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

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 overtur...

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Vydané v:	eLife Ročník 10
Hlavní autori:	Munoz, Marcia A, Fletcher, Emma K, Skinner, Oliver P, Jurczyluk, Julie, Kristianto, Esther, Hodson, Mark P, Sun, Shuting, Ebetino, Frank H, Croucher, David R, Hansbro, Philip M, Center, Jacqueline R, Rogers, Michael J
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England eLife Sciences Publications Ltd 30.12.2021 eLife Sciences Publications, Ltd
Predmet:	alveolar macrophage Animals Bacterial infections bisphosphonate Bisphosphonates Bone Density Conservation Agents - administration & dosage Bone Density Conservation Agents - pharmacology Bone diseases Bone loss Bone marrow Bronchus Chemokines Chemokines - metabolism Chromatography Cytokines Cytokines - metabolism Drug dosages Female Flow cytometry Fractures Immune response Immunosuppressive agents inflammasome Lavage Lipopolysaccharides - toxicity Lung - drug effects Lung - metabolism Macrophages Macrophages, Alveolar - drug effects Macrophages, Peritoneal - drug effects Mass spectrometry Medicine Mevalonate pathway Mevalonic acid Mevalonic Acid - metabolism Mice Mice, Inbred C57BL Mortality Osteoclasts Osteoporosis Pneumonia prenylation Protein Prenylation - drug effects Proteins Scientific imaging Short Report Skeleton Streptococcus infections Zoledronic acid Zoledronic Acid - administration & dosage Zoledronic Acid - pharmacology mouse alveolar macrophage pneumonia inflammasome bisphosphonate prenylation medicine osteoporosis
ISSN:	2050-084X, 2050-084X
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.72430