Cystic Fibrosis Lung Immunity: The Role of the Macrophage

Bruscia, Emanuela M.; Bonfield, Tracey L.

doi:10.1159/000446825

Cited by 137 publications

(177 citation statements)

References 103 publications

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“…This study demonstrates that macrophage function in CF is abnormal and plays a central role in the inflammatory response. Recent studies also suggest that CF macrophages have difficulty switching classes, demonstrate a hyper‐inflammatory phenotype, have difficulty resolving inflammation, inadequately clear bacteria through phagocytosis, and have impaired efferocytosis . It is not clear if these impairments are due to dysfunctional CFTR, factors in the CF lung environment, or a combination of both.…”

Section: Cellular Contributions To the Cf Airway Inflammatory Responsementioning

confidence: 99%

Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

198

221

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Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti-inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF.

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Section: Cellular Contributions To the Cf Airway Inflammatory Responsementioning

confidence: 99%

Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

198

221

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“…Overall, the complex multifunctionality of AM, interacting as antigen-presenting cells with T cells, clearing apoptotic and necrotic cells through efferocytosis, and killing pathogens and releasing both pro- and anti-inflammatory factors, makes a “good-versus-bad-cop” assignment for these cells for the majority of lung diseases challenging. In vivo macrophage depletion studies revealed different outcomes depending on the lung disease model and the time point of intervention used [64, 65, 79, 80]. Idiopathic pulmonary fibrosis (IPF) is a prototypic example of a complex chronic lung disease in which the role of pulmonary macrophages remains controversial.…”

Section: Macrophagesmentioning

confidence: 99%

Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine

et al. 2018

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The respiratory tract is faced daily with 10,000 L of inhaled air. While the majority of air contains harmless environmental components, the pulmonary immune system also has to cope with harmful microbial or sterile threats and react rapidly to protect the host at this intimate barrier zone. The airways are endowed with a broad armamentarium of cellular and humoral host defense mechanisms, most of which belong to the innate arm of the immune system. The complex interplay between resident and infiltrating immune cells and secreted innate immune proteins shapes the outcome of host-pathogen, host-allergen, and host-particle interactions within the mucosal airway compartment. Here, we summarize and discuss recent findings on pulmonary innate immunity and highlight key pathways relevant for biomarker and therapeutic targeting strategies for acute and chronic diseases of the respiratory tract.

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“…Studies showed that neutrophils lacking SYK reduce the host defense against bacterial infection [96]. The macrophages and neutrophils from CF patients, in particular, are already quite dysfunctional and have many abnormal signaling pathways; this impairs phagocytes, intracellular killing, and cellular migration [97]. Thus, there is a very fine balance to be maintained between damping the proinflammatory response and preserving the host defense against infected pathogens.…”

Section: Potential Complications Associated With Syk Inhibitionmentioning

confidence: 99%

Spleen Tyrosine Kinase as a Target Therapy for <b><i>Pseudomonas aeruginosa</i></b> Infection

Alhazmi

2018

J Innate Immun

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Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase which associates directly with extracellular receptors, and is critically involved in signal transduction pathways in a variety of cell types for the regulation of cellular responses. SYK is expressed ubiquitously in immune and nonimmune cells, and has a much wider biological role than previously recognized. Several studies have highlighted SYK as a key player in the pathogenesis of a multitude of diseases. Pseudomonas aeruginosa is an opportunistic gram-negative pathogen, which is responsible for systemic infections in immunocompromised individuals, accounting for a major cause of severe chronic lung infection in cystic fibrosis patients and subsequently resulting in a progressive deterioration of lung function. Inhibition of SYK activity has been explored as a therapeutic option in several allergic disorders, autoimmune diseases, and hematological malignancies. This review focuses on SYK as a therapeutic target, and describes the possibility of how current knowledge could be translated for therapeutic purposes to regulate the immune response to the opportunistic pathogen P. aeruginosa.

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Cystic Fibrosis Lung Immunity: The Role of the Macrophage

Cited by 137 publications

References 103 publications

Inflammation in cystic fibrosis: An update

Inflammation in cystic fibrosis: An update

Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine

Spleen Tyrosine Kinase as a Target Therapy for <b><i>Pseudomonas aeruginosa</i></b> Infection

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