Role of Macrophages in Acute Lung Injury and Chronic Fibrosis Induced by Pulmonary Toxicants

Our plain-English summary of Role of Macrophages in Acute Lung Injury and Chronic Fibrosis Induced by Pulmonary Toxicants, by D.L. Laskin, R. Malaviya, J.D. Laskin (Toxicological Sciences, 2019).

The study

• Authors: D.L. Laskin, R. Malaviya, J.D. Laskin
• Journal: Toxicological Sciences
• Published: 2019;168(2):287-301
• Type of article: Review
• Cited by: 216 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

A diverse group of toxicants has been identified that cause injury to the lung including gases (eg, ozone, chlorine), particulates/aerosols (eg, diesel exhaust, fly ash, other combustion products, mustards, nanomaterials, silica, asbestos), chemotherapeutics (eg, bleomycin), and radiation. The pathologic response to these toxicants depends on the dose and duration of exposure and their physical/chemical properties. A common response to pulmonary toxicant exposure is an accumulation of proinflammatory/cytotoxic M1 macrophages at sites of tissue injury, followed by the appearance of anti-inflammatory/wound repair M2 macrophages. It is thought that the outcome of the pathogenic responses to toxicants depends on the balance in the activity of these macrophage subpopulations. Overactivation of either M1 or M2 macrophages leads to injury and disease pathogenesis. Thus, the very same macrophage-derived mediators, released in controlled amounts to destroy injurious materials and pathogens (eg, reactive oxygen species, reactive nitrogen species, proteases, tumor necrosis factor α) and initiate wound repair (eg, transforming growth factor β, connective tissue growth factor, vascular endothelial growth factor), can exacerbate acute lung injury and/or induce chronic disease such as fibrosis, chronic obstructive pulmonary disease, and asthma, when released in excess. This review focuses on the role of macrophage subsets in acute lung injury and chronic fibrosis. Understanding how these pathologies develop following exposure to toxicants, and the contribution of resident and inflammatory macrophages to disease pathogenesis may lead to the development of novel approaches for treating lung diseases.

© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: [email protected].

In plain English

This article was a review, not a new study. The authors summarized published research, mostly rodent experiments, on how macrophages (immune cells) contribute to sudden (acute) lung injury and long-term scarring (fibrosis) caused by toxicants including ozone, particulate matter, silica, asbestos, bleomycin and radiation. The article named no specific asbestos fiber types and reported no exposure levels or disease rates. The authors described early inflammatory 'M1' and later anti-inflammatory, wound-repair 'M2' macrophages, which lie on a continuum rather than being fixed types; overactive M2 cells are thought to drive fibrosis. Citing earlier work, they reported three things. M2 cells increased in animal lungs after asbestos and other exposures. Blocking the signaling molecule TNF early reduced fibrosis caused by asbestos and other agents. The NLRP3 inflammasome, a cell sensor, has been linked to lung injury from asbestos and silica. The authors concluded that uncontrolled macrophage activity can worsen acute injury or lead to chronic lung disease. They noted they did not discuss how dose, exposure duration or frequency, animal species, or the toxicants' mechanisms of action affect these responses.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published experimental and clinical literature
• Who was studied: No new subjects. The review drew mainly on published animal (largely mouse and rodent) experiments, with some references to lungs of human patients with idiopathic pulmonary fibrosis, COPD and cystic fibrosis.
• Exposure: A wide range of lung toxicants: gases (ozone, chlorine), particulate matter, nanoparticles, silica, asbestos, chemotherapeutics such as bleomycin, and radiation. Asbestos fiber types were not specified.
• Main results:
  • The authors described M1 and M2 macrophages as existing on a continuum, not as two fixed, separate types.
  • The authors wrote that chronic diseases such as fibrosis are thought to result from hyper-responsive M2 macrophage subpopulations.
  • Reviewed studies reported that anti-inflammatory/wound repair M2 macrophages increased in the lungs of animals exposed to various toxicants, including asbestos.
  • In animals treated with fibrosis-causing agents including asbestos, reviewed studies found macrophages persistently increased near collagen-producing cells during the scarring phase.
  • In reviewed experimental studies, blocking or losing TNF activity early reduced fibrosis caused by bleomycin, silica, asbestos and mustard agents.
  • Reviewed studies suggested that the NLRP3 inflammasome contributes to acute lung injury from several agents, including asbestos.
  • Cited work reported increased IL-1 and IL-18 in alveolar macrophages from patients with idiopathic pulmonary fibrosis and from asbestos-induced fibrosis.
  • Across several experimental models (not asbestos-specific), suppressing or depleting macrophages reduced or prevented lung damage.
• The authors' conclusion: The authors concluded that macrophage activity must be carefully controlled, and that without control mechanisms overactivated macrophages worsen acute injury and/or lead to chronic lung disease. They suggested that understanding macrophage activation may lead to better treatments.
• Limitations the authors state:
  • The authors did not discuss how exposure dose, duration or frequency, animal species, or the toxicants' mechanisms of action influence the response. They presented a general overview instead.
  • Macrophages are not the only source of these mediators in the lung. The relative contribution of other cells remains to be established.

Topics

Medical terms in this study, explained in our Lexicon: Macrophage, Fibrosis, Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS), Necrosis.

Related studies

• Pulmonary toxicants and fibrosis: innate and adaptive immune mechanisms — R. Malaviya, H.M. Kipen, et al. (2020)
• Alveolar macrophage cytokine and growth factor production in a rat model of crocidolite-induced pulmonary inflammation and fibrosis — K.E. Driscoll, J.K. Maurer, et al. (1995)
• Alveolar macrophage stimulation of lung fibroblast growth in asbestos-induced pulmonary fibrosis — I. Lemaire, H. Beaudoin, et al. (1986)
• Asbestos-induced alveolar injury. Evidence for macrophage-derived PDGF as a mediator of the fibrogenic response — J.C. Bonner, A.R. Brody (1991)
• Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure — S. Murthy, J.L. Larson-Casey, et al. (2015)
• Selective differences in macrophage populations and monokine production in resolving pulmonary granuloma and fibrosis — I. Lemaire (1991)

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