Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD

Bewley, Martin A.; Belchamber, Kylie; Chana, Kirandeep K.; Budd, Richard J.; Donaldson, Gavin C.; Wedzicha, Jadwiga A.; Brightling, Christopher E.; Kilty, Iain; Donnelly, Louise E.; Barnes, Peter J.; Singh, Dave; Whyte, Moira K. B.; Dockrell, David H.; Copdmap,

doi:10.1371/journal.pone.0163139

Cited by 52 publications

(53 citation statements)

References 83 publications

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“…There has been a lot of interest in looking if inhibiting downstream pathways of phagocytosis can improve macrophage function in COPD as these pathways can have different effects [70] , [71] . Previous research as part of COPD MAP cohort demonstrated that inhibition of the individual subunits of PI3K or ROCK pathways did not alter phagocytosis or intracellular killing of bacteria by alveolar macrophages [72] . However ROCK inhibition reversed defective efferocytosis highlighting potential differences in pathways regulating bacterial phagocytosis versus efferocytosis [72] .…”

Section: Pharmacological Restoration Of Phagocytosismentioning

confidence: 87%

“…Previous research as part of COPD MAP cohort demonstrated that inhibition of the individual subunits of PI3K or ROCK pathways did not alter phagocytosis or intracellular killing of bacteria by alveolar macrophages [72] . However ROCK inhibition reversed defective efferocytosis highlighting potential differences in pathways regulating bacterial phagocytosis versus efferocytosis [72] . The team of Sandra Hodge recently also described an effect for thymoquinone on improved macrophage efferocytosis and phagocytosis in COPD [73] .…”

Section: Pharmacological Restoration Of Phagocytosismentioning

confidence: 87%

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Macrophage phagocytosis cracking the defect code in COPD

2017

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In the normal non-diseased lung, various macrophage populations maintain homeostasis and sterility by ingesting and clearing inhaled particulates, pathogens and apoptotic cells from the local environment. This process of phagocytosis leads to the degradation of the internalized material, coordinated induction of gene expression, antigen presentation and cytokine production, implicating phagocytosis as a central regulator of innate immunity. Phagocytosis is extremely efficient and any perturbation of this function is deleterious. In inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD), despite their increased numbers, macrophages demonstrate significantly reduced phagocytic capacity of bacteria and apoptotic cells. This defect could play a role in dysbiosis of the lung microbiome contributing to disease pathophysiology. In this review, we will discuss lung macrophages, describe phagocytosis and its related downstream processes and the reported phagocytosis defects in COPD. Finally, we will briefly examine current strategies that focus on restoring the phagocytic capabilities of lung macrophages that may have utility in COPD.

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Section: Pharmacological Restoration Of Phagocytosismentioning

confidence: 87%

Section: Pharmacological Restoration Of Phagocytosismentioning

confidence: 87%

Macrophage phagocytosis cracking the defect code in COPD

2017

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“…Although bronchodilators have been the primary treatment option for airflow limitations typical in COPD [ 24 ], they predominantly address the symptoms and not the underlying immune pathogenesis of the disease. Novel treatments target specific molecular pathways thought to be pivotal in the pathogenesis of the disease, such as small molecule inhibitors with anti-inflammatory activity against p38 mitogen-activated protein kinases, phosphatidyl-inositol-3 kinase, and Rho kinase [ 53 ].…”

Section: Therapeutic Targeting Of Macrophages In Copdmentioning

confidence: 99%

Lung Macrophage Phenotypes and Functional Responses: Role in the Pathogenesis of COPD

Yamasaki

Eeden

2018

IJMS

106

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Lung macrophages (LMs) are essential immune effector cells that are pivotal in both innate and adaptive immune responses to inhaled foreign matter. They either reside within the airways and lung tissues (from early life) or are derived from blood monocytes. Similar to macrophages in other organs and tissues, LMs have natural plasticity and can change phenotype and function depending largely on the microenvironment they reside in. Phenotype changes in lung tissue macrophages have been implicated in chronic inflammatory responses and disease progression of various chronic lung diseases, including Chronic Obstructive Pulmonary Disease (COPD). LMs have a wide variety of functional properties that include phagocytosis (inorganic particulate matter and organic particles, such as viruses/bacteria/fungi), the processing of phagocytosed material, and the production of signaling mediators. Functioning as janitors of the airways, they also play a key role in removing dead and dying cells, as well as cell debris (efferocytic functions). We herein review changes in LM phenotypes during chronic lung disease, focusing on COPD, as well as changes in their functional properties as a result of such shifts. Targeting molecular pathways involved in LM phenotypic shifts could potentially allow for future targeted therapeutic interventions in several diseases, such as COPD.

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“…In another report, the expression of the macrophage scavenger receptor 1 in monocyte-derived macrophages was associated with genetic variants which also controlled in vitro cell adhesion and survival in culture [ 227 ]. Finally, conflicting data have been published concerning the involvement of p38, ERK1/2, PI3K, ROCK, and p65 kinases and cytoskeletal changes in AM phagocytosis in COPD [ 147 , 228 ].…”

Section: Ams In Copdmentioning

confidence: 99%

Dysregulated Functions of Lung Macrophage Populations in COPD

Kapellos

Baßler

Aschenbrenner

et al. 2018

Journal of Immunology Research

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Chronic obstructive pulmonary disease (COPD) is a diverse respiratory disease characterised by bronchiolitis, small airway obstruction, and emphysema. Innate immune cells play a pivotal role in the disease's progression, and in particular, lung macrophages exploit their prevalence and strategic localisation to orchestrate immune responses. To date, alveolar and interstitial resident macrophages as well as blood monocytes have been described in the lungs of patients with COPD contributing to disease pathology by changes in their functional repertoire. In this review, we summarise recent evidence from human studies and work with animal models of COPD with regard to altered functions of each of these myeloid cell populations. We primarily focus on the dysregulated capacity of alveolar macrophages to secrete proinflammatory mediators and proteases, induce oxidative stress, engulf microbes and apoptotic cells, and express surface and intracellular markers in patients with COPD. In addition, we discuss the differences in the responses between alveolar macrophages and interstitial macrophages/monocytes in the disease and propose how the field should advance to better understand the implications of lung macrophage functions in COPD.

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Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD

Cited by 52 publications

References 83 publications

Macrophage phagocytosis cracking the defect code in COPD

Macrophage phagocytosis cracking the defect code in COPD

Lung Macrophage Phenotypes and Functional Responses: Role in the Pathogenesis of COPD

Dysregulated Functions of Lung Macrophage Populations in COPD

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