Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages

Dean

The Journal of Heart and Lung Transplantation

et al. 2011

Short running title: Decreased efferocytosis and MBL in BOSwith BOS) and 14 healthy controls. Abstract & Manuscript 2Results: In plasma, MBL levels were highly variable (0-17.538 g/mL), but increased in infected subjects vs control (p=0.09) or stable groups (p=0.003). There was a similar increase in UC4 in infected patients and a significant correlation between MBL and UC4. There was no correlation between MBL and time post-transplant. In BAL, MBL levels were less variable (0-73.3 ng/mL) and significantly reduced in patients with BOS vs controls and stable groups. 3Lung transplantation is now recognized as an effective treatment option for a variety of end-stage lung diseases and is associated with improvements in life expectancy and quality of life. However the five-year survival is currently only around 60%, the worst of any solid organ transplant, with death beyond the acute phase being largely due to progressive and treatment refractory airway remodeling (obliterative bronchiolitis, OB) manifest clinically as bronchiolitis obliterans syndrome (BOS). BOS is thought to follow persistent alloreactive, infective, and non-specific epithelial injury with dysregulated epithelial repair 1 . Although the predominant histopathologic finding in patients with OB is of fibro-proliferative small airway obliteration, large airways are also affected with the eventual development of bronchiectasis, leading directly to patient morbidity and mortality.The well-ordered process of apoptosis is important for regulation and maintenance of normal tissue homeostasis. During resolution of airway inflammation, apoptotic epithelial cells are removed by phagocytosis by alveolar macrophages (a process termed 'efferocytosis'). The pathological concept of failed efferocytosis has been described in regard to a number of lung diseases including pulmonary fibrosis 2 , cystic fibrosis 3 chronic granulomatous disease 4 smokers and patients chronic obstructive pulmonary disease (COPD) 5-8 .It is considered that the failed efferocytosis results in a net increase in apoptotic material that may lead to secondary necrosis of this material resulting in increased tissue damage and chronic inflammation. This was clearly shown in our studies of COPD where we found evidence of secondary necrosis (increased lactate dehydrogenase in BAL) and that the increased numbers of apoptotic bronchial epithelial cells negatively correlated with efferocytosis 6,9 . In lung transplant recipients we have also described an accumulation of apoptotic material associated with an increase in the cytotoxic mediator granzyme b in the airways 10,11 .Mannose binding lectin (MBL) is a key mediator of both innate immunity and efferocytosis and is thus likely to be important in protecting against lung tissue damage. In other inflammatory chronic lung diseases including COPD, we have shown reduced levels of MBL that correlated with a defect in the 4 ability of alveolar macrophages to phagocytose apoptotic bronchial epithelial cells (efferocytosis) 8 . We further showed that treatm...

Section: Efferocytosis Of Apoptotic Bronchial Epithelial Cells By Alvmentioning

confidence: 99%

Decreased efferocytosis and mannose binding lectin in the airway in bronchiolitis obliterans syndrome

Dean

The Journal of Heart and Lung Transplantation

et al. 2011

“…We found that airway macrophages from cigarette smokers and COPD subjects have a reduced ability to phagocytose bacteria, including NTHi (Hodge et al. 2006; Ween et al. 2016) which can potentially give rise to increased lung infections such as pneumonia.…”

Section: Introductionmentioning

confidence: 99%

Phagocytosis and Inflammation: Exploring the effects of the components of E-cigarette vapor on macrophages

et al. 2017

E‐cigarettes are perceived as harmless; however, evidence of their safety is lacking. New data suggests E‐cigarettes discharge a range of compounds capable of physiological damage to users. We previously established that cigarette smoke caused defective alveolar macrophage phagocytosis. The present study compared the effect E‐cigarette of components; E‐liquid flavors, nicotine, vegetable glycerine, and propylene glycol on phagocytosis, proinflammatory cytokine secretion, and phagocytic recognition molecule expression using differentiated THP‐1 macrophages. Similar to CSE, phagocytosis of NTHi bacteria was significantly decreased by E‐liquid flavoring (11.65–15.75%) versus control (27.01%). Nicotine also decreased phagocytosis (15.26%). E‐liquid, nicotine, and E‐liquid+ nicotine reduced phagocytic recognition molecules; SR‐A1 and TLR‐2. IL‐8 secretion increased with flavor and nicotine, while TNF α, IL‐1β, IL‐6, MIP‐1α, MIP‐1β, and MCP‐1 decreased after exposure to most flavors and nicotine. PG, VG, or PG:VG mix also induced a decrease in MIP‐1α and MIP‐1β. We conclude that E‐cigarettes can cause macrophage phagocytic dysfunction, expression of phagocytic recognition receptors and cytokine secretion pathways. As such, E‐cigarettes should be treated with caution by users, especially those who are nonsmokers.

Am J Respir Cell Mol Biol

“…Of these, CR3, CD14, CD31, CD36, CD44, LRP, vitronectin receptor, and the phosphatidylserine receptor have been previously observed to be expressed on human AMs (24,(49)(50)(51)(52), and MERTK has been noted to be expressed on cultured blood monocytes, the cells from which AMs are derived (5). In the present study, expression by MERTK by AMs was observed by microarray, TaqMan RT-PCR, immunocytochemistry, Western analysis, and flow cytometry.…”

Section: Expression Of Mertk On Amsmentioning

confidence: 99%

Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers

Kazeros

Harvey²,

Carolan³

et al. 2008

Mononuclear phagocytes play an important role in the removal of apoptotic cells by expressing cell surface receptors that recognize and remove apoptotic cells. Based on the knowledge that cigarette smoking is associated with increased lung cell turnover, we hypothesized that alveolar macrophages (AMs) of normal cigarette smokers may exhibit enhanced expression of apoptotic cell removal receptor genes. AMs obtained by bronchoalveolar lavage of normal nonsmokers (n 5 11) and phenotypic normal smokers (n 5 13; 36 6 6 pack-years) were screened for mRNA expression of all known apoptotic cell removal receptors using Affymetrix HG-U133 Plus 2.0 microarray chips with TaqMan RT-PCR confirmation. Of the 14 known apoptotic receptors expressed, only MER tyrosine kinase (MERTK), a transmembrane tyrosine kinase receptor, was significantly up-regulated in smokers. MERTK expression was then assessed in AMs of smokers versus nonsmokers by TaqMan RT-PCR, immunocytochemistry, Western analysis, and flow analysis. Smoker AMs had up-regulation of MERTK mRNA levels (smoker vs. nonsmoker: 3.6-fold by microarray, P , 0.003; 9.5-fold by TaqMan RT-PCR, P , 0.02). Immunocytochemistry demonstrated a qualitative increase in MERTK protein expression on AMs of smokers. Increased protein expression of MERTK on AMs of smokers was confirmed by Western and flow analyses (P , 0.007 and P , 0.0002, respectively). MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AMs, and its expression is up-regulated in AMs of cigarette smokers. This up-regulation of MERTK may reflect an increased demand for removal of apoptotic cells in smokers, an observation with implications for the development of chronic obstructive pulmonary disease, a disorder associated with dysregulated apoptosis of lung parenchymal cells.Keywords: apoptosis; MER tyrosine kinase; alveolar macrophages MER receptor tyrosine kinase (MERTK), a 110-kD transmembrane protein member of the receptor tyrosine kinase family of cell surface receptors, plays a role in the clearance of apoptotic cells (1-4). The MERTK gene is normally expressed on mononuclear phagocytes, dendritic cells, retinal pigment epithelial (RPE) cells, and reproductive tissue (5-8). In mice, deletion of MERTK results in delayed clearance of apoptotic cells and development of autoimmune disease (1, 9, 10). In humans, mutations in MERTK result in retinitis pigmentosa, a disease characterized by a defect in the RPE phagocytosis pathway, where the RPE cells are unable to ingest the shed apoptotic tips of photoreceptor cells (11)(12)(13)(14).In the lung, the clearance of apoptotic cells is the normal function of alveolar macrophages (AMs), the monocyte-derived pulmonary representative of the mononuclear phagocyte system (15-18). Because phagocytosis of apoptotic cells by mononuclear phagocytes invokes an array of receptors on the phagocyte that interacts with bridging molecules and cell-specific ligands on the apoptotic cells, the control of expression of apoptotic receptors on the phagocyte plays ...