scholarly journals Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Marcia A Munoz ◽  
Emma K Fletcher ◽  
Oliver P Skinner ◽  
Julie Jurczyluk ◽  
Esther Kristianto ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Mevalonate Pathway ◽  
Respiratory Infections ◽  
Peritoneal Macrophages ◽  
Protein Prenylation ◽  
Risk Of Death ◽  
Cytokines And Chemokines ◽  
Bronchoalveolar Fluid ◽  
Mechanistic Basis

Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.

scholarly journals Bisphosphonate drugs have actions outside the skeleton and inhibit the mevalonate pathway in alveolar macrophages

2021 ◽  
Author(s):  
Michael J Rogers ◽  
Marcia A Munoz ◽  
Emma K Fletcher ◽  
Oliver P Skinner ◽  
Julie Jurczyluk ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Mevalonate Pathway ◽  
Respiratory Infections ◽  
Peritoneal Macrophages ◽  
Protein Prenylation ◽  
Risk Of Death ◽  
Cytokines And Chemokines ◽  
Bronchoalveolar Fluid ◽  
Mechanistic Basis

Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently-labelled bisphosphonate is internalised by alveolar macrophages and peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.

scholarly journals Mycoplasma pneumoniae-Derived Lipopeptides Induce Acute Inflammatory Responses in the Lungs of Mice

2007 ◽  
Vol 76 (1) ◽  
pp. 270-277 ◽  
Author(s):  
Takashi Shimizu ◽  
Yutaka Kida ◽  
Koichi Kuwano
Keyword(s):  
Mycoplasma Pneumoniae ◽  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Peritoneal Macrophages ◽  
Necrosis Factor Alpha ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
Mouse Peritoneal Macrophages

ABSTRACT The pathogenesis of Mycoplasma pneumoniae infection is considered to be in part attributable to excessive immune responses. In this study, we investigated whether synthetic lipopeptides of subunit b of F0F1-type ATPase (F0F1-ATPase), NF-κB-activating lipoprotein 1 (N-ALP1), and N-ALP2 (named FAM20, sN-ALP1, and sN-ALP2, respectively) derived from M. pneumoniae induce cytokine and chemokine production and leukocyte infiltration in vivo. Intranasal administration of FAM20 and sN-ALP2 induced infiltration of leukocyte cells and production of chemokines and cytokines in bronchoalveolar lavage fluid, but sN-ALP1 failed to do so. The activity of FAM20 was notably higher than that of sN-ALP2. FAM20 and sN-ALP2 induced tumor necrosis factor alpha (TNF-α) through Toll-like receptor 2 in mouse peritoneal macrophages. Moreover, in the range of low concentrations of lipopeptides, FAM20 showed relatively high activity of inducing TNF-α in mouse peritoneal macrophages compared to synthetic lipopeptides such as MALP-2 and FSL-1, derived from Mycoplasma fermentans and Mycoplasma salivarium, respectively. These findings indicate that the F0F1-ATPase might be a key molecule in inducing cytokines and chemokines contributing to inflammatory responses during M. pneumoniae infection in vivo.

scholarly journals Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

2021 ◽  
Vol 11 ◽  
Author(s):  
Isabella Giacomini ◽  
Federico Gianfanti ◽  
Maria Andrea Desbats ◽  
Genny Orso ◽  
Massimiliano Berretta ◽  
...  
Keyword(s):  
De Novo ◽  
Mevalonate Pathway ◽  
Cholesterol Metabolism ◽  
Tumor Development ◽  
Cholesterol Homeostasis ◽  
Metabolic Reprogramming ◽  
Protein Prenylation ◽  
Pharmacological Targets

Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.

scholarly journals Phagocytosis of microparticles by alveolar macrophages during acute lung injury requires MerTK

2018 ◽  
Vol 314 (1) ◽  
pp. L69-L82 ◽  
Author(s):  
Michael P. Mohning ◽  
Stacey M. Thomas ◽  
Lea Barthel ◽  
Kara J. Mould ◽  
Alexandria L. McCubbrey ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Primary Objective ◽  
Cytochalasin D ◽  
Inflammatory Signaling ◽  
Macrophage Population ◽  
Bronchoalveolar Fluid

