Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Munoz MA

PROVIDER: S-EPMC8718110 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Munoz Marcia A MA Fletcher Emma K EK Skinner Oliver P OP Jurczyluk Julie J Kristianto Esther E Hodson Mark P MP Sun Shuting S Ebetino Frank H FH Croucher David R DR Hansbro Philip M PM Center Jacqueline R JR Rogers Michael J MJ

eLife 20211230

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. ...[more]

PMID: 34967731

Similar Datasets

Project description:IntroductionAcute lung injury (ALI) and its subsequent progression to acute respiratory distress syndrome (ARDS) are severe respiratory conditions. They are marked by rapid lung function deterioration and extensive pulmonary inflammation, often resulting in critical patient outcomes. Alveolar macrophages (AMs) and monocyte-derived macrophages (MDMs) are two distinct subsets of lung macrophages present in the alveoli during ALI. Both are critical mediators of pulmonary inflammation. Our study examined the interplay between AMs and MDMs in the inflammatory environment of ALI/ARDS.MethodsMice were treated with lipopolysaccharide (LPS) to establish ALI models. The lung tissues of mice were subjected to hematoxylin-eosin staining to observe the degree of tissue damage. In vivo, CCR2-deficient mice or depleting peripheral blood mononuclear cells by clodronate liposomes were used to reduce MDMs recruitment. The bronchoalveolar lavage fluid (BALF) supernatants were used for cytokine and total protein analyses. AMs and MDMs in the BALF were analyzed by flow cytometry. The levels of AMs death were determined through propidium iodide staining and measured by flow cytometry. In vitro, primary AMs were exposed to MDM-conditioned medium or TNF-α, and their death levels were assessed under a fluorescence microscope with propidium iodide staining.ResultsAMs significantly decrease in number and undergo extensive cell death during ALI. The reduced MDMs recruitment can increase the number of AMs, reduce AMs death, and alleviate lung injury. In vitro, MDM-conditioned medium can induce AMs death and TNF-α is one of the major secretions. It indicates that TNF-α stimulation in vitro promotes AMs death. In vivo, MDMs are identified as the primary cells secreting TNF-α. Additionally, the treatment with TNF-α antagonists can reduce AMs death and the severity of lung injury.ConclusionOur study demonstrates that MDMs contribute to AMs death during ALI through TNF-α. Targeting TNF-α may offer a therapeutic strategy to mitigate AMs death and lung injury in ALI/ARDS.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets