodies promote bacterial opsonization and augment the phagocytic activity of polymorphonuclear neutrophils

Anti-Pseudomonas aeruginosaIgY antibodies promote bacterial opsonization and augment the phagocytic activity of polymorphonuclear neutrophils

Cystic Fibrosis

Galectin-9 Signaling through TIM-3 Is Involved in Neutrophil-Mediated Gram-Negative Bacterial Killing: An Effect Abrogated within the Cystic Fibrosis Lung

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