Microparticles are a newly recognized class of mediators in the pathophysiology of lung inflammation and injury, but little is known about the factors that regulate their accumulation and clearance. The primary objective of our study was to determine whether alveolar macrophages engulf microparticles and to elucidate the mechanisms by which this occurs. Alveolar microparticles were quantified in bronchoalveolar fluid of mice with lung injury induced by LPS and hydrochloric acid. Microparticle numbers were greatest at the peak of inflammation and declined as inflammation resolved. Isolated, fluorescently labeled particles were placed in culture with macrophages to evaluate ingestion in the presence of endocytosis inhibitors. Ingestion was blocked with cytochalasin D and wortmannin, consistent with a phagocytic process. In separate experiments, mice were treated intratracheally with labeled microparticles, and their uptake was assessed though microscopy and flow cytometry. Resident alveolar macrophages, not recruited macrophages, were the primary cell-ingesting microparticles in the alveolus during lung injury. In vitro, microparticles promoted inflammatory signaling in LPS primed epithelial cells, signifying the importance of microparticle clearance in resolving lung injury. Microparticles were found to have phosphatidylserine exposed on their surfaces. Accordingly, we measured expression of phosphatidylserine receptors on macrophages and found high expression of MerTK and Axl in the resident macrophage population. Endocytosis of microparticles was markedly reduced in MerTK-deficient macrophages in vitro and in vivo. In conclusion, microparticles are released during acute lung injury and peak in number at the height of inflammation. Resident alveolar macrophages efficiently clear these microparticles through MerTK-mediated phagocytosis.

scholarly journals In vivo requirement of protein prenylation for maintenance of retinal cytoarchitecture and photoreceptor structure.

1995 ◽  
Vol 130 (2) ◽  
pp. 431-439 ◽  
Author(s):  
S J Pittler ◽  
S J Fliesler ◽  
P L Fisher ◽  
P K Keller ◽  
L M Rapp
Keyword(s):  
Intravitreal Injection ◽  
Cultured Cells ◽  
Mevalonate Pathway ◽  
Specific Inhibitor ◽  
Metabolic Inhibitors ◽  
Squalene Epoxidase ◽  
Protein Prenylation ◽  
Photoreceptor Layer ◽  
Isoprenoid Metabolism

Recent studies have demonstrated that inhibition of mevalonate synthesis in cultured cells leads to altered cell morphology due to inhibition of protein prenylation. To investigate the effects in vivo of mevalonate deprivation in nondividing, terminally differentiated neural cells, we have analyzed the effects on retinal tissue of intravitreal injection of lovastatin, a potent inhibitor of the mevalonate-producing enzyme, HMG-CoA reductase. A single injection of lovastatin (0.25 mumol) produced profound dysplastic-like changes in adult rat retinas primarily involving the photoreceptor layer. Within 2 d after injection, photoreceptor nuclei migrated in a circular pattern resulting in the formation of rosette-like structures by 4 d. Also during this period, photoreceptor inner and outer segment degeneration was evident. By 21 d, intact photoreceptor nuclei with remnants of inner and outer segments were dispersed throughout all retinal layers. To investigate the biochemical specificity of the lovastatin-induced alterations, and to distinguish the relative importance of the various branches of the mevalonate pathway, the incorporation of [3H]acetate into retinal lipids was examined in the presence and absence of metabolic inhibitors. HPLC analysis of lovastatin-treated retinas revealed a dramatic reduction in the incorporation of intravitreally injected [3H]acetate into nonsaponifiable lipids, compared with controls. In contrast, intravitreal injection of NB-598, a specific inhibitor of squalene epoxidase, eliminated the conversion of newly synthesized squalene to sterols without obvious pathology. Hence, involvement to the sterol branch of isoprenoid metabolism in the lovastatin-induced morphologic disruption was obviated. Intravitreal injection of 0.27 mumol of N-acetyl-S-trans,trans-farnesyl-L-cysteine (AFC), an inhibitor of carboxyl methyltransferase activity and prenylated protein function, produced morphologic changes that were virtually indistinguishable from those induced with lovastatin. These results implicate a defect in protein prenylation in the lovastatin-induced retinal degeneration, and suggest the presence of a dynamic pathway in the retina that requires isoprenylated proteins to maintain retinal cytoarchitecture.

scholarly journals Chronic cigarette smoking enhances spontaneous release of tumour necrosis factor-α from alveolar macrophages of rats

