scholarly journals Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span

2017 ◽  
Vol 214 (8) ◽  
pp. 2387-2404 ◽  
Author(s):  
Alexander V. Misharin ◽  
Luisa Morales-Nebreda ◽  
Paul A. Reyfman ◽  
Carla M. Cuda ◽  
James M. Walter ◽  
...  
Keyword(s):  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Lung Fibrosis ◽  
Relative Importance ◽  
Macrophage Differentiation ◽  
Macrophage Depletion ◽  
Human Alveolar Macrophages ◽  
Genetic Deletion ◽  
One Year ◽  
Normal Lungs

Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

scholarly journals Tissue factor and factor VII messenger RNAs in human alveolar macrophages: effects of breathing ozone

Blood ◽  
1990 ◽  
Vol 75 (1) ◽  
pp. 122-127 ◽  
Author(s):  
MP McGee ◽  
R Devlin ◽  
G Saluta ◽  
H Koren
Keyword(s):  
Alveolar Macrophage ◽  
Tissue Factor ◽  
Alveolar Macrophages ◽  
Factor Vii ◽  
Fibrinopeptide A ◽  
Factor Activity ◽  
Tissue Factor Activity ◽  
Mrna Concentration ◽  
Human Alveolar Macrophages

Abstract This study was performed to determine if genes for tissue factor and factor VII proteins are expressed and regulated in vivo in lung macrophages during inflammation. Human alveolar macrophages and alveolar fluids were obtained 18 hours after healthy male adults were exposed, for 2 hours during intermittent exercise, to either air or air with 0.4 ppm ozone, added as a model toxic respiratory agent. Messenger RNA (mRNA) for both tissue factor and factor VII were demonstrated in macrophages isolated after subjects were exposed to unpolluted control air. With the same subjects examined after breathing ozone, the following changes were observed: tissue factor mRNA concentration in macrophages increased 2.6 +/- 0.47-fold. Factor VII mRNA concentration was reduced 0.64 +/- 0.24-fold. Total numbers of macrophages recovered did not change significantly. Ratios of nuclear:cytoplasmic areas of cytocentrifuged macrophages were augmented by 24.8% +/- 3%, giving morphometric evidence that immature cell forms increased in the population. In the lavage, tissue factor activity was increased 2.1 +/- 0.3-fold, while amounts of lipid phosphorous, which estimate total membrane lipids, and estimated volumes of alveolar fluid were not significantly changed. Factor VII activity and fibrinopeptide A levels in lavage were increased approximately twofold. These results using rapidly isolated, noncultured cells indicate that tissue factor and factor VII mRNA are synthesized in the alveolar macrophage population in vivo. In addition, evidence was found that as a result of breathing ozone, a shift in alveolar macrophage maturity occurred in association with tissue factor mRNA, tissue factor activity, and factor VII activity increases, and with formation of fibrinopeptide A in alveolar fluids.

scholarly journals Macrophages mediate lung inflammation in a mouse model of ischemic acute kidney injury

2012 ◽  
Vol 302 (4) ◽  
pp. F421-F432 ◽  
Author(s):  
Christopher Altmann ◽  
Ana Andres-Hernando ◽  
Rachel H. McMahan ◽  
Nilesh Ahuja ◽  
Zhibin He ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Lung Inflammation ◽  
Kidney Injury ◽  
Capillary Leak ◽  
Blood Monocytes ◽  
Wild Type ◽  
Macrophage Depletion ◽  
Reduced Renal Function

Serum IL-6 is increased in acute kidney injury (AKI) and inhibition of IL-6 reduces AKI-mediated lung inflammation. We hypothesized that circulating monocytes produce IL-6 and that alveolar macrophages mediate lung inflammation after AKI via chemokine (CXCL1) production. To investigate systemic and alveolar macrophages in lung injury after AKI, sham operation or 22 min of renal pedicle clamping (AKI) was performed in three experimental settings: 1) systemic macrophage depletion via diphtheria toxin (DT) injection to CD11b-DTR transgenic mice, 2) DT injection to wild-type mice, and 3) alveolar macrophage depletion via intratracheal (IT) liposome-encapsulated clodronate (LEC) administration to wild-type mice. In mice with AKI and systemic macrophage depletion (CD11b-DTR transgenic administered DT) vs. vehicle-treated AKI, blood monocytes and lung interstitial macrophages were reduced, renal function was similar, serum IL-6 was increased, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In wild-type mice with AKI administered DT vs. vehicle, serum IL-6 was increased. In mice with AKI and alveolar macrophage depletion (IT-LEC) vs. AKI with normal alveolar macrophage content, blood monocytes and lung interstitial macrophages were similar, alveolar macrophages were reduced, renal function was similar, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In conclusion, administration of DT in AKI is proinflammatory, limiting the use of the DTR-transgenic model to study systemic effects of AKI. Mice with AKI and either systemic mononuclear phagocyte depletion or alveolar macrophage depletion had reduced lung inflammation and lung CXCL1, but increased lung capillary leak; thus, mononuclear phagocytes mediate lung inflammation, but they protect against lung capillary leak after ischemic AKI. Since macrophage activation and chemokine production are key events in the development of acute lung injury (ALI), these data provide further evidence that AKI may cause ALI.

scholarly journals Human alveolar macrophages express Ia-like antigens

Blood ◽  
1981 ◽  
Vol 58 (5) ◽  
pp. 1040-1042 ◽  
Author(s):  
W Hocking ◽  
R Billing ◽  
K Foon ◽  
D Golde
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibody ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Cellular Interactions ◽  
Human Alveolar Macrophages

Abstract Monoclonal antibody to la-like antigens was used to demonstrate the presence of these antigens on human alveolar macrophages. Immunoprecipitation demonstrated the 27,000 and 34,000 molecular weight peaks that correspond to the la-like antigen subunits. Immunofluorescence confirmed the presence of la-like antigens on alveolar macrophages but not on other bronchoalveolar cells. The presence of alveolar macrophage la-like antigens may be important in cellular interactions.

Lipopolysaccharide stimulates de novo synthesis of PGH synthase in human alveolar macrophages

1992 ◽  
Vol 262 (1) ◽  
pp. L78-L85
Author(s):  
R. J. Pueringer ◽  
G. W. Hunninghake
Keyword(s):  
Arachidonic Acid ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Actinomycin D ◽  
De Novo ◽  
Pge2 Production ◽  
De Novo Synthesis ◽  
New Synthesis ◽  
Human Alveolar Macrophages ◽  
Pg E2

Lipopolysaccharide (LPS)-stimulated human alveolar macrophages (HAMs) produce large amounts of prostaglandin (PG) E2 for up to 72 h. The mechanism of this enhanced and prolonged metabolism of arachidonic acid to PGE2 is unknown. To determine whether LPS-stimulated HAM PGE2 production is due in part to an increase in the new synthesis of the first committed enzyme, PGH synthase, we measured PGE2 formation, PGH synthase activity, and newly synthesized PGH synthase at 2, 6, and 24 h after LPS-stimulation. PGE2, measured by radioimmunoassay, was not increased at 2 h but was increased at 6 and 24 h after stimulating HAMs with LPS. Unstimulated HAMs did not produce PGE2. Likewise, the activity of PGH synthase extracted from HAMs was not increased at 2 h but was increased at 6 and 24 h after LPS stimulation. Cycloheximide and actinomycin D markedly inhibited PGE2 production in LPS-stimulated HAMs. Newly synthesized PGH synthase measured by immunoprecipitating 35S-labeled PGH synthase was not detected at 2 h but was detected at 6 and 24 h after stimulation. The parallel increases in PGE2 production, PGH synthase activity, and newly synthesized PGH synthase coupled with the dependence of PGE2 on the ability of the alveolar macrophage to synthesize protein suggest that LPS-stimulated HAM PGE2 production is in part regulated by the de novo synthesis of PGH synthase.

scholarly journals Human alveolar macrophages express Ia-like antigens

Blood ◽  
1981 ◽  
Vol 58 (5) ◽  
pp. 1040-1042
Author(s):  
W Hocking ◽  
R Billing ◽  
K Foon ◽  
D Golde
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibody ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Cellular Interactions ◽  
Human Alveolar Macrophages

Monoclonal antibody to la-like antigens was used to demonstrate the presence of these antigens on human alveolar macrophages. Immunoprecipitation demonstrated the 27,000 and 34,000 molecular weight peaks that correspond to the la-like antigen subunits. Immunofluorescence confirmed the presence of la-like antigens on alveolar macrophages but not on other bronchoalveolar cells. The presence of alveolar macrophage la-like antigens may be important in cellular interactions.

scholarly journals TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during Respiratory Syncytial Virus infection

2020 ◽  
pp. 2003764
Author(s):  
Leonardo Duarte Santos ◽  
Krist Helen Antunes ◽  
Stéfanie Primon Muraro ◽  
Gabriela Fabiano de Souza ◽  
Amanda Gonzalez da Silva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Loss ◽  
Respiratory Syncytial Virus ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Dependent Manner ◽  
Macrophage Depletion ◽  
Primary Mouse ◽  
Rsv Infection ◽  
Syncytial Virus

Respiratory Syncytial Virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. Here we report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3-, and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, Ripk3-/- mice were protected from RSV-induced weight loss and presented reduced viral loads in the lungs.Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of Ripk3 and Mlkl gene expression induced by RSV infection in the lung tissue.Autocrine TNF mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, Tnfr1-/- mice had a marked decrease in Ripk3 and Mlkl gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis.We propose that targeting TNF and/or the necroptotic machinery may be valuable as therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children.

scholarly journals CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages

2022 ◽  
Vol 219 (2) ◽  
Author(s):  
Elza Evren ◽  
Emma Ringqvist ◽  
Jean-Marc Doisne ◽  
Anna Thaller ◽  
Natalie Sleiers ◽  
...  
Keyword(s):  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Fetal Liver ◽  
Fetal Lung ◽  
Gene Signature ◽  
Human Macrophage ◽  
Humanized Mouse Model ◽  
Human Alveolar Macrophages ◽  
Macrophage Precursors

Despite their importance in lung health and disease, it remains unknown how human alveolar macrophages develop early in life. Here we define the ontogeny of human alveolar macrophages from embryonic progenitors in vivo, using a humanized mouse model expressing human cytokines (MISTRG mice). We identified alveolar macrophage progenitors in human fetal liver that expressed the GM-CSF receptor CD116 and the transcription factor MYB. Transplantation experiments in MISTRG mice established a precursor–product relationship between CD34−CD116+ fetal liver cells and human alveolar macrophages in vivo. Moreover, we discovered circulating CD116+CD64−CD115+ macrophage precursors that migrated from the liver to the lung. Similar precursors were present in human fetal lung and expressed the chemokine receptor CX3CR1. Fetal CD116+CD64− macrophage precursors had a proliferative gene signature, outcompeted adult precursors in occupying the perinatal alveolar niche, and developed into functional alveolar macrophages. The discovery of the fetal alveolar macrophage progenitor advances our understanding of human macrophage origin and ontogeny.

scholarly journals Tissue factor and factor VII messenger RNAs in human alveolar macrophages: effects of breathing ozone

Blood ◽  
1990 ◽  
Vol 75 (1) ◽  
pp. 122-127
Author(s):  
MP McGee ◽  
R Devlin ◽  
G Saluta ◽  
H Koren
Keyword(s):  
Alveolar Macrophage ◽  
Tissue Factor ◽  
Alveolar Macrophages ◽  
Factor Vii ◽  
Fibrinopeptide A ◽  
Factor Activity ◽  
Tissue Factor Activity ◽  
Mrna Concentration ◽  
Human Alveolar Macrophages

This study was performed to determine if genes for tissue factor and factor VII proteins are expressed and regulated in vivo in lung macrophages during inflammation. Human alveolar macrophages and alveolar fluids were obtained 18 hours after healthy male adults were exposed, for 2 hours during intermittent exercise, to either air or air with 0.4 ppm ozone, added as a model toxic respiratory agent. Messenger RNA (mRNA) for both tissue factor and factor VII were demonstrated in macrophages isolated after subjects were exposed to unpolluted control air. With the same subjects examined after breathing ozone, the following changes were observed: tissue factor mRNA concentration in macrophages increased 2.6 +/- 0.47-fold. Factor VII mRNA concentration was reduced 0.64 +/- 0.24-fold. Total numbers of macrophages recovered did not change significantly. Ratios of nuclear:cytoplasmic areas of cytocentrifuged macrophages were augmented by 24.8% +/- 3%, giving morphometric evidence that immature cell forms increased in the population. In the lavage, tissue factor activity was increased 2.1 +/- 0.3-fold, while amounts of lipid phosphorous, which estimate total membrane lipids, and estimated volumes of alveolar fluid were not significantly changed. Factor VII activity and fibrinopeptide A levels in lavage were increased approximately twofold. These results using rapidly isolated, noncultured cells indicate that tissue factor and factor VII mRNA are synthesized in the alveolar macrophage population in vivo. In addition, evidence was found that as a result of breathing ozone, a shift in alveolar macrophage maturity occurred in association with tissue factor mRNA, tissue factor activity, and factor VII activity increases, and with formation of fibrinopeptide A in alveolar fluids.

Hypoxia triggers an antimicrobial pathway in human alveolar macrophages

Pneumologie ◽  
2010 ◽  
Vol 64 (S 03) ◽  
Author(s):  
S Stenger ◽  
D Nickel ◽  
M Wagner ◽  
JH Ficker ◽  
C Schumann
Keyword(s):  
Alveolar Macrophages ◽  
Human Alveolar Macrophages

Preliminary investigations into the life cycle of Ventruia inaequalis (Cooke) WINT. in South Australia.

1953 ◽  
Vol 4 (4) ◽  
pp. 415 ◽  
Author(s):  
MW Jeffery
Keyword(s):  
Life Cycle ◽  
Primary Infection ◽  
South Australia ◽  
Late Summer ◽  
Relative Importance ◽  
New Information ◽  
One Year

Investigation into the possible sources of primary infection by the fungus Ventruia inaequalis (Cooke) Wint. in spring has been carried out. The results present new information on the life cycle of the pathogen under South Australian conditions. Sources of primary infection, such 'as lesions on one-year-old wood or overwintering superficial conidia on the trees, do not appear important. Bud-scale infection of dormant buds has been shown, and its relative importance is discussed. Ascospores are the most important source of primary infection. Their period of discharge extends to a later date than previously reported for South Australia and is considered in relation to leader shoot and late summer spot infection.

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