1993 ◽  
Vol 2 (6) ◽  
pp. 423-428 ◽  
Author(s):  
G. P. Pessina ◽  
L. Paulesu ◽  
F. Corradeschi ◽  
E. Luzzi ◽  
M. Tanzini ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Alveolar Macrophages ◽  
Superoxide Anion ◽  
Biological Effects ◽  
Peritoneal Macrophages ◽  
Control Group ◽  
Polymorphonuclear Cells ◽  
Tnf Α ◽  
Activated State ◽  
Bronchoalveolar Fluid

Some biological effects of chronic cigarette smoking (two cigarettes for 2 h, daily for 4 months) in rats were evaluated. During the smoking period, body weight of smoker rats was always significantly lower than that of control rats. Immediately after the last smoking session the carboxyhaemoglobin concentration in the blood was about 8.5% and the polymorphonuclear cells in the bronchoalveolar fluid increased significantly. At the same time, enzymatic analyses on the supernatants of bronchoalveolar fluid revealed a significant increase of β-glucuronidase in the smoker group. Alveolar macrophages, collected 0, 8 and 24 h after the last smoking session, significantly increased the generation of superoxide anion and, after incubation for 24 h at 37°C in a humidified atmosphere, released significantly high amounts of TNF-α. When challenged with lipopolysaccharide, alveolar macrophages of smoker rats released much more TNF-α but, in such a case, TNF-α release was about one half of that observed in the control group. Peritoneal macrophages of both control and smoker rats were unable either to generate high levels of superoxide anion or to release significant amounts of TNF-α. The results clearly demonstrated the activated state of alveolar macrophages and the resting state of peritoneal macrophages.

scholarly journals Combined HMG-COA reductase and prenylation inhibition in treatment of CCM

2017 ◽  
Vol 114 (21) ◽  
pp. 5503-5508 ◽  
Author(s):  
Sayoko Nishimura ◽  
Ketu Mishra-Gorur ◽  
JinSeok Park ◽  
Yulia V. Surovtseva ◽  
Said M. Sebti ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
Neurological Deficits ◽  
Protein Prenylation ◽  
Hmg Coa Reductase ◽  
Cavernous Malformations ◽  
The Central Nervous System ◽  
Primary Astrocytes ◽  
Approved Drugs ◽  
Coa Reductase

Cerebral cavernous malformations (CCMs) are common vascular anomalies that develop in the central nervous system and, more rarely, the retina. The lesions can cause headache, seizures, focal neurological deficits, and hemorrhagic stroke. Symptomatic lesions are treated according to their presentation; however, targeted pharmacological therapies that improve the outcome of CCM disease are currently lacking. We performed a high-throughput screen to identify Food and Drug Administration-approved drugs or other bioactive compounds that could effectively suppress hyperproliferation of mouse brain primary astrocytes deficient for CCM3. We demonstrate that fluvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase and the N-bisphosphonate zoledronic acid monohydrate, an inhibitor of protein prenylation, act synergistically to reverse outcomes of CCM3 loss in cultured mouse primary astrocytes and in Drosophila glial cells in vivo. Further, the two drugs effectively attenuate neural and vascular deficits in chronic and acute mouse models of CCM3 loss in vivo, significantly reducing lesion burden and extending longevity. Sustained inhibition of the mevalonate pathway represents a potential pharmacological treatment option and suggests advantages of combination therapy for CCM disease.

scholarly journals THE FATE OF BACTERIA WITHIN PHAGOCYTIC CELLS

1964 ◽  
Vol 120 (5) ◽  
pp. 869-883 ◽  
Author(s):  
Zanvil A. Cohn
Keyword(s):  
Alveolar Macrophages ◽  
Peritoneal Macrophages ◽  
Immune Serum ◽  
Soluble Form ◽  
Phagocytic Cells ◽  
E Coli ◽  
Heat Stable ◽  
Immune Globulins

The fate of a heat-stable Escherichia coli agglutinogen within three types of rabbit phagocytic cells was examined. A system is described whereby quantitative ingestion of viable E. coli by suspensions of PMN leucocytes, BCG-induced alveolar macrophages, and oil-induced peritoneal macrophages took place in vitro. After various periods of intracellular residence aliquots were injected intraperitoneally into NCS mice and the resulting agglutinins assayed. The loss of immunogenicity within phagocytes was estimated by comparison with a dose-response titration prepared with bacteria alone. Under these conditions no increase in immunogenic mass occurred in vivo or in vitro when viable organisms were employed. PMN leucocytes and alveolar macrophages destroyed the majority of the immunogen within 2 hours of intracellular residence. In contrast, the immunogenicity of E. coli was maintained within peritoneal macrophages for periods up to 5 hours. The use of heat-killed bacilli or specific immune serum did not significantly influence the intracellular fate of the immunogen. Residual immunogenicity was associated with a particle having the same centrifugal properties as the intact organism and essentially none was released in a soluble form. Intracellular residence within phagocytic cells did not influence the resulting temporal sequence of antibody formation nor the proportions of mercaptoethanol-sensitive and resistant immune globulins.

Activated macrophages in highly irradiated cercariae-induced immunity toSchistosoma japonicumin rats

Parasitology ◽  
1991 ◽  
Vol 102 (1) ◽  
pp. 65-72
Author(s):  
C. Xu ◽  
S. Xu
Keyword(s):  
Alveolar Macrophages ◽  
Sheep Erythrocyte ◽  
Peritoneal Macrophages ◽  
Rat Serum ◽  
Sheep Erythrocytes ◽  
Proteose Peptone ◽  
Normal Rat ◽  
Induced Immunity

SUMMARYThe results of studies on the schistosomulicidal activity of activated peritoneal and alveolar macrophages (pMø and aMø) from rats immunized with highly irradiated (50 krad.)Schistosoma japonicumcercariae are reported. The authors have examined the activation of these macrophages in terms of spreading, adhesion and ingestion of sheep erythrocytes and pinocytosis of horse-radish peroxidase. Using three criteria, peritoneal macrophages and alveolar macrophages from immunized rats and from rats intraperitoneally injected with BCG were significantly more active than those from normal rats or rats stimulated with 10% proteose-peptone or 1% sodium thioglycolate. A significantly higher percentage of adhesion and ingestion was obtained with the sheep erythrocytes that were co-opsonized by heat-inactivated rat anti-sheep erythrocyte serum and fresh normal rat serum. Schistosomulicidal effects were observed with macrophages from irradiated cercariae-immunized rats in two activation systems:in vitroactivation in the presence of macrophage-activating factor (MAF), andin vivoactivation by the intraperitoneal challenge with sonicated cercarial antigens.

Rat alveolar macrophages express preprotachykinin gene-I mRNA-encoding tachykinins

1997 ◽  
Vol 273 (5) ◽  
pp. L1073-L1081 ◽  
Author(s):  
Cheryl R. Killingsworth ◽  
Stephanie A. Shore ◽  
Francesca Alessandrini ◽  
Richard D. Dey ◽  
Joseph D. Paulauskis
Keyword(s):  
Alveolar Macrophages ◽  
Peritoneal Macrophages ◽  
Northern Analysis ◽  
Neurokinin A ◽  
Polymerase Chain ◽  
Preprotachykinin Gene ◽  
Lps Treatment

Although the tachykinins substance P (SP) and neurokinin A have been largely localized to neurons, eosinophils have also been shown to express these peptides. Our aim was to determine whether rat alveolar macrophages (AM) express preprotachykinin gene-I (PPT-I) mRNA that encodes these tachykinins and to examine expression during inflammation. PPT-I mRNA was detected by reverse transcription (RT)-polymerase chain reaction (PCR) in AM and brain (control) but not in peritoneal macrophages. Northern analysis showed that PPT-I mRNA was induced two- to fourfold by in vivo treatment of rats with intratracheal lipopolysaccharide (LPS) and in vitro after 4 h of exposure to LPS. This increase was inhibited by dexamethasone. In situ RT-PCR and immunocytochemistry further confirmed that AM express PPT-I mRNA and SP-like immunoreactivity, respectively, which was enhanced by LPS treatment. A 1.3-kb transcript consistent with PPT-I mRNA was detected by Northern analysis of bronchoalveolar lavage neutrophils. Therefore, rat AM express PPT-I mRNA that is upregulated in AM by LPS and is attenuated by dexamethasone. PPT-I mRNA was also detected in lung neutrophils.